Xenobiotics in Chemical Carcinogenesis: Translational Aspects in Toxicology 0323905609, 9780323905602

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XENOBIOTICS IN CHEMICAL CARCINOGENESIS

XENOBIOTICS IN CHEMICAL CARCINOGENESIS TRANSLATIONAL ASPECTS IN TOXICOLOGY

Akhileshwar Kumar Srivastava CSIR-Central Food Technological Research Institute, Mysore, India

Dhruv Kumar Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Noida, India

Divya Singh Central Sericultural Research and Training Institute, Mysore, India

Rajesh Kumar Singh Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2022 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-323-90560-2 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisitions Editor: Kattie Washington Editorial Project Manager: Pat Gonzalez Production Project Manager: Punithavathy Govindaradjane Cover Designer: Mark Rogers Typeset by MPS Limited, Chennai, India

Dedication

This book is dedicated to the late grandparents Smt. Kamlavati Devi and Shri Krishna Lal, India.

Contents Hazards from xenobiotic molecules 42 Xenobiotics in carcinogenesis 42 Removal of xenobiotics molecules 43 Risk assessment for exposure of humans to toxic compounds 44 Exposure to food carcinogens 45 Assessment of exposure to food carcinogens 47 Cellular adaptation to xenobiotic compounds 48 Detection of xenobiotic-induced toxicity 50 Human biomonitoring in the assessment of common population exposure to xenobiotics 51 Challenges of human biomonitoring 52 Conclusions and future prospective 53 References 54

Preface xi 1. Historical review and future prospective of chemical carcinogenesis Introduction 1 Cancer caused by mutation or environmental factors 2 Potential of carcinogens 3 Early studies for identification of carcinogens 3 Carcinogenesis models 5 Theories for chemical carcinogenesis 6 Bioassay of carcinogens 9 Issues with carcinogenic and noncarcinogenic categorization of chemicals 10 Long-term bioassays 11 Chemical carcinogenesis and genetically engineered models 13 References 15

4. Incidences of crucial environmental xenobiotics for inducing cancers Introduction 57 Pesticides in carcinogenesis 57 Role of environmental agents in human cancer 58 Exposure of biomarkers and assessment of human exposures 59 Conclusions 59 References 60

2. Xenobiotic metabolism(s) in carcinogenesis Introduction 21 Function of aryl hydrocarbon receptors 24 Role of cytochrome P450 in the biotransformation of xenobiotics in carcinogenesis 26 Modulation of xenobiotic-metabolizing enzymes by transcription factors 28 Formation of carcinogenic xenobiotics during food processing 29 Role of pesticides in breast cancer progression 31 Conclusions 31 References 32

5. Toxicokinetics and toxicodynamics of xenobiotics in cancer development Introduction 61 Role of toxicokinetics and toxicodynamics in risk assessments 65 In silico approach to risk assessment 67 Bayesian population approach to toxicokinetic/ toxicodynamic models in risk analysis 68 Systematical implication of effective biomarkers in population and occupational biomonitoring 69 The pivotal function of xenobiotic receptors and cytochrome P450 induction in toxicokinetics and toxicodynamics 71

3. Recalcitrant toxic xenobiotics and their routes of exposure to humans Introduction 37 Recalcitrant xenobiotic molecules 40 Routes of xenobiotic exposure 41

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Genotoxic and nongenotoxic mechanisms of xenobiotics in carcinogenesis 75 Conclusions 77 References 78

6. Mechanism of oxidative stress in carcinogenesis induced by xenobiotics Introduction 83 Oxidative DNA damage 85 Modification of gene expression 86 Endogenous factors of ROS 86 Exogenous sources of ROS 87 Arrays of oxidative stress 87 Oxidative stress linked with xenobiotic compounds in carcinogenesis 88 Xenobiotic-induced ROS generation in embryos 89 Oxidative stress-associated mechanisms with xenobiotics in anemia cells 90 Time-dependent cellular adaptations to oxidative stress in normal cells 90 Impact of ROS and RNS on the tumor microenvironment 92 Quantitative determination of oxidative stress in cancer cells via gene expression 100 Conclusion and future prospective 102 References 102

7. Genotoxic and non-genotoxic activities of xenobiotics in carcinogenesis Introduction 111 How to identify the mode of action of carcinogenic chemicals? 112 How to identify the mode of action of non-carcinogenic compounds? 116 Suppression of gap-junction intercellular communications 120 Conclusions 122 References 122 Further reading 125

8. Modulation of the epigenome by xenobiotics in cancer Introduction 127 DNA methylation in development of cancer Conclusions and perspectives 147 References 147

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9. Carcinogenic effects of nanomaterials with an emphasis on nanoplastics Introduction 155 Generation of nanoplastic in the environment 158 Major paths of human exposure to nanomaterials 160 Cellular uptake and intracellular consequences of nanoplastic materials 161 Major toxic impact of nanoplastics on human health 163 Carcinogenic impacts of nanomaterials 165 Conclusions and outlook 168 References 168

10. Endocrine disruptor activity of xenobiotics in carcinogenesis Introduction 175 Endocrine regulators in the food chain 181 Endocrine disruptors action on mechanism of estrogen and androgen 182 Data associated with exposure to endocrine disruptors in carcinogenesis 184 Incidence of breast cancer due to endocrine disrupting chemicals 186 Impact of endocrine disruptors on the development of cancer in women 188 Health issues 190 Conclusions and future prospective 191 References 192

11. Environmental exposures as xenoestrogens (bisphenol A and phthalates) enhance risk for breast cancer Introduction 197 Bisphenol A and breast cancer 202 Government policy for bisphenol A 202 Phthalates 205 Conclusion 209 References 210

12. Biotransformation of toxic xenobiotics by human gut microbiota Introduction 217 Habitat of microbes in human body 221 Role of microbes in health and disease 222

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Microbiome regulation of toxicity 222 The metabolome of microbes 224 Function of gut microbes in cellular physiology 224 Gut microbial interactions with xenobiotics 225 The complementary chemistry of microbial xenobiotic metabolism 226 Metabolization of environmental chemicals by GI microbiota 226 Effect of environmental chemicals on the activity of GI microbes 231 Factors affecting the rate and level of gut microbes in xenobiotic metabolism 232 Advanced technologies for the identification of xenobiotic-degrading microbes 234 Computational method for the prognosis of species-specific biotransformation of xenobiotic compounds by gut microbiota 235 Methods 235 Conclusion 236 References 237

13. Mechanism of resistance to toxic xenobiotics in humans Introduction 245 Link between environmental chemicals and chemoresistance 255 Conclusions 256 References 256

14. Profiling the reactive metabolites of xenobiotics in cancer Introduction 261 Experimental methods for the assessment of reactive metabolites 263 Analysis of covalent binding to proteins 264 Trapping and identifying reactive metabolites 264 Time and cofactor-based cytochrome P450 suppression 265 High-throughput NMR in xenobiotics toxicology 266 Target analysis and suspect screening 271 Profiling of seasonal variation in and cancer risk assessment of benzo(a)pyrene and heavy metals in drinking water 272 Toxicological analysis of anthropogenic xenobiotics associated with environmental metabolomics 274 Conclusions 276 References 277

15. Toxicogenomics for the prediction of carcinogenicity of xenobiotic substances Introduction 283 Genetic toxicology: transcriptomics 290 Prediction of carcinogenicity effects of xenobiotics by toxicogenomics methods 295 Conclusions and future prospective 299 References 300

Index 307

Preface nanomaterials, nanoplastics found in the environment transfer into the human body through the food chain and are responsible for the development of various types of cancers. The bioaccumulation of xenobiotic substances depends on toxicokinetic and toxicodynamic activity of chemicals. Toxicokinetic refers to the quantification and determination of the time course of the disposition or ADME (absorption, distribution, metabolism, and excretion) for a toxic xenobiotic. Toxicodynamic is defined as what a toxicant does physiologically, biochemically, and molecularly to an animal’s body following exposure. Exposure to toxic xenobiotic agents is an unavoidable consequence of modern society. Currently, carcinogenic chemicals are comprised into two groups: (1) genotoxic—DNA damaging agents and (2) non-genotoxic—nonDNA damaging carcinogens. After a long exposure to xenobiotic compounds, such as pesticides, detergents, and PAHs, the epigenome alters gene expression to increase the possibility of cancer development. Several xenobiotics chemicals have been identified as endocrine disruptors, for example, bisphenol A, some organochlorines, polybrominated flame retardants, and perfluorinated substances involved in carcinogenesis. In addition, other environmental pollutants like bisphenol A and phthalates act as estrogen-like activities and are known as environmental xenoestrogens playing critical role in the development of breast cancer. The detoxification of toxic xenobiotic molecules is a natural process in all biological

The history of chemical carcinogenesis has been elucidated on the basis of epidemiologic observations and animal experiments, from which accumulated toxic chemicals had been detected. In 1914, Boveri revealed alterations in chromosomes and set the onset instance of human cancer for fundamental research. The meaning of xenobiotic is “foreign to life,” and is generally referred to synthetic chemicals like plant constituents, drugs, pesticides, cosmetics, flavorings, fragrances, food additives, industrial chemicals, and environmental factors. Several inorganic and organic xenobiotic compounds, for example, polycyclic aromatic hydrocarbons (PAHs), pentachlorophenol (PCP), hexachlorocyclohexane (HCH), and polychlorinated biphenyls (PCBs) are highly resistant to biodegradation and cause a variety of toxicities in biological systems. The accumulation of these xenobiotics induces carcinogenesis by altering several metabolic events in human body. Moreover, a number of anthropogenic agents act as xenoestrogens, such as some food additives, pesticides, antibiotics, environmental pollutants, which mimic the structural parts of physiological estrogen compounds leading to the development of breast cancer by altering gene expression (e.g., BRCA1 and BRCA2), metabolizing enzyme polymorphisms, epidermal growth factor, and its receptor. Reactive oxygen species trigger multiple signaling pathways, such as HIF1a, Nrf2, AP-1, and NF-kB, for cancer development. Nanoparticles such as dust storms and volcanic ash produce biological toxicity and are termed nanotoxicants. Moreover, some metallic and semiconductor nanotoxicants induce carcinogenesis in humans. Like other

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systems. Many exogenous xenobiotic compounds and endogenous toxic metabolic products describe the evolutionary pressure of all organisms to evolve molecular mechanisms to detoxify and excrete harmful substances from the body. Microbes residing in the intestinal tract of humans are a potent site for xenobiotic metabolism. The gut microbiome modifies the metabolic outcome of environmental toxicants, heavy metals, and pharmaceuticals by altering their pharmacokinetics. Advanced field toxicogenomics explain the genetic environmental interactions in carcinogenesis and detection of genetic aberrations in cancer genomes by next-generation sequencing technology. Moreover, several metabolomic approaches describe the bioactive components of toxic xenobiotic in cancer. These advanced research fields are involved in profiling genes and xenobiotic metabolites in cancer for the development of anticancer regimens.

This book will be helpful for academic and research purposes for the researcher of universities/institutes interested in toxicology sciences, oncology, environment sciences, pharmaceutical sciences, and biotechnology at both the undergraduate and postgraduate levels. Moreover, the students (MS and MPH) of medical sciences will also benefit from screening the toxic xenobiotic compounds against cancer for the development of therapy regimens. The current understanding of the relevant information presented in the book will be able to fulfill the requirement of oncologists, environmentalists, molecular biologists, pharmacologists, and related researchers, who want to work in the field of toxicology targeting cancer research. Akhileshwar Kumar Srivastava Dhruv Kumar Divya Singh Rajesh Kumar Singh

C H A P T E R

1 Historical review and future prospective of chemical carcinogenesis Introduction

and synthetic polymers, (2) use of natural and man-made chlorinated organic compounds in the paper and pulp bleaching process, which are released in the environment, (3) heavy metal release into biogeochemical cycles due to mining, (4) accidental discharge of fossil fuels into the ecosystem via oil spill, (5) huge amounts of pesticides and fertilizers delivered to the environment via agriculture (Quadir et al., 2017). The entry of xenobiotic compounds in the food chain makes them harmful. Xenobiotics are omnipresent, so their exposure to humans is unavoidable. The use of some xenobiotics such as antibiotics, dietary supplements, drugs etc. are beneficial for human health. Daily use of xenobiotics includes food ingredients (flavor and color compounds, preservatives, dyes, emulsifiers, stabilizers, salt compounds etc.), personal care and cosmetic products (soaps, hair dyes, perfumes, makeup) and house cleaning products (bug sprays, chlorine bleach, cleaners, etc.) that may increase the threat of exposure (Fig. 1.1) (Soucek, 2011). In the present scenario, removal of xenobiotics from the living world is impossible. Common apprehension about xenobiotic compounds may be because of their toxicity to living organisms. Various xenobiotics are the cause of genotoxicity or carcinogenesis. Most procarcinogens become carcinogens by metabolic processes.

Chemical substances found in an organism that are mostly foreign to the whole biological system and naturally not expected to be present within that organism are known as xenobiotic. However, it covers all the substances that are present in abnormally higher concentrations. For example, phosphorus, an essential element, is not usually a xenobiotic. However, release of phosphorus in aquatic systems results in eutrophication and can be considered xenobiotic for this system. Drugs like antibiotics are considered as xenobiotic compounds because they are neither a part of human food nor produced by the human body. Xenobiotics also include natural compounds that are transferred from one organism to another, such as the uptake of natural human hormone by fish present in the downstream of a sewage treatment plant or chemical defense developed by some organisms against predators. The term xenobiotics is generally used for pollutants (polychlorinated biphenyls and dioxins) and their influence on biota, as xenobiotics exist as foreign substances in the biosphere, that is, substances that did not exist in the environment before being synthesized by humans. Xenobiotic compounds may enter the environment through (1) pharmaceutical and chemical industries that produce various drugs

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00007-8

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© 2022 Elsevier Inc. All rights reserved.

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1. Historical review and future prospective of chemical carcinogenesis

FIGURE 1.1

Sources of xenobiotics exposure to humans.

Cancer caused by mutation or environmental factors Cancer is a bewildering and alarming disease/set of diseases. It is usually accepted as a genetic disease. The concept is supported by evidence from the recognition of mutated genes in tumors as well as use of genetically engineered mouse models (GEMMs) designed to carry out mutations in the orthologous genes that become mutated in human cancers. Experimental models have provided significant evidence for the genetic ground of cancer. However, present studies indicate that inherited genetic disposition has minor contributions in the development of most cancers (Lichtenstein et al., 2000). These estimates show that most mutations related to cancer are somatically

acquired by natural processes or influenced by environmental exposure. The etiology of human cancer indicates that cancer is also evoked by the environment (Doll & Peto, 1981; IARC, 1990). Everything that acts upon humans is considered as its environment including sunlight, radiation (natural and medical), exposure from lifestyles and workplace, drugs, and substances present in soil, water, and air (OTA, 1981). However, GEMMs show similarities to biologic, genetic, and pathologic characteristics of human cancer, and they are unable to consider the complications of environmental exposure responsible for cancer. A combination of environmental exposures and chemicals with GEMMs provides a valuable experimental set studying interactions of environmental exposure and genotype to ultimately detect cancer risks.

Xenobiotics in Chemical Carcinogenesis

Early studies for identification of carcinogens

Potential of carcinogens The capability of a chemical to stimulate cancer under a range of doses and routes of exposure as well as duration of exposure is explained by the potential of carcinogens. The potential of carcinogens can be defined as the dose that produces cancer in 50% of treated animals, or the median effective dose (ED50). However, long-term bioassay studies have derived the estimation of carcinogenic potential in the form of tumorigenic dose rate 25 (TD25), tumorigenic dose rate 50 (TD50), or bench mark dose (BMD). Tumorigenic dose rate defines the potency of a chemical to induce tumors in x% of treated animals within the life cycle of the species. Further, BMD determines the dose of a chemical required to develop x% of treated animal tumors at a particular tissue site after correction for the occurrence of a spontaneous tumor within the lifespan of the species. In these estimations, the duration of treatment is set for 2 years, assuming equivalence to the lifecycle of experimental species. These studies are helpful only in the comparison of chemicals, not for evaluating effects of exposure periods. Moreover, a mathematical model was used by Cohen and Ellwein (1990) to evaluate carcinogenic potential. They suggested that chemicals (e.g., dimethylnitrosamine, diethylnitosamine and N-[4-(5-nitro2-furyl)-2-dithiazol] formamide) or their metabolites (e.g., 2-acetylaminofluorene) that directly interact with DNA can develop cancer early in the process because interaction with DNA may lead to mutations that can be continued in dividing cells. Generally, they are not supposed to show a threshold. However, there is sufficient evidence showing that this may not be true as assessments of genotoxicity based on quantitative dose response have shown practical thresholds. Chemicals stimulating cell proliferation without DNA interactions can be grouped into two classes: (1) those directly interacting with

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the cell receptor, and (2) those that do not directly interact with the cell receptor. The activation of cell receptor by chemicals such as hormones, phorbol esters, and dioxins (that react with receptors) requires specific dose. Less than that dose, the receptor cannot be activated that will not trigger cell proliferation, and ultimately no carcinogenic response will be observed. Chemicals (e.g., chloroform) that follow other mechanisms, such as cytotoxicity, are unable to induce tumors below the dose level that is required for cytotoxic response. Nongenotoxic mechanisms that result in tumors are responses of adverse reactions of an organism towards repetitive application of chemicals for long durations. Some chemicals do not have carcinogenic potential to cause genotoxicity, cytotoxicity, or cell proliferation. Therefore carcinogenic potential can be defined as a function of dose and time of exposure essential to enhance tumors through different responses such as cellular proliferation, cytotoxicity, and genotoxicity. The development of tumors at low doses of chemicals with short duration of treatment indicates high carcinogenic potential. Exposure of chemical at dose levels and duration of treatment that do not affect these responses will not increase cancer.

Early studies for identification of carcinogens The International Agency for Research on Cancer (IARC) has published 128 volumes of monographs evaluating the carcinogenicity of chemicals. Since 1971, more than 1000 chemicals have been assessed and more than 400 chemicals have been recognized as carcinogens (https://publications.iarc.fr). The history of chemical carcinogenesis has been illustrated by several epidemiologic observations and experiments using animals, in which cancer-causing

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chemicals were detected. In eighteenth century, the keen clinical observations of John Hill and Percival Pott indicated the occurrence of chemical carcinogenesis. Hill (1761) observed the frequency of cancer in snuff-users when exposed to snuff. Pott (1775) reported high rates of occurrence of cutaneous cancers in the scrotum of chimney sweeps. Dr. Pott noticed that patients having scrotal skin cancer worked as chimney sweeps in their early life (youth). These young employees were constantly exposed to high levels of coal tar and soot, which was the cause of cancer development after a long latency. The relevance of environmental factors in the development of human cancers can be ascertained by the remarkable observations of John Hill and Percival Pott. In 1823, Earle studied some clinical features of chimney sweeps and were surprised of the influence of constitutional predisposing factors that enhanced the susceptibility of these individuals to the carcinogenic effect of soot. This study raised the question whether genetic characteristics could alter the risk of cancer in exposed individuals. Unfortunately, these reports were unable to increase the awareness of chemical carcinogenesis at that time but initiated a collection of evidence related to cancer caused by chemical exposure at the workplace. Over 100 years later, Ludwig Rehn, a German surgeon (1895) observed a high frequency of urinary bladder cancer of workers in the dye industry. Experimental studies using animals as models were not reported for the study of cutaneous cancer until the second decade of the 20th century. In 1915, Japanese investigators, Yamagawa and Ichikawa, showed that frequent application of crude coal tar induced neoplasms in the skin of the rabbit ears. The report was published in English in 1918. This work was among the first published articles showing the skin of experimental animals as a practical model for cancer research. Similary, Tsutsui (1918) also noted that application of

coal tar to the skin of mice produced skin tumors. During the 1930s, pure chemical compounds such as benzo[a]pyrene (BP), dibenz[a,h] anthracene, and 3-methylcholanthrene were reported to evoke tumors in mice, establishing defined chemicals as a cause of cancer (Cook et al., 1932; Kennaway, 1955). However, Kennaway and Hieger (1930) evaluated the repetitive application of 1,2,5,6-benzanthracene isolated from coal tar and evoked cutaneous tumors in experimental models. Consequently, British investigators isolated the active carcinogenic compound from crude coal tar and identified it as benzo[a]pyrene (BP), a polycyclic aromatic hydrocarbon (PAH) (Cook et al., 1933). This influential observation directed extensive studies that authenticated the carcinogenic properties of several PAHs as byproducts of the incomplete combustion of fossil fuels. In 1945, Cowdry (1945) published a manuscript explaining PAHs-induced chemical carcinogenesis in The Journal of Investigative Dermatology. During this period, most researchers considered that repeated skin application of carcinogenic chemicals was the only mode to induce skin neoplasms, but Cramer and Stowell (1943) reported that skin carcinogenesis could also develop with a single application of PAH. Bereblum and Shubik (1947a, 1947b) showed that single applications of a carcinogenic chemical followed by repeated application of noncarcinogenic compounds could evoke skin tumor. Forty years after the Rehn (1895) publication about bladder cancer of workers in the dye industry, Sasaki and Yoshida (1935) induced liver cancer in rats through azo dye oamidoazotoluene feed. Kinosita (1936) observed that 4-dimethyl-aminoazobenzene could develop liver cancer. In 1941, a report was published showing 2-acetylaminofluorineinduced bladder cancer and other cancers in rats (Weisberger & Weisburger, 1958). Studies on azo dyes suggested that some chemicals require metabolic activation in the host for

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Carcinogenesis models

developing cancer. However, Boyland and Levi (1935) reported that animals can convert toxic hydrocarbons into more active compounds or detoxify into harmless substances. Animals and humans tend to metabolize almost all xenobiotic compounds and some of them, such as cromoglycate and saccharin, are excreted without any changes. In the metabolic process, enzymes transfer lipid soluble compounds to water soluble chemicals that are excreted in urine or bile. This metabolic process reduces toxicity of chemicals and protects organisms from the harmful effects of environmental chemicals. However, the enzymatic detoxification process of some carcinogenic chemicals converts them into reactive metabolites that can react with genetic material to induce genotoxicity, which can damage embryos (risk of teratogenesis) or induce mutations and cancers. Daudel et al. (1975) suggested that the benzotalpyrene metabolite could react with DNA by a dihyroxydihydro epoxide. In 1974, diol epoxide was identified by Booth and Sims (1974) as a metabolite of benz[a] anthracene, the active carcinogen of benzo[a] pyrene is (1 )-7p/8a-dihydroxy-9a,10aepoxy7,8,9,10-tetrahydrobenzo[a]pyrene. In addition, animals were used as models to study the relationship between cancer and environmental exposure to carcinogens. During 1950 75, urethane (ethyl carbamate) was utilized as a sedative. In 1943, Nettleship et al. (1943) suggested urethane-induced lung cancer in mice, but decades elapsed before its use was stopped (Miller, 1991). Ethyl carbamate is present in many foods (by-product of fermentation) at low levels. Similar to many carcinogens, urethane involves metabolic activation by the p450 system to vinyl carbamate epoxide (by p450 system) that covalently binds to DNA to form DNA adducts (Forkert, 2010). Another important group of carcinogens are N-nitroso compounds. Among them, N-nitrosodimethylamine (DMN) was reported as a cause of cancer in rats (Magee & Barnes, 1956).

Consequently, many N-nitroso compounds were identified for carcinogenic effects on animals, and almost every tested species is able to induce cancer through DMN or N-nitrosodiethylamine (DEM) (Magee & Barnes, 1967). In 1979, Miller and Miller (1979) reported that nitrosamines present in the environment or produced in digestion may cause cancer. Earlier studies on animals established a relationship between environmental exposure and cancer including UV-induced skin cancer (Findlay, 1928) and X-ray-produced ovarian cancer, lymphomas, and other tumors (Furth & Furth, 1936). In 1959, Griffin (1959) noticed carcinogenicity of psoralens in his experiment including interaction of ultraviolet C and psoralens administered to mice through diet (0.5 mg kg21 foodstuff) or intraperitoneally (0.4 mg 1 h before irradiation) as well as controls with drug and without light and vice versa. Oral administration of psoralen protects against UVCinduced cancer, while intraperitoneally application induced tumors to a greater extent in comparison to UVC alone. Accordingly, these notable studies during the early to mid-20th century confirmed univocal novel connections between exposure of chemical or radiation and subsequent cancer development (Boyland, 1969). Notably, these studies helped in the reduction of human exposure to most of these agents and the subsequent reduction of cancer hazard through a variety of mechanisms including change in lifestyle, different industry practices, and government regulation.

Carcinogenesis models Accumulation of multiple errors of DNA in a single cell may develop tumors. Considering the events of tumor development, numerous multistage models have been established after the hypothesis of the initiation-promotion model (Berenblum & Shubik, 1947b). The initiationpromotion model states that chemical carcinogenesis in the skin of a mouse has been controlled by

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two discrete events: (1) initiation: specific and irreversible preliminary changes produced by the carcinogen; and (2) promotion: a process of tumor stimulation requiring repetitive application of specific noncarcinogenic/irritant chemicals (promoters) whose influences are primarily reversible, but their repetitive exposure led to irreversible impacts. By the 1950s, it was apparent that two distinct phenomena initiation and promotion was involved in the chemical carcinogenesis of skin. Subsequently, Boutwell (1964) and Slaga et al. (1982) added progression/conversion in the initiation-promotion model as a third event to explain that many tumors that develop during the process of initiation and promotion are noncancerous and regress spontaneously if promotion of the tumor ceases. However, continuous exposure of tumor promoters induces noncancerous tumors to undergo malignant progression/ conversion and develop squamous cell carcinomas. Similar multistage information was assessed in the liver and urinary bladder of a rat. Although this multistep (initiation, promotion and progression) model has some limitations, it markedly differentiates chemicals into two classes, where the first class belongs to the chemicals that react with DNA and another class belongs to those that do not react with DNA. Therefore initiators react with DNA while promoters enhance the chances of tumor development from the initiated cells through proliferation. However, Armitage and Doll (1957) developed another multistage model employing epidemiology data by observing the occurrence of tumors in human with age. Even though this theory is suitable with the epidemiology of various tumors such as urinary bladder, colon, and lung, it does not fit with the incidence of childhood tumors, germ cell tumors (in males), osteosarcoma, Hodgkin’s disease, and breast carcinomas. The two assumptions in the hypothesis of Armitage and Doll were incorrect. They supposed that the number of stem cells and stem cell replications in a tissue stayed consistent throughout its lifespan. Tomasetti and Vogelstein (2015) and

Tomasetti et al. (2017) proposed a model similar to Armitage and Doll. They suggested that spontaneous error in DNA replication is the cause of most cancers. Generalized carcinogenesis models were established by Moolgavkar and Knudson (1981) and Cohen et al. (1982). However, Moolgavkar and Knudson observed the occurrence of breast cancer and utilized data in their hypothesis whereas Cohen and his colleagues exploited epidemiology data for animals. Both models indicated that increase in cell proliferation/DNA reactivity alone could raise the risk of cancer or the synergistic interaction between them could increase cancer threat. This model fits with the etiology of cancer by exposure of various chemicals in human and experimental models as well as nonchemical causes of cancer (Cohen & Arnold, 2011; Cohen et al., 1991).

Theories for chemical carcinogenesis The fundamental concept of chemical carcinogenesis is adapted from the NRC (2007) report on toxicity testing. The report elucidates the toxicity pathway as a disruption at the cellular and molecular level that can lead to adaption or promotion of cell and tissue response. This response is identified as damage at the cellular or tissue level. The model incorporates the basic principle of toxicology where the dose of agent makes it poisonous and is mandatory for an organism to be exposed at an adequate dose that causes perturbation in biological pathways resulting in cellular alterations responsible for tumor development (Fig. 1.2). It establishes the concepts presented in the staged clonal growth model and several factors that influence cell and tissue to evoke the tumor (Tomasetti & Vogelstein, 2015). The cell/tissue is influenced by environmental factors that directly interact with DNA or induced cell replication by mitogenic stimulus or secondarily as the regeneration subsequent to cytotoxic effects. Environmental factors can

Xenobiotics in Chemical Carcinogenesis

Theories for chemical carcinogenesis

7 FIGURE 1.2 Population model of chemical carcinogenesis that requires sufficient exposure and sustained stress environment.

execute independently or in combination with hereditary factors (e.g., inherited mutation of control genes) and increase normal constitutive replication. In response to these internal and external alterations, cells increase proliferation having some risk of mutation. The initiation of mutation can result in rigorous cell disability and death or repair. The process of repair restores the cell to its original stage or forms a new normal stage that incorporates mutations allowing cells to function in its new environment (Fig. 1.3). The new normal stage of the

cell is an adaptation to the microenvironmental conditions that are influenced by various environmental factors. The evolutionary adaptation of the cell appears within the cell population. The selection of flexible benefits by the cell is considered a selfish cell. The components of selfish cells provide an advantage to the individual cell that develop the component. In selfish cells, adaptive mutations are survival characteristics selected by natural processes. These adaptive mutations appear as a response to environmental stimuli. Carcinogenesis is a

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FIGURE 1.3 Environmental factors can act independently or in combination with hereditary factors and increase normal constitutive replication. The parent cell divides with the risk of mutation. These mutations may be repaired (complete/incomplete) or induce cell death. The outcome of incomplete repair is a daughter cell with a mutated gene and complete repair produces a daughter cell, clone of parent cell.

process where natural selection of adaptive traits within the continuous environmental stimulus results in selection of cells having adaptive traits that will be helpful for survival. Such cells will gradually evolve from normality by premalignant stages overcoming anticancer defenses and develop into metastatic cells (Martincorena et al., 2017). Identical mutations have been observed in several cancers indicating that addition of some mutations is related with the natural selection process at the level of cell from microenvironmental conditions. A few mutations are generally identified in various types of tumors and in identical cancers across the species. For example, epithelial tumors show a frequent mutation in the p53 gene. These p53 mutations have been reported in most skin cancers (Roshan & Jones, 2012). The p53 mutation is not only common in human nonmelanoma skin cancers but also frequently appeared in carcinomas of rodent squamous cells. In the carcinogenesis of liver cells, various signaling cascades are transformed despite of the initiation ensuing in a heterogeneous molecular profile. Initiating cause and specific mutations has a

relationship with some being more pervasive than others that are not identified as the cause. For example, hepatocellular carcinoma (liver cancer) has single or more genetic alterations like mutations in β-catenin, TP53, or other oncogenes, tumor suppressor genes, chromosomal deletions and amplifications (Nault, 2014). Even though the macroenvironment drives species evolution, the continuous stress in the microenvironment of tissue results in adaptive cellular evolution (Martincorena et al., 2017). The process of cell proliferation is ensuing in most tissues during life, but the occurrence of spontaneous error in cell proliferation may cause induction of cancer in these tissues (Tomasetti & Vogelstein, 2015). A chemical agent may increase the risk of cancer by increasing cell proliferation or DNA damage. The probability of cancer development within a particular tissue is not only depending on the environmental stimulus but also affected by the number of dividing cells because only these cells are at the risk of mutation (Greaves & Maley, 2012). The risk of cancer increases with the continuity of stimulus. The possibility of cancer

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Bioassay of carcinogens

development is determined by cell proliferation, longevity of a cell/population of cells and rate of mutation (Nunney, 2013). The cell overcomes its ability of maintaining genome integrity for the development of cancer. The competence of the cell to monitor change in DNA or DNA damage and to repair it can rectify mutations or cause cell death to eliminate the mutated cell. Thus transition from a normal cell to a metastatic cell is rare at the level of organism. The transition process is unlikely to appear during a typical lifespan of a cell but occurs often in the life span of an organism. The number of mutations in the coding gene leading to malignant phenotype ranges from 2 to 12 per tumor in different tumors. There is no difference in the estimated number of mutations/tumors in cancer genes during early malignant tumors and metastatic lesions (Martincorena et al., 2017). This study suggests that mutations are not induced during replication but continuous environmental stress multiplies the number of cells having mutations. Replication drives other mutations that are required for the development of malignancy because similar mutations present in nonmalignant lesions indicate that they are essential but not adequate for malignancy (Reddy et al., 2017; Roshan & Jones, 2012). Several risk factors can increase the probability of cancer. The DNA reactivity combined with proliferation enhancers increases the number of DNA errors increasing the possibility of cancer. If replication is considerable, then small numbers of environmentally-induced or genetic errors are required to enhance the likelihood of cancer and vice versa (Tomasetti & Vogelstein, 2015). The environmental influences can be further divided into those environmental stressors or chemicals that directly react with the genome causing DNA damage (genotoxic) and those that generate sustained stress environments result in induced replication (nongenotoxic). Both nongenotoxic and genotoxic carcinogens enhance the risk of cancer. The model also explains the multiplicity

characteristics of tumors within an organ that are generally observed in rodents and has been reported to develop in humans (Comertpay et al., 2014; Knudson, 1971). The environmental stimulus is not only responsible for accumulation of mutations within a cell but also acts on partially repaired cells. Each partially repaired cell has some possibility to follow similar pathways of mutation as the precursor cell moves through. In the sustained environmental stress condition, each of many different inheritors of original cell has the potential to follow similar biological pathways to develop separate tumors in an organ.

Bioassay of carcinogens During the 1940s and 1950s, rodents were used as experimental models to evaluate only some classes of potent carcinogens (Weisburger & Williams, 1984). In the 1970s, chemical-induced carcinogenesis was confirmed in animal models and numerous epidemiologic studies. During this period, rapid increases in the chemical industry escalated environmental pollution and exposure of pollutants. All these issues led the National Cancer Institute (NCI) to identify prospective carcinogens and determine their safe levels of exposure. The NCI conducted a carcinogenesis bioassay program until establishment of the National Toxicology Program (NTP). The mission of NTP is to direct central toxicology programs and analyze toxicology and carcinogenesis tests (National Toxicology Program, 2011). Chemicals selected for analysis are subjected to a 2-year bioassay including both male and female sexes of rats or mice mostly inbred and outbred strains exposed to various predetermined doses (Fung et al., 1995). Moreover, NTP utilizes GEMMs for a short period depending on the case hypothesis (Pritchard et al., 2003). The major sources of information from laboratory tests on animal models are used to establish regulatory standards for prospective human exposure. The data from 5000

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1. Historical review and future prospective of chemical carcinogenesis

experiments involving 1298 chemicals in over 1000 research papers and 400 technical reports available from NCI/NTP are summarized in the Handbook of Carcinogenic Potency and Genotoxicity Databases (Gold & Zeiger, 1997). The quality of hazard identification studies is really good, but these studies are still unable to provide significant data required by regulatory agencies. On the basis of various studies and assessment of NCI or NTP, it is apparent that some chemicals that evoke cancer in rodents show little or no hazardous effects on humans. About 25% of the chemical substances identified as carcinogens in animals are causally or firmly linked to human cancer. Authenticating the significance of carcinogen testing in animal models, about 30 chemicals first shown to be carcinogenic in animals were consequently associated with human cancer by epidemiologic studies. These chemicals include 4-aminobiphenyl, asbestos, 1,3 butadiene, bis(chloromethyl)ether, dichlorodiphenyltrichloroethane (DDT), diethylstilbestrol, formaldehyde, estrogen, 2,3,7,8-tetrachlorodibenzodioxin (TCDD), vinyl chloride, and radon gas (Huff, 1993; Rall, 2000). Early studies suggested that the time of tumor initiation is associated with the total dose of chemical dispensed. Studies of persuasive carcinogens such as aromatic azo compounds, polycyclic aromatic amines, and nitrosamines have supported this concept (Monro, 1992; Page, 1977). Even though the experimental design has been influenced by the concept of cumulative dose, this concept appears inadequate for nongenotoxic chemicals. Cohen and Ellwein (1990) observed a different dose response of 2-acetylaminofluorene for the urinary bladder and liver because of 2acetylaminofluorene inducing cell proliferation in the urinary bladder. The probability of different responses by organs is not considered in most risk assessment models. However, accumulated data from rodent bioassay allows some interpretations when comparing the susceptibility of cancer in human and rodent. The rate of

cancer development in the forestomach, liver (except hepatitis C associated cancer), kidney, and thyroid gland is high in rodents and low in humans. The rate of cancer development is high in both species in skin, oral cavity, hematopoietic system, mammary gland, and lung. Cancer development rate is low in rodents and high in humans in the pancreas, prostate gland, uterus/ cervix, and rectum or colon. Considering the rodent carcinogen bioassay, threshold levels, mechanisms of action and dose response patterns of the test chemicals are involved in the determination of suitable levels of human exposure. As a component of this process, chemical carcinogens are classified into two broad groups: (1) genotoxic and (2) nongenotoxic. These groups are further divided into eight subclasses that include procarcinogens, directacting carcinogens, hormones, solid-state carcinogens, cocarcinogens, immunosuppressors, and promoters (Weisburger & Williams, 1981). For many of these chemicals, the mechanism of action and safe levels of exposure remains to be determined. The reports from NCI/NTP bioassays have been used by central and state agencies for reducing the exposure of mutagenic carcinogens. These studies also helped in the development of short-term genotoxic assays generally used for screening of chemicals before human exposure.

Issues with carcinogenic and noncarcinogenic categorization of chemicals Many regulatory systems such as European Union Classification, Labeling and Packaging (ECHA, 2012), United Nations Global Harmonized Scheme (UN, 2012), and International Agency for Research on Cancer (IARC, 2021) have classified carcinogenicity. However, these accesses can identify only the carcinogenic risk not carcinogenic potential. Therefore chemicals having substantial differences in their carcinogenic potential (CPDB,

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Long-term bioassays

2017) have been classified in the same category. They evaluate the consistency of carcinogenic evidence not carcinogenic potential. Ames (1979) studied the mechanism of action of chemical carcinogens for humans and revealed a link between carcinogenesis and mutagenesis. The results from 2-year rodent’s bioassay supported this study. An increase in the incidence of tumors was observed when the animals (rats/mice) were treated with human carcinogens for 2 years. These carcinogens were found to be mutagenic in those animals. However, uncharacterized chemicals were analyzed in the 2-year bioassay and results suggested that about 50% of those uncharacterized chemicals increased the number of neoplasms but many of them were not found to be mutagenic (Ames & Gold, 1990; Gold et al., 1989). The accuracy of these bioassays is uncertain for their capability to differentiate between carcinogenic and noncarcinogenic chemicals under real-world conditions. A chemical is considered carcinogenic if shown to be related to increases in tumors in a long-term bioassay using rodents (although enough evidence are available for different mode of action). Further, a chemical is considered noncarcinogenic if having no treatmentrelated increase in tumors under long-term bioassay using rodents. This concept is conflicts with the present knowledge of cancer etiology. The probability of cancer can be enhanced by chemicals through direct interactivity with DNA or augmentation of cell proliferation. The continuous exposure of chemical can increase the probability of cancer development in both cases. The prospect of cancer induction depends on the potential of the chemical, dose administration, toxicokinetic characteristics of the chemical, and the duration of exposure. In long-term bioassays, many chemicals should influence the frequency of tumors because treatment of chemicals at particular doses exert a biological effect that would perturb the biochemical

environment of the animal and alter the pattern of tumors including their number and type. The frequency of tumors can be enhanced or reduced. The frequency of tumors was decreased significantly in more than 20% of the long-term bioassays. Salsburg (1989) raised the question whether the decrease in the frequency of tumor should be considered as significantly as the increase, disagreeing to group the chemicals into carcinogens and noncarcinogens (Salsburg, 1989). Goodman and Wilson (1991) also noticed the issue and suggested that classification of chemicals into carcinogenic and noncarcinogenic category was unhelpful. Instead of following the same classification, all the chemicals could be presumed as carcinogenic with some of them having low potency to significantly increase tumors in specific experimental conditions. This idea is refused by scientific community because many chemicals have different modes of action that do not induce tumor formation. Even though there are no exact criteria to differentiate carcinogens and noncarcinogens, some chemicals are based on continuum showing efficient potential, some no impact, and others exhibiting the potential impact at a certain point with the continuum. Even low doses of chemicals may produce adverse effects that might lead to cancer because of the continuum. The insinuation for cancer prevention is not only based on the potential of a chemical that will induce cancer in experimental models (rats/mice) at certain doses but also the circumstances that will increase the development of cancer in humans. The potency of a chemical and mode or mechanisms of action will establish the necessary measures for prevention of cancers in humans.

Long-term bioassays Long-term bioassays are used to determine the carcinogenicity of a chemical for humans.

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1. Historical review and future prospective of chemical carcinogenesis

Using maximum dose and duration of exposure, these experiments are planned to maximize the probability of evoking tumors. Even though the classification of chemicals does not express carcinogenic potential, the bioassay can determine the chemical potency within a range of doses for tumor induction. Chemicals having high potential can induce tumors in 2-year bioassays. On the other hand, chemicals without carcinogenic potential do not induce tumors. However, treatment of rodents with the chemicals having intermediate or low carcinogenic potential may or may not develop tumors in long term bioassays. The induction of neoplasms depends on the experimental conditions and chemical concentration. Carcinogenesis is a multistage process having high heritable variability. Therefore it signifies that managing the reproducibility in cancer bioassays would be difficult. This was revealed by Gottman et al. (2005) during a comparison of 121 rodent carcinogenicity tests from the Carcinogenic Potency Database (CPDB) in two parts (NCI, NTP and open literatures) to evaluate the accuracy of these experiments. They showed 57% concurrence between comprehensive rodent carcinogenicity categories using both sources. They also studied the quantitative relationship for carcinogenic potential. Another factor responsible for variability in long-term bioassays is the mode of dose setting. The experimental models treated with the highest dose are considered as the maximum tolerated dose (MTD) when it will not decrease the body weight greater than 10% or shorten the lifetime of experimental models (Rhomberg et al., 2007). This dose is based on the toxicity causing chemical potential. If the toxic potency is low, MTD will be high and vice versa. Many chemicals have more than one adverse effect as one mode of action results in dose-limiting toxicity while another may lead to tumor development. The occurrence of dose-limiting toxicity at lower doses of chemical in comparison to

tumorigenic effects indicates that inadequate quantities of chemicals will be executed to evoke tumors in long-term bioassays and vice versa. Hence, chemicals having identical carcinogenic potential could be categorized differently on the basis of the relationship between carcinogenic mode of action and doselimiting toxic effects. Duration of exposure is another important variable responsible for dose and mode of action for tumor development. Short-term exposure of a chemical is hardly inducing nongenotoxic tumors in rodents. Most chemicals require repetitive long-term treatment for the development of cancer. Despite the issues, some meaningful conclusions can be drawn from long-term rodent bioassay. 1. Chemicals that stimulate tumor development in 2-year bioassays either have cell proliferation or genotoxic activity at doses identical or lower than the doses required for inducing toxicity that specify the quantity of chemical that can be tolerated. 2. Chemicals that do not stimulate tumor development in 2-year bioassays have no cell proliferation or genotoxic activity or such activity appears at the doses higher than the doses required for inducing toxicity that specify the quantity of chemical that can be tolerated. Although long-term bioassays play important roles in the evaluation of chemical toxicity, comparatively few chemicals have been analyzed by this method. About 50,000 chemicals are used commercially (Fischetti, 2010), but the assessment of only B1500 chemicals is reported in databases for long-term bioassay (CPDB, 2017) because long-term bioassay is time consuming, expensive, and uses a large number of animals coupled with the absence of regulatory requirement in most cases. Presently, more appropriate tools are used for accomplishing information to ascertain the carcinogenic

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Chemical carcinogenesis and genetically engineered models

potential in humans. A new trend in toxicology is promoting hypothesis-based testing that depends on various information including molecular approaches. Therefore several efforts have been made to find alternative methods to evaluate carcinogenic potential that are quicker, less expensive, and more predictive and use few or no animals.

Chemical carcinogenesis and genetically engineered models Over the last few decades, the use of GEMMs as an experimental model for cancer has been increased. Various articles and reviews are focused on these models (Becher & Holland, 2006; Frese & Tuveson, 2007; Van Dyke & Jacks, 2002). Complex interactions between genetic vulnerability and environmental exposure may cause cancer. Chemical carcinogenesis and genetically engineered models are used collectively to unravel these interactions. Exposure of carcinogens/radiations enhances the spectrum of tumors in some GEMMs as the combined effect of chemical exposure with genetics. It was observed that p53 (tumor suppressor gene) knockout mice were vulnerable to sarcomas and lymphomas, but epithelial tumors were not evoked in these mice. This study was interesting because p53 is often mutated in the epithelial tumors of both mouse and human. To resolve this mystery, Kemp et al. (1993) applied 7,12-dimethylbenz[a] anthracene (DMBA) or 12-o-tetradecaoylphorbol-13-acetate (TPA) protocol for development of multistage skin tumors in p53-deficient mice. The result indicated that there was no increase in the initiation or promotion of skin tumors in p53 deficient mice, but the developed tumors progressed rapidly to malignant invasive and metastatic cancer. Several subsequent studies also suggested that p53 might have an important role in suppressing malignant progression (Jackson et al., 2005; Lewis et al., 2005). These

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experiments also demonstrated a collaboration between Ras and p53 mutations during malignant progression. However, p53-deficient mice are prone to UV-induced skin cancer, DMNinduced hemangiosarcoma, radiation-induced sarcomas and lymphomas as well as susceptible to other chemicals and agents (Harvey et al., 1993; Jiang et al., 1999; Kemp et al., 1994; Tennant et al., 1999). The sensitivity of Arfdeficient mice to chemically developed hemangiosarcoma (Busch et al., 2012), lung cancer (Busch et al., 2013), and progression of DMBA/ TPA induced skin cancer (Kelly-Spratt et al., 2004) indicates Arf/p53 signaling as an important obstruction to radiation and chemical induced carcinomas. A cyclin-dependent kinase inhibitor p27 (CDKN1B) is another remarkable example explaining the significance of combining radiation and chemical carcinogenesis using GEMMs. The function of p27 as an inhibitor of cyclin/ cyclin-dependent kinase complexes made it a tumor suppressor, the preliminary dearth of CDKN1B mutations in neoplasms doubt on its significance in human carcinomas (PhilippStaheli et al., 2001). In addition, p27 knockout mice exhibited moderate sensitivity to spontaneous tumor development that is confined to the pituitary gland (Kiyokawa et al., 1996). These results were difficult to integrate with clear relationship of low expression of p27 protein with poor diagnoses in lung, breast, colon, prostate, and other cancers (Chu et al., 2008). This mystery was partially resolved when p27-deficient mice were exposed to ionizing radiation or chemical carcinogens. The observations suggested that in comparison to wild-types, both p27 heterozygous and null mice were susceptible to cancer in different tissues including prostate, small intestine, lung, colon, and hematopoietic tissue (KellySpratt et al., 2009; Philipp-Staheli et al., 2002). In addition, evaluation of tumors from p271/mice did not show mutation or loss of heterozygosity in wild-type Cdkn1b allele clearly indicating the haploinsufficiency of tumor suppressor

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1. Historical review and future prospective of chemical carcinogenesis

gene. Similarly, Donehower et al. (1992) reported that p53 also confirmed the haploinsufficient tumor suppression. Before these studies, tumor suppressor gene was believed to function in a recessive manner as well as requiring mutations in both alleles for the development of cancer. However, these experiments also suggested that loss of a single gene was adequate for carcinomas induction. Now, haploinsufficiency has been illustrated for many tumor suppressor genes (Payne & Kemp, 2005; Scuoppo et al., 2012). Hence, the combination of chemical carcinogenesis with GEMMs was involved in modification of one of the central dogmas of cancer genetics. Recent data from the projects of cancer genome sequencing illustrate that CDKN1B is significantly mutated in human breast cancer (Ellis et al., 2012), emphasizing the prophetic value of mouse models for the identification of tumor suppressor genes. Phenotypic analysis of GEMMs requires appropriate environmental or dietary exposures. The different range of tumors observed in mice and humans has been associated with differences in inherent genetics between the species and has been used as one of the reasons against the utilization of mice as an experimental model of human cancer (Anisimov et al., 2005). However, some of these differences occur undoubtedly because of the variation in environmental exposures between humans and experimental mice. Another probable bewildering difference when comparing the susceptibility of mice and humans to cancer is that experiments related to mouse model are executed in one or two inbreed stains, whereas human population is very diverse (genetically). It is apparent that risk of cancer in both human and mice is affected by genetic background (Dragani, 2003).

Genetic modifiers of cancer The susceptibility of inbred strains towards spontaneous or chemically induced tumors is

widely different in most of the tissues including liver, lung, colon, and skin (Demant, 2003). Mostly, induction of tumors by tissue specific chemical carcinogens is a crucial approach for the detection, mapping, and identification of genetic modifiers of cancer. For example, a highly sensitive SENCAR mouse strain was developed by topical application of DMBA (carcinogen) for mapping and characterization of multiple skin cancer susceptibility loci (Skts) using interspecies crosses and inbred strains (Quigley et al., 2009). The A/J and other mice strains was treated with N-ethyl-N-nitrosourea (ENU) or urethane to find the loci of lung cancer susceptibility including Par, Pas, and Sluc alleles (Liu et al., 2006). NNitrosodiethylamine (DEN) urethane or ENU treatment of inbred strains to develop tumors in liver revealed remarkable dissimilarity in susceptibility for hepatocarcinogenesis that lead to the identification of modifier alleles Hcr and Hcs (Poole et al., 1996). The colon and small intestine cancer susceptibility alleles Scc and mutations were identified in the germline susceptible strain ApcMin treated with azoxymethane (AOM) and 1,2-dimethylhydrazine (DMH) (Bissahoyo et al., 2005). The analysis of these modifiers will approach epistatic or gene 3 gene interactions predicting risk of cancer, novel mechanisms in the progression of cancer, and by projection human’s susceptibility for cancer. The increased sensitivity of some GEMMs to chemical carcinogens is important for revealing processes of genotype 3 environment interaction and selecting genes that regulate environmentally-induced cancer.

Future of chemical carcinogenesis Despite evidence of chemically-induced carcinogenesis, new chemicals and therefore new carcinogens are often identified and synthesized for industry. Ultimately, these chemicals are introduced into the environment. However, experimental and epidemiological studies of chemical carcinogenesis in animal models have

Xenobiotics in Chemical Carcinogenesis

References

major roles in the establishment of the fact that reducing exposure of mutagenic carcinogens is the most effective method to prevent cancer. However, many chemicals and agents are only carcinogenic not mutagenic including some metals, asbestos, phenobarbital, hormones, and chlorinated hydrocarbons (polychlorinated biphenyls and DDT). Treatment of selected GEMMs with these agents may help in revealing the additional mechanisms of carcinogenesis. It can be predicted reasonably that epigenetic events will be involved in some of these mechanisms. Several molecular and epidemiologic studies have suggested epigenetic mechanisms as an important component in linking environmental exposure and risk of cancer (Jirtle & Skinner, 2007). For example, carcinogens such as diethylstilbestrol, arsenic, and nickel can induce epigenetic alterations (Anderson, 2004; Herceg, 2007). Combining GEMMs with environmental exposures novel approaches are required for determination of environmental causes of epigenetic changes and the role of these changes in cancer development. Clonal study of cancer has verified the phenotypical and genetical heterogeneous nature of tumors (Driessens et al., 2012; Greaves & Maley, 2012). This tumor heterogeneity causes failure of treatment and their modeling in mouse is also very challenging. These animal models may provide useful tools to study heterogeneity in tumors and indications for tumor response to therapy. Animal models combining both environmental and genetic factors will play vital roles in the journey of reducing the risk of cancer on the human population. The future of cancer research seems interesting and hope carried by different routes and disciplines. Substantially more attention and importance should be given to prevention measures. Accordingly, incidence of cancer will be reduced with decreases in the overuse and misuse of chemicals. We hope that in the near future the period between detection of

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carcinogenic risk of causative agents and their exposure will be shortened.

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metastasis of Hras-driven carcinomas through p53dependent and -independent pathways. PLoS Biology, 2, 1138 1149. Kelly-Spratt, K. S., Philipp-Staheli, J., Gurley, K. E., HoonKim, K., Knoblaugh, S., & Kemp, C. J. (2009). Inhibition of PI-3K restores nuclear p27Kip1 expression in a mouse model of Kras-driven lung cancer. Oncogene, 38, 3652 3662. Kemp, C. J., Donchower, L. A., Bradley, A., & Balmain, A. (1993). Reduction of p53 gene dosage does not increase initiation or promotion but greatly enhances malignant progression of chemically induced skin tumors. Cell, 74, 813 822. Kemp, C. J., Wheldon, T., & Balmain, A. (1994). p53 deficient mice are extremely susceptible to radiationinduced tumorigenesis. Nature Genetics, 8, 66 69. Kennaway, E. L., & Hieger, T. (1930). Carcinogenic substances and their fluorescence spectra. British Medical Journal, 1, 1044 1046. Kennaway, E. L. (1955). The identification of a carcinogenic compound in coal tar. British Medical Journal, ii, 749 752. Kinosita, R. (1936). Researches on the carcinogenesis of the various chemical substances. Gann 5 Gan, 30, 423 426. Kiyokawa, H., Kineman, R. D., Manova-Todorova, K. O., Soares, V. C., Hoffman, E. S., Ono, M., Khanam, D., Hayday, A. C., Frohman, L. A., & Koff, A. (1996). Enhanced growth of mice lacking the cyclin dependent kinase inhibitor function of p27(Kip1). Cell, 85, 721 732. Knudson, A. G. (1971). Mutation and cancer: Statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America, 68, 820 823. Lewis, B. C., Klimstra, D. S., Socci, N. D., Xu, S., Koutcher, J. A., & Varmus, H. E. (2005). The absence of p53 promotes metastasis in a novel somatic mouse model for hepatocellular carcinoma. Molecular and Cellular Biology, 25, 1228 1237. Lichtenstein, P., Holm, N. V., Verkasalo, P. K., Iliadou, A., Kaprio, J., Koskenvuo, M., Pukkala, E., Skytthe, A., & Hemminki, K. (2000). Environmental and heritable factors in the causation of cancer-Analyses of cohorts of twins from Sweden, Denmark, and Finland. The New England Journal of Medicine, 343, 78 85. Liu, P., Wang, Y., Vikis, H., Maciag, A., Wang, D., Lu, Y., Liu, Y., & You, M. (2006). Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice. Nature Genetics, 38, 888 895. Magee, P. N., & Barnes, J. M. (1956). The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine. British Journal of Cancer, 10, 114 122. Magee, P. N., & Barnes, J. M. (1967). Carcinogenic nitroso compounds. Advances in Cancer Research, 10, 163 246.

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1. Historical review and future prospective of chemical carcinogenesis

Martincorena, I., Raine, K. M., Gerstung, M., Dawson, K. J., Haase, K., Loo, P. V., Davies, H., Stratton, M. R., & Campbell, P. J. (2017). Universal patterns of selection in cancer and somatic tissues. Cell, 171, 1 13. Miller, E. C., & Miller, J. A. (1979). Milestones in chemical carcinogenesis. Seminars in Oncology, 6, 445 460. Findlay, G. M. (1928). Ultra-violet light and skin cancer. The Lancet, ii, 1070 1073. Miller, J. A. (1991). The need for epidemiological studies of the medical exposures of Japanese patients to the carcinogenic ethyl carbamate (urethane) from 1950 to 1975. Japanese Journal of Cancer Research: Gann, 82, 1323 1324. Monro, A. (1992). Contemporary issues in toxicology: What is an appropriate measure of exposure when testing drugs for carcinogenicity in rodents? Toxicology and Applied Pharmacology, 112, 171 181. National Toxicology Program. (2011). 12th report on carcinogens. U.S. Department of Health and Human Services Public Health Service National Toxicoloy Program. Gold L.S. & Zeiger E. (1997). Handbook of carcinogenic potency and genotoxicity databases. CRC Press, Boca Raton, FL. Nault, J.-C. (2014). Pathologenesis of hepatocellular carcinoma according to aetiology. Best Practice & Research. Clinical Gastroenterology, 28, 937 947. Nettleship, A., Henshaw, P. S., & Meyer, H. L. (1943). Induction of pulmonary tumors in mice with ethyl carbamate (urethane). Journal of the National Cancer Institute, 4, 309 319. NRC, (2007). Toxicity testing in the 21st century: A vision and a strategy. National Research Council 2007. The National Academies Press, Washington, DC. ,https://doi.org/ 10.17226/11970.. Moolgavkar, S., & Knudson, A. (1981). Mutation and cancer: A model for human carcinogenesis. Journal of the National Cancer Institute, 66, 1037 1052. Nunney, L. (2013). The real war on cancer: The evolutionary dynamics of cancer suppression. Evolutionary Applications, 6, 11 19. OTA (Office of Technology Assessment). (1981). Assessment of technologies for determining cancer risks from the environment. Office of technology assessment. Washington, DC: U. S. Government Printing Office. Page, N. P. (1977). Concepts of a bioassay program in environmental carcinogenesis. In H. Kraybill, & M. C. Mehlman (Eds.), Environmental cancer (pp. 87 171). New York, NY: Wiley. Payne, S. R., & Kemp, C. J. (2005). Tumor suppressor genetics. Carcinogenesis, 26, 2031 2045. Philipp-Staheli, J., Kim, K. H., Payne, S. R., Gurley, K. E., Liggitt, D., Longton, G., & Kemp, C. J. (2002). Pathwayspecific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice. Cancer Cell, 1, 355 368.

Philipp-Staheli, J., Payne, S. R., & Kemp, C. J. (2001). p27 (Kip1): Regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Experimental Cell Research, 264, 148 168. Poole, T. M., Chiaverotti, T. A., Carabeo, R. A., & Drinkwater, N. R. (1996). Genetic analysis of multistage hepatocarcinogenesis. Progress in Clinical and Biological Research, 395, 33 45. Pott P. (1775). Chirugical observations relative to the cancer of the scrotum, Hawes, Clarke, and Collins, London. Reprinted in National Cancer Institute Monograph 10:7-13 (1963). Pritchard, J. B., French, J. E., Davis, B. J., & Haseman, J. K. (2003). The role of transgenic mouse models in carcinogen identification. Environmental Health Perspectives, 111, 444 454. Quadir, A., Hashmi, M. Z., & Mahmood, A. (2017). Xenobiotics, types, and mode of action. In M. Hashmi, V. Kumar, & A. Varma (Eds.), Xenobiotics in the soil environment. Soil biology (49, pp. 1 7). Cham: Springer. Quigley, D. A., To, M. D., Perez-Losada, J., Pelorosso, F. G., Mao, J. H., Nagase, H., Ginzinger, D. G., & Balmain, A. (2009). Genetic architecture of mouse skin inflammation and tumour susceptibility. Nature, 458, 505 508. Rall, D. P. (2000). Laboratory animal tests and human cancer. Drug Metabolism Reviews, 32, 119 128. Reddy, B. Y., Miller, D. M., & Tsao, H. (2017). Somatic driver mutations in melanoma. Cancer, 123, 2104 2117. Rehn, L. (1895). Blasengeschwu¨lste bei Fuchsinarbeitern. Archiv fu¨r Klinische Chirurgie, 50: 588 Yamagiwa K, Ichikawa K. 1918. Experimental study of the pathogenesis of carcinoma. The Journal of Cancer Research, 3, 1 29. Roshan, A., & Jones, P. H. (2012). Chronic low dose UV exposure and p53 mutation: Tilting the odds in early epidermal preneoplasia? International Journal of Radiation Biology, 88, 682 687. Sasaki, T., & Yoshida, T. (1935). Liver carcinoma induced by feeding O-amidoazotoluene. Archive for Pathological Anatomy, 295, 175 220. Scuoppo, C., Miething, C., Lindqvist, L., Reyes, J., Ruse, C., Appelmann, I., Yoon, S., Krasnitz, A., Teruya-Feldstein, J., Pappin, D., et al. (2012). A tumour suppressor network relying on the polyamine-hypusine axis. Nature, 487, 244 248. Slaga, T. J., et al. (1982). Studies on the mechanisms involved in multistage carcinogenesis in mouse skin. Journal of Cellular Biochemistry, 18, 99 119. Soucek, P. (2011). Xenobiotics. In M. Schwab (Ed.), Encyclopedia of cancer (pp. 3964 3967). Berlin, Heidelberg: Springer. Tennant, R. W., Stasiewicz, S., Mennear, J., French, J. E., & Spalding, J. W. (1999). Genetically altered mouse models for identifying carcinogens (pp. 123 150). IARC Scientific Publications.

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2 Xenobiotic metabolism(s) in carcinogenesis Introduction

(Rodriguez-Antona & Ingelman-Sundberg, 2006). In advanced cancers, these enzymes could explore the results of anticancer regimens and changed expressions of P450s could redefine cancer development and lead to drug resistance (McFadyen, McLeod, et al., 2001; McFadyen, Cruickshank, et al., 2001). In the case of environmental carcinogen exposure, such xenobiotic chemicals sometimes respond within the body’s metabolic enzymes of the mucosal surfaces (lung, gastrointestinal tract, urogenital system, etc.) and liver. Such enzyme groups are cytochrome P450 (5), glutathione-S-transferase (GST), uridine glucuronyl transferases (UGTs) superfamilies, alcoholmetabolizing enzymes, and sulfatases. The metabolic enzymes are classified into two different groupings (Table 2.1): (1) Phase I, enzymes that catalyze oxidation, reduction, hydroxylation, etc., which include cytochromes, esterases, and alkoreductases; and (2) Phase II, where the enzymes catalyze conjugation of the Phase I enzyme metabolites with different moieties having glutathione and glucuronide, UGTs, and GSTs. Such enzymes can either deactivate these compounds or, in some conditions, produce reactive moieties that lead to cancer. Such metabolic enzymatic systems are polymorphic and inducible and thus their

The human body is highly exposed to extraneous chemicals, both purposely (e.g., medicines) and accidentally (e.g., environmental pollutants), and these foreign compounds known as xenobiotics are metabolized by several enzymes like cytochrome P450s (P450). P450s are hemethiolate enzymes involved in the biotransformation of xenobiotic compounds and the formation of several essential endogenous chemicals like steroid hormones, prostaglandins, and leukotrienes (Nelson et al., 1996; Tama´si et al., 2011). Their expression is considered to be greatly controlled, where certain P450s are expressed only in particular tissues at specific times. In the same way, the expression mode of several P450s varies at every developmental step and differs in females and males. Contradictorily, such enzymes catalyze the production of reactive intermediates of thousands of compounds that can damage DNA including lipids and proteins. P450 expression can also influence the formation of proliferation-promoting components of arachidonic acid and changes several downstream signal-transduction mechanisms. Reactive intermediates, induced carcinogens, and components of arachidonic acid can be precursors to malignancy and lead to chemical carcinogenesis

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00012-1

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© 2022 Elsevier Inc. All rights reserved.

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2. Xenobiotic metabolism(s) in carcinogenesis

TABLE 2.1 Classes of metabolic enzymes (Singh & Michael, 2009). Phase I enzymes

Phase II enzymes

CYP, monoamine oxidase, peroxidases, oxidases, lipoxygenases, Acetyltransferases, acyltransferases, methyltransferases, monooxygenases, dioxygenases, cyclooxygenases, hydroxylases, transaminases, epoxidases, uridine diphosphate aldoketoreductases, hydrolases, sulfatases, glycosylases, glucuronostyltransferases, glutathione transferases glucuronidases, aldoketoreductases, reductases, NADdependent enzymes Such categorization of enzymes is not definite and the same enzyme might play as a Phase I and Phase II enzyme under distinct conditions.

function could differ between individuals. Therefore, the careful examination of the impact of carcinogenic exposures and the incidence of cancer formation based on polymorphism distributions need to be investigated (Singh & Michael, 2009). If P450s are the “bridges” between the environment and human body, their role could be associated in several modes to carcinogenesis: they induce xenobiotic compounds to eventual carcinogens though at the same time they metabolize drugs employed for cancer therapy. In certain cancers, the malignant tissue balances its drug resistance with changed expression of P450s, which explains why they are crucial targets for cancer treatment. Predominantly, dose P450s can be related to chemical carcinogenesis that participate in xenobiotic metabolism (CYP1 4 family). Development of cancer is a highly complex method involving alterations in several genes. All biological or mechanistic activity of xenobiotic metabolizing genes in cancer formation must be taken against such fundamental principles. Subsequently, research conducted to date most likely provides only a few descriptions of the linkage between polymorphism in xenobiotic metabolizing genes and individual risk to cancer development (Gemignani et al., 2002). Several chemical carcinogens need metabolic stimulation for their carcinogenic impact. Commonly, metabolic induction has been associated with initiation, such as the early stages of carcinogenic methods. However, metabolic

stimulation can also play a vital role in the latter stages of carcinogenesis and mechanisms following initiation, which provides more possibilities for differentiation (Fig. 2.1) (Gemignani et al., 2002). Various lines of proof suggest that metabolic induction and consequent DNA binding of reactive metabolites is an important situation for chemical carcinogenesis. However, it is not clear whether induction is an appropriate condition. These strides as an escape from repair and angiogenesis are needed for completion in cancer development. Presently, most outcomes for potential activation are derived from knockout mouse models. Mouse lines with altered genes encoding CYP1A2, CYP2E1, CYPIB1, microsomal epoxide hydrolase (mEH) and NADPHquinone oxidoreductase have been generated. No mice show complete aberrant phenotypes, indicating that the xenobiotic-metabolizing enzymes have no major functionality in mammalian development and physiological homeostasis. This elucidates why some such genes are largely polymorphic in humans. However, such null mice do reveal notable variations to the susceptibilities of toxic results, such as cancer development, establishing the major function of xenobiotic metabolism in chemical toxicities (Gemignani et al., 2002). Several chemical carcinogens and toxins are dormant and need metabolic stimulation by cellular enzymes to produce adverse impacts. Xenobiotic-metabolizing enzymes play vital roles in either regulating the toxicity of xenobiotic chemicals via metabolic induction of pro-toxins and

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Introduction

Xenobiotics

Xenobiotics DE

AE

AE

DE

Xenobiotics

Xenobiotics

AE

AE

DE

DE

Stimulation/suppression of metabolism

Activated carcinogens DE

Activated carcinogens DE

DE

Activated carcinogens

DE

Accumulation of DNA-adduct

DNA Repair

Activated carcinogens

Time

Accumulation of mutation

Proliferation Apoptosis Immunogenicity

Angiogenesis cancer

Suppression of angiogenesis

FIGURE 2.1 Potential “rainfall” model for xenobiotic metabolism in chemical carcinogenesis. AE, activating enzyme; DE, deactivating enzyme.

procarcinogens or inversely shielding the organism by expeditiously converting chemicals to inert components that can be readily removed. P450s, as an extensive superfamily of proteins, are the primary enzymes participating in the oxidation of external chemicals like therapeutically-implicated drugs and the metabolic induction of carcinogenic compounds and toxins. Studies of such enzymes are crucial for a full understanding of toxic events and chemical carcinogenesis and yet are intricated by species variations in the expressions and catalytic functions of P450s. It may have negative effects to employ rodent models in research and chemical investigation for human prevention. Particularly, P450s in the elementary CYP2 family, which have a higher number of P450s participating in drug metabolism, exhibit appreciable variations in the expression, modulation, and catalytic functionality between rats, mice, and humans. Xenobiotic metabolism mainly results in nonelectrophilic or substantial derivatives. However, certain compounds are induced to electrophilic derivatives like quinones and epoxides. This is

conducted by a rather specific class of enzymes, where each one metabolizes certain classes of chemical carcinogens. CYP1A1 and CYP1B1 are involved in the metabolic induction of polycyclic aromatic hydrocarbons (PAHs). CYP1A2 performs the N-hydroxylation of arylamine carcinogens and heterocyclic amine (HCA) food mutagens, which is followed by O-esterification or sulfate through transferase enzymes and produces unstable electrophilic derivatives which could lead to cell toxicity, death, or transformation. CYP1A2 also metabolically induces aflatoxin B1 to its final carcinogenic metabolite, the 8,9epoxide. CYP2E1 plays an important role in the metabolism of several low molecular weight toxins and carcinogens like N-nitrosodimethylamine, benzene, and vinyl halides. In contrast to several other CYP2 subfamily members involved in the metabolism of drugs to non-electrophilic components, P450s metabolize and induce carcinogens that are highly conserved in their catalytic function and expression in several mammalian species. Such conservation suggests that they may

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2. Xenobiotic metabolism(s) in carcinogenesis

have vital functions in mammalian development and/or physiological homeostasis (Gonzalez & Kimura, 2001). Several other enzymes have been grouped into the “phase II” category of xenobiotic metabolizing enzymes (XMEs) involved in the conversion of oxidized chemicals into highly hydrophilic components that can be readily removed via urine or bile. This group contains glutathione S-transferases (GST), N acetyltransferases (NAT), sulfotransferases (ST), UDPglucuronosyltransferases (UGT), and NAD(P) H-quinone oxidoreductase (NQO1). Certain phase II enzymes, namely GSTs, STs and UGTs, are found in diverse patterns in mammals and have a greater frequency of overlapping substrate specificity in distinct forms. They also reveal polymorphisms and species variations in expression and catalytic functions. Species variations in the transferases, although relevant, are not as readily with the P450s and have a minimal effect due to the relevant overlap in substrate specificity (Gonzalez & Kimura, 2001). The biological events of cancer formation are achieved due to the involvement of both environmental and genetic factors. Among the environmental factors, tobacco and alcohol are identified as one of the potential causative components in the formation of cancer whereas genetic differentiation in phase I and phase II XMEs play a vital role in determining the result of exposure to environmental carcinogens. The genes involved in cancer formation fall into three wide groups, including tumor suppressor genes, oncogenes, and DNA repair genes. Cytochrome P450s (CYPs) are one of the most crucial superfamilies of phase I XMEs whereas phase II GSTs conjugate a broad area of electrophilic substrates with the ample cellular nucleophile-glutathione (GSH) stimulating their metabolism, detoxification, and excretion. It has been inferred when exploring gene-environment interactions that the incidence of cancer related to certain environmental exposures like tobacco and alcohol vary with the

functional polymorphisms of such genes. Several studies have been performed concerning various genes and different cancers and the results; however, they are sometimes irrelevant and aid in developing etiological information of cancer. Exploration of gene-environmental interaction is crucial to improve correctness and precision in the analysis of both genetic and environmental impacts in inducing cancer. Gene-environment interactions also have significant applications for public health as it helps in determining cancer rates and gives a basis for relevant suggestions for cancer prevention (Ruwali & Shukla, 2021). This chapter will elucidate the basic events of xenobiotic metabolism in cancer development to unravel precautionary and therapeutic strategies.

Function of aryl hydrocarbon receptors Even though the aryl hydrocarbon receptor (AhR) has been identified as the regulator of the toxicity of certain xenobiotics like dioxins, the conventional functionality of this transcription component in several biological events is its initiation to be characterized. Insights of AhR-targeted genes and signaling pathways suggest participation of AhR in basic cell-regulatory pathways. Marked limitations in the morphology and activity of particular tissues in the lack of AhR point to crucial roles for such proteins in developmental events. Simultaneously, the data indicate that the AhR has a significant role in regulating the equity among methods participating in cell proliferation, death, and differentiation. In another way, dysfunction of such methods has been identified to contribute to mechanisms like tumor initiation, promotion, and progression that finally cause malignant tumor development. Epidemiological and experimental animal data, along with other comprehensive information of how AhR plays a vital role in controlling specific signaling events, contribute support for the relationship between unnatural AhR activity and cancer (Gasiewicz et al., 2008).

Xenobiotics in Chemical Carcinogenesis

Function of aryl hydrocarbon receptors

AhR in humans Generally, human AhR (hAhR) has an order of magnitude lower potential for xenobiotic ligands than laboratory animal strains (Connor & Aylward, 2006). This observation is primarily due to variations at two residues, such as valine at position 381 and proline at position 480, which are also available in the low-affinity AhRs of specific strains of mice (Dolwick et al., 1993). Various polymorphisms of the hAhR have been explored that are restricted to the transactivation domain, although some have been highly related with either variations in response to TCDD or any certain disease condition (Connor & Aylward, 2006; Harper et al., 2002). The most frequent single nucleotide polymorphism is 1661G to A (Arg554Lys), which is linked with a decreased incidence of breast cancer in a portion of the Chinese population (Long et al., 2006). However, such polymorphism is not observed to be related with modified TCDD binding, AhRE binding of the AhR-Arnt complex, or stimulation of CYP1A/ B function (Wong, Harper, et al., 2001). A variant in African populations, Val570Ile, is related with Arg554Lys, and this genotype reveals a decreased inducibility of CYP1A1 by TCDD (Wong, Okey, et al., 2001). Lys401Arg and Asn487Asp variants are also linked with reduced transactivation activity, and reduced expression of AhR protein has been a determinant transfection of such mutant genes into HeLa cells (Koyano et al., 2005). The outcomes that polymorphisms in the hAhR are comparatively rare and are not observed to be linked with crucial modification in activity indicate a fundamental physiological requirement to maintain the hAhR structure. Humans were observed to have a receptor shape with lower potential for xenobiotic ligands, which is also informative of certain resistances to xenobiotics chemicals. Notably, transgenic mice having hAhR showed lower responsiveness in comparison to wild-type mice to TCDD via both

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enzyme stimulation and specific signs of toxicity (Moriguchi et al., 2003). In another way, it was observed from animal studies that ligand potential is only one of several components that explores sensitivity. Further, it is not well understood yet how such polymorphisms impact binding of endogenous ligands or natural activity of the AhR.

The AhR as a cofactor in carcinogenesis The present outcome highly elucidates a function of the AhR in methods regulating the balance in proliferation, cell death, and differentiation which describes normal developmental events. Accordingly, it is rational to doubt that abnormality in such functions can directly or indirectly lead to mechanisms like cancer initiation, promotion, and development. In fact, there is increasing evidence based on AhR to the development of several types of cancers. Mechanisms associated with cancer initiation There is little of no evidence to suggest that TCDD is itself a cancer initiator. However, AhR readily participates in cancer initiation if it is a potential regulator of the expression of enzymes impacting xenobiotic metabolism and disposition. CYP1A1, CYP1A2, and CYP1B1 are modulated by the AhR, and the modification of their expression has been associated toxicity and tumor formation via metabolic activation and/or changed metabolic clearing of toxic or carcinogenic xenobiotics (Nebert & Dalton, 2006; Roos & Bolt, 2005). Evidence indicating that enhanced CYP gene expression might lead to carcinogenesis with increasing DNA adduct synthesis (Mollerup et al., 2006), oxidative DNA damage through the generation of reactive oxygen species (ROS) (Park et al., 1996), and induction of environmental procarcinogens and oxidative metabolism of estrogens and latter might change the identified

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2. Xenobiotic metabolism(s) in carcinogenesis

cancer-enhancing impacts in particular endocrine tissues (Cribb et al., 2006; Vijayalakshmi et al., 2005). It is essential to identify that the impact on tumorigenesis might be either positive or negative based on the chemicals moving through the metabolism and cellular context; especially, the corresponding presence of more metabolizing enzymes like phase II. For instance, the estrogenic chemical diethylstilbestrol (DES) has been associated with enhanced breast cancer incidence in humans, whereas the anticarcinogenic compound di-allylsulfide has been implied to counter DES-based DNA damage via enhancing the expression of the CYP1A1 and CYP1B1 enzymes, leading to increased DES metabolism (Green et al., 2007). In another way, upregulation of CYP1A1 expression, readily occurring through an AhRunderlying event ensuring exposure to respirable quartz, has been used in the induction of procarcinogens found in cigarette smoke (Becker et al., 2006). As explained above, the enhanced AhR extents and nuclear translocation, as well as upregulation CYP1A1 expression, had been related with more incidences of gastric cancer in a Chinese cohort. Different CYP1A1 gene polymorphisms in exon 7 have been associated with either increased or decreased incidence of prostate cancer in a South Indian population (Vijayalakshmi et al., 2005). AhR has shown direct evidence of the induction of procarcinogens via the upregulation of the CYP enzymes in several animal studies. For instance, the genotoxic and tumorigenic reaction to benzo[a]pyrene or dibenzo [a, L]pyrene are eliminated or adequately inhibited in mice lacking AhR or by AhR antagonist therapies (Nakatsuru et al., 2004; Shimizu et al., 2000). In another way, the paucity of AhR in maternal tissues of KO mice was observed to increase the presence of procarcinogens to fetal tissue, hence enhancing the incidence of tumorigenesis in the fetus (Miller et al., 1998; Nakatsuru et al., 2004).

Role of cytochrome P450 in the biotransformation of xenobiotics in carcinogenesis Humans are faced with environmental xenobiotics and drugs throughout their lives. Environmental hazards and long-course medications could be a major risk factor for the generation of several pathologies, including cancer. The metabolic processes of xenobiotics are performed by families of P450s such as CYP1, CYP2 and CYP3. It had been observed that the enzymes of such families, mainly CYP1A1, CYP1B1, CYP2B6, CYP2C8, CYP2E1, CYP2D6, CYP3A4, CYP3A5, CYP3A7, are activated in both cancerous and normal cells (Maksymchuk & Kashuba, 2019). Though the major biotransformation of xenobiotic compounds is accomplished in the liver, data on the expression of CYPs might suggest the local metabolic event of xenobiotics in cells (Obligacion et al., 2006). This intracellular metabolism of xenobiotics has a crucial impact on the event of cancer development, particularly, its activation, and the generation of chemoresistance (Murray et al., 1995; Sterling & Cutroneo, 2004). Moreover, major alterations in the expression extents of maximum CYPs genes had been observed in prostate cancer in contrast to normal tissue (Murray et al., 1995). It has been shown that cytochrome P450 is a major enzyme of the first step of biotransformation of xenobiotics chemicals. CYPs conduct the metabolic modification of hydrophobic and low reactive exogenous xenobiotics to hydrophilic, extremely reactive metabolites which likely react with cellular biomolecules, leading to their deterioration and dysfunction (Maksymchuk & Kashuba, 2019). Apart from that, free radicals are also produced during the catalytic cycle of cytochrome P450, particularly the superoxide anion radical and hydrogen peroxide. Certain cytochrome P450 enzymes like CYP2E1, are identified by the potential to form ROS in the inoperative cycle, and hence highly impact the pro-oxidant-antioxidant equilibrium

Xenobiotics in Chemical Carcinogenesis

Role of cytochrome P450 in the biotransformation of xenobiotics in carcinogenesis

in cells (Hrycay & Bandiera, 2015). Instead, the reality that ROS are physiological pathway components, governing both their local intracellular and systemic metabolism and accumulation in cells may cause oxidative stress (Hrycay & Bandiera, 2015). As result of oxidative stress, redox-sensitive transcription factors like NF-kB, AP-1, Nrf2, etc. are induced and such transcription factors control the expression of genes by involving in the cell proliferation, differentiation, and apoptosis. Such counters to oxidative stress are thought as an adaptive mechanism of normal tissues, causing programmed death of stressdamaged cells. However, in cancer cells, due to dysfunction of biomolecules and dysregulation of signaling events, oxidative stress is responsible for cancer development (Sajadimajd & Khazaei, 2017). It has been observed that certain transcription factors had been impeded by epigenetic events in carcinogenesis that stimulated the proliferation, metastasis, and formation of chemoresistance (Sajadimajd & Khazaei, 2017). It had been shown that redox-sensitive transcription factors control the expression of P450s that participate in the metabolism of steroids, cholesterol, PUFAs, and vitamin D including the biotransformation of xenobiotics materials (Maksymchuk & Kashuba, 2019). For instance, NF-kB could directly interact with the promoters of the CYP1A1, CYP2E1, CYP3A7 as well as impact them indirectly by suppressing certain nuclear receptors such as AhR, CAR, GR, PXR, RXR, PPAR, FXR, and LXR, that control CYPs genes expression (Zhang et al., 2021). It has been considered that the expression of several nuclear receptors is altered in cancer (Maksymchuk & Kashuba, 2019) that necessitate a contravention in the expression of most CYP genes. The change in the expression of transcription factor, AP-1, is highly related with the development of several cancers including prostate cancer (Maksymchuk & Kashuba, 2019), and CYPs enzymes regulated by such factors have an important function in cancer formation.

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Enhanced CYPs expression extent causes to the generation of oxidative stress and an aggregation of induced metabolites that may reveal mutagenic and carcinogenic impacts in cells. As a consequence of oxidative stress, transcription factors are triggered causing regulation of the expression extent of some CYPs participating in the metabolism of endogenous chemicals like PUFAs, cholesterol, steroids, and vitamin D. The alteration in the metabolism of these chemicals is a main factor for the induction and development of cancer. In addition, modifications in the metabolism of endogenous chemicals result in the regulation of the activity of transcription factors and receptors which govern the expression of CYPs. Particularly, it was revealed that the androgen receptor could induce the AhR (Fujii-Kuriyama & Mimura, 2005), one of the crucial modulators of CYPs gene expression. Another research angle analyzes the incidence for cancer as the plausible metabolic stimulation of xenobiotics into metabolites that are carcinogenic agents for prostate cancer. It has been explored that cytochrome P450 enzymes metabolize several hazards and drugs into potential carcinogenic factors. Particularly, CYP1A1, CYP1B1, CYP2B6, CYP2E1, and CYP3A4 are involved in the metabolism of procarcinogens like N, N-dimethylamino benzene, benzo[α]pyrene, polychlorinated biphenyls, nitrosamines, vinyl chloride, furans, etc., inducing them to electrophilic metabolites which are able to integrate with DNA and produce mutations. Several drugs, implicated to treat diseases such as diabetes, hypercholesterolemia etc., also might lead to cell dysfunction. The wide varieties of such drugs are substrates and activators of CYPs (CYP2C8, CYP2D6, CYP3A5 and CYP3A7). Hence, the usage of such drugs causes either enhanced or reduced CYPs expression. Such methods regulate CYP-underlying metabolism in prostate tissues that undergo carcinogenesis. In addition, xenobiotics could lead to the modulation of the expression extents of particular CYPs causing the metabolism of

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2. Xenobiotic metabolism(s) in carcinogenesis

anticancer drugs. Such disorders would cause alterations in the therapeutic impact, up to the generation of chemoresistance. Anticancer drugs are also ligands for several P450s participating in the metabolism of xenobiotics and endogenous chemicals. It had been revealed that the conventional drugs for prostate cancer are ligands for cytochrome P450 enzymes (CYP3A4/5/7, CYP1B1, CYP2C8/9, CYP2E1, CYP2B6, etc). Various CYPs have essential functionalities in the stages of androgenesis, metabolism of vitamin D, PUFAs, and cholesterol. The treatment results highly depend on the expression extent of cytochrome P450 metabolizing anticancer regimens. It had been revealed that the inhibition of CYP3A4 expression caused a reduction in the abiraterone level and enhanced cell proliferation that highly decreased the impact of chemotherapy (Qin et al., 2018). The function of CYPs in stimulation of procarcinogens and metabolism of anticancer drugs had been explained in several studies (Wahlang et al., 2015). The individual differentiation in CYPs expression extents in cells that are governed by both genetic components and life circumstances could have a potential effect on all methods of cancer development. It had been exhibited that the polymorphism of highly clinically significant CYPs (CYP2D6, CYP1B1, and CYP1A2) causes an alteration in drug metabolism that could highly impact carcinogenesis and lead to the development of drug resistance (Maksymchuk & Kashuba, 2019). At the same period, such data could be highly applicable for the optimization of the treatment procedure and enhanced impact of anticancer drugs, employed for patients and belonging to distinct populations.

Modulation of xenobiotic-metabolizing enzymes by transcription factors The revelation of nonmembrane-integrated receptors for hormones and xenobiotics that

regulate gene expression developed knowledge of carcinogenesis and the events which govern such diseases. For instance, the seminal exploration of the glucocorticoid receptor and the estrogen receptor (ER) (Patterson et al., 2018) developed a basis for myriad experiments investigating the assumptions that endogenous ligands controlled cellular activity by mediating gene expression. Such an idea was readily extended into investigating how exogenous compounds may interact with endogenous receptors and perturb the normal physiological activities. In fact, this is one of the novel fundamental ideas of the advanced toxicology, where that structural resemblance between xenobiotics and natural compounds could lead to toxicity/cancer by obstructing typical homeostasis. Hence, as more soluble and cell surface receptors were recognized and described, the probability that compounds can develop or suppress cancer via receptormediated events became highly tenable. Intriguingly, one of the highly perceptive explorations in the area of receptor-mediated carcinogenesis was the recognition and explanation of the AhR (Amjad et al., 2015). The timing of such a discovery was highly associated with the modern developmental biology where “knockout” mice had been generated with the implication of homologous recombination in embryonic stem cells (Capecchi, 1989). The generation of knockout mice was useful in explaining how certain genes/proteins had been involved in toxicologic and carcinogenic impacts. For instance, the first Ahr-null mouse had been formed in 1995 and resulted in the first actual evidence that this soluble receptor regulated the toxicological impacts triggered by AHR agonists like tetrachloro-dibenzodioxin (Fernandez-Salguero et al., 1995; Patterson et al., 2018). This designed the platform for various studies by different laboratories investigating the function of soluble receptors in toxicity and cancer. For instance, it was envisaged for years that the peroxisome

Xenobiotics in Chemical Carcinogenesis

Formation of carcinogenic xenobiotics during food processing

proliferator-induced receptor-a (PPARa) regulated the toxicity and hepatocarcinogenic impacts stimulated by PPARa agonists, the outcomes that para-null mice had developed resistant to liver cancer stimulated by a PPARa agonist (Patterson et al., 2018) led to potential evidence that a receptor-mediated event was needed for such impacts. If PPARa agonists do not produce direct DNA damage, they are referred to as non-genotoxic carcinogens. The crucial mutations are possible consequences of enhanced oxidative stress which could develop mutations in proto-oncogenes and cancer suppressor genes. Several studies by other laboratories explain similar needs for other xenobiotic receptors like constitutive androstane receptor and pregnane X receptor in regulating the toxicologic/carcinogenic impacts of relative agonists (Xie et al., 2000; Yamamoto et al., 2004). In addition, highly complex models, such as knockout models and knock-in mouse models, humanize mice to elicit human homologs of certain genes that will provide further concepts about the major regulatory functionalities of soluble receptors in carcinogenesis and species variation triggered by xenobiotic compounds. One of the great instances of this is the explanation that mice regulating the human PPARa, but not the mouse PPARa, had developed resistance to hepatocarcinogenic impacts activated by PPARa agonists (Patterson et al., 2018; Yang et al., 2008). The event based this effect on the species variations in the PPARa-based modulation of Let-7C micro RNA that consequently controlled an oncogene MYC, which enhanced cell proliferation with mutant DNA (Shah et al., 2007). Therefore, the carcinogenic impact appearing in mice might not always be significant to humans. Moreover, several compounds which induce xenobiotic receptors are able to regulate their carcinogenic impact while also controlling the expression of genes participating in xenobiotic transport and phases I and II xenobiotic metabolism. However, there are

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various other molecular events that can be regulated by induction of soluble receptors. This is crucial because of the same time period the development had being constructed on the molecular events regulated by chemical carcinogens regulate bioactivation and detoxification, several other cellular events had also been explored that regulated critical signaling such as cell proliferation, cellular differentiation, apoptosis, and inflammation. Overall, these explorations helped to explain that xenobiotics could develop cancer by not only directly producing mutations in important genes, but also regulating the function of soluble receptors that subsequently control the expression of XMEs, and readily altering the normal cellular signaling mechanism which are fundamental to the consequences of cell division and/or cell death (Patterson et al., 2018).

Formation of carcinogenic xenobiotics during food processing However, the specific mechanism by which meat is associated with cancer is not well explored; various studies have hypothesized the thermal generation of several carcinogens while cooking like HCAs and PAHs, the usage of N nitroso compounds (NOCs) to cured meats, the endogenous NOC generation from heme iron and the production of lipid and protein oxidation products, have been considered for potential pathways based on such xenobiotic compounds (Nogacka et al., 2019). In this aspect, heme iron being associated with the formation of NOCs at the intestinal level, has led to the formation of aldehydes with cytotoxic and genotoxic impacts (Bastide et al., 2011). Moreover, meat processing has been studied with respect to the usage of nitrites, salt, and smoke and the implication of several levels of temperature based on the cooking process (Knuppel et al., 2020), all of which are associated with increasing

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incidences of colon cancer. From xenobiotics, HCAs have garnered the highest scientific data as cancer risk components in epidemiological and interventional studies and have been categorized by the IARC as major carcinogens. Presently, more than 25 HCAs have been recognized in daily food products (Viegas et al., 2012), produced from creatinine, creatine, hexoses, amino acids, and certain dipeptides that are usually found in the muscle of meats and fish (Chiavarini et al., 2017; Martı´n-Calero et al., 2010). HCAs can be categorized into two wide groups based on their molecular structures and metabolic mechanism: aminocarbolines (ACs), or pyrolytic amines, and aminoimidazoazarenes (AIAs), or thermal amines. ACs are produced through the pyrolysis of proteins at temperatures greater that 300 C, whereas AIAs are produced by using temperatures from 100 C to 300 C to dietary factors of sugars, amino acids, and creatinine (Khan et al., 2008). As the mutagenic potential of HCAs grows with temperature and with the browning degree of cooked food, cooking processes like frying, grilling, or roasting causes the generation of greater amounts of HCAs in comparison to boiling, steaming, or braising (Nogacka et al., 2019). From these studies, the results from the European Prospective Investigation into Cancer and Nutrition (EPIC) exhibited the presence of a higher differentiation in the consumption of such foodstuffs and in the cooking process over European countries. The Netherlands has been observed to be the population with the highest consumption of red meat cooked at high temperature i.e. average value of consumption of 39.4 and 59.7 g/day for women and men, respectively (Rohrmann et al., 2015). PAHs are produced in different kinds of foods, such as oils, grains and vegetables, after using heat treatment for cooking or processing. Several kinds of PAHs categorized by the IARC, benzo(a)pyrene (BaP) have been

identified as carcinogenic to humans (Moorthy et al., 2015). However, providing the omnipresence of PAHs in food as hazards, it is very difficult to analyze to what level the amount taken from food might lead to the formation of cancer. PAHs (Larsson et al., 1983) can be generated by pyrolysis of organic matter at elevated temperatures through direct connection of lipid droplets with a heat agent, by the smoke formed while cooking, or by the partial combustion of coal or wood in barbecues or grills (Alomirah et al., 2011; Flores-Balca´zar et al., 2015; Nogacka et al., 2019). The highest amounts of PAHs have been observed in cured foods and roasted meats (Nogacka et al., 2019). As with several other dietary ingredients, the effect of xenobiotics compounds on health associated with food processing underlies the dose of consumption and rate of exposure to the toxic elements. In this aspect, there has been focus by some authors that chronic exposure to hazards might steadily stimulate a lowgrade inflammatory situation in the host, partially regulated by the AhR, a cytosolic transcription component triggered by several hydrophobic compounds (Tamaki et al., 2004) and occur in various mammalian cells. With appreciable differentiation among countries, the dose of HCAs intake is usually associated with the cooking procedure, temperature, the meat, or fish itself and the nutritional constituents of the foodstuffs (Busquets et al., 2004; Joshi et al., 2015). However, such components are highly difficult to precisely analyze via dietary questionnaires for various causes. First, cooking procedures are highly inconsistent over time. Second, there are no standardized techniques presently available like photographs of scales, to evaluate the extent of browning in foods, hence it provides greater differentiation among studies. Third, the interactions between the several factors of the diet are highly difficult to analyze over long periods of time. Moreover, after the consumption of red meat, other carcinogenic agents related

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Conclusions

with various processed meats like NOCs, may be produced endogenously (Joshi et al., 2015) by the intestinal microbes and act as carcinogens (Trichopoulou et al., 2014).

Role of pesticides in breast cancer progression Breast cancer is the major reason of cancerassociated death in women throughout the world. Various studies have explained the association between cancer in humans and agricultural pesticide exposure. Outcomes suggest that exposure to organophosphorus pesticides like parathion and malathion happens due to occupational agents since they are highly implicated in insect studies. In another way, estrogens have been known to be helpful to the organism; although, epidemiological studies have noticed an enhanced breast cancer incidence in both humans and animals. Experimental female rat mammary gland cancer models have been exposed to parathion, malathion, eserine, an acetylcholinesterase inhibitor, and estrogen permitting the assessment of the indications of carcinogenicity as changes in cell proliferation, receptor expression, genomic volatility, and cell metabolism. Hence, pesticides enhanced proliferative ducts succeeded by ductal carcinoma and 17β-estradiol stimulated proliferative lobules followed by lobular carcinomas. The integration of both pesticides and either eserine- or estrogenactivated cancers with both kinds of structures succeeded by mammary gland cancers and metastasis to the lung and kidneys upon eight months of a 5-day treatment. Studies also exhibited that such pesticides and eserine decreased three to five times the acetylcholinesterase potential in the serum in comparison to controls while terminal end buds escalated in number, while being suppressed by atropine. Genomic instability had been assessed in these tissues (mp53, CYP1A2, c-myc, c-fos,

ERα, M2R), and pesticides enhanced protein expression which had been induced by estrogens but suppressed by atropine. Eserine also converted the epithelium of the rat mammary gland due to estrogen and escalated the number of terminal end buds upon treatment stimulating mammary carcinomas. Further, enzymatic degradation of these structures caused cells with enhanced DNA formation and stimulated enlacement independence. Hence, it has been altered in the epithelium of the mammary gland affecting the development of breast cancer. Further, such compounds and acetylcholine also exhibited the indication of carcinogenicity in vitro as cell proliferation, receptor expression (ERα, ErbB2, M2R), genomic instability (c-myc, mp53, ERα, M2R), and cell metabolism. An important cellular model has also been introduced on the basis of the implication of MCF-10 F, a non-carcinogenic cell line which has a novel clinically translatable experimental method which recognizes the mechanistic relationship between pesticides and estrogen as human carcinogenic components (Calaf, 2021).

Conclusions Recently, the study of xenobiotic metabolism in chemical carcinogenesis has widely interested researchers. This area has explored important horizons of cancer research like enzymology and gene transcription, mechanistic chemistry, mutagenesis. Xenobiotic-metabolizing enzymes have astounding value in explaining that P450s regulates the toxic and carcinogenic impacts of xenobiotic compounds. It has been revealed that P450s metabolize the various endogenous and exogenous xenobiotic compounds in organisms including the human body. CYPreliant metabolites play vital roles in mediating the cell cycle, proliferation, apoptosis, etc. Alteration in such events leads to cancer

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initiation, promotion, metastasis, and generation of severe modes of cancer. Also, it has been observed that inappropriate regulation of AhR activity due to xenobiotic chemicals leads to the development of cancer. All these factors associated with xenobiotics can act as a biomarker for cancer detection as well as oncotherapeutic events. The above explanations on various aspects of xenobiotic metabolism in carcinogenesis are highly facilitative for further studies in the area of chemical carcinogenesis.

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Murray, G. I., Taylor, V. E., McKay, J. A., Weaver, R. J., Ewen, S. W. B., Melvin, W. T., & Burke, M. D. (1995). The immunohistochemical localization of drugmetabolizing enzymes in prostate cancer. The Journal of Pathology, 177(2), 147 152. Available from https://doi. org/10.1002/path.1711770208. Nakatsuru, Y., Wakabayashi, K., Fujii-Kuriyama, Y., Ishikawa, T., Kusama, K., & Ide, F. (2004). Dibenzo[a,l] pyrene-induced genotoxic and carcinogenic responses are dramatically suppressed in aryl hydrocarbon receptor-deficient mice. International Journal of Cancer, 112(2), 179 183. Available from https://doi.org/ 10.1002/ijc.20365. Nebert, D. W., & Dalton, T. P. (2006). The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nature Reviews. Cancer, 947 960. Available from https://doi.org/ 10.1038/nrc2015. Nelson, D. R., Koymans, L., Kamataki, T., Stegeman, J. J., Feyereisen, R., Waxman, D. J., Waterman, M. R., Gotoh, O., Coon, M. J., Estabrook, R. W., Gunsalus, I. C., & Nebert, D. W. (1996). P450 superfamily: Update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics, 1 42. Available from https://doi.org/10.1097/00008571-199602000-00002. Nogacka, A. M., Go´mez-Martı´n, M., Sua´rez, A., Gonza´lezBernardo, O., De los Reyes-Gavila´n, C. G., & Gonza´lez, S. (2019). Xenobiotics formed during food processing: Their Relation with the Intestinal Microbiota and Colorectal Cancer. International Journal of Molecular Sciences, 20(8), 2051. Available from https://doi.org/ 10.3390/ijms20082051. Obligacion, R., Murray, M., & Ramzan, I. (2006). Drugmetabolizing enzymes and transporters: Expression in the human prostate and roles in prostate drug disposition. Journal of Andrology, 138 150. Available from https://doi.org/10.2164/jandrol.05113. Park, J. Y. K., Shigenaga, M. K., & Ames, B. N. (1996). Induction of cytochrome P4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin or indolo(3,2-b)carbazole is associated with oxidative DNA damage. Proceedings of the National Academy of Sciences of the United States of America, 93(6), 2322 2327. Available from https://doi.org/10.1073/ pnas.93.6.2322. Patterson, A. D., Gonzalez, F. J., Perdew, G. H., & Peters, J. M. (2018). Molecular regulation of carcinogenesis: Friend and foe. Toxicological Sciences, 277 283. Available from https://doi.org/10.1093/toxsci/kfy185. Qin, S., Liu, D., Kohli, M., Wang, L., Vedell, P. T., Hillman, D. W., Niu, N., Yu, J., Weinshilboum, R. M., & Wang, L. (2018). TSPYL family regulates CYP17A1 and CYP3A4 expression: Potential mechanism contributing to abiraterone response in metastatic castration-resistant prostate

cancer. Clinical Pharmacology and Therapeutics, 104(1), 201 210. Available from https://doi.org/10.1002/cpt.907. Rodriguez-Antona, C., & Ingelman-Sundberg, M. (2006). Cytochrome P450 pharmacogenetics and cancer. Oncogene, 1679 1691. Available from https://doi.org/ 10.1038/sj.onc.1209377. Rohrmann, S., Nimptsch, K., Sinha, R., Willett, W. C., Giovannucci, E. L., Platz, E. A., & Wu, K. (2015). Intake of meat mutagens and risk of prostate cancer in a cohort of U.S. Health professionals. Cancer Epidemiology Biomarkers and Prevention, 24(10), 1557 1563. Available from https://doi.org/10.1158/1055-9965.EPI-15-0068-T. Roos, P. H., & Bolt, H. M. (2005). Cytochrome P450 interactions in human cancers: New aspects considering CYP1B1. Expert Opinion on Drug Metabolism and Toxicology, 187 202. Available from https://doi.org/ 10.1517/17425255.1.2.187. Ruwali, M., & Shukla, R. (2021). Interactions of environmental risk factors and genetic variations: Association with susceptibility to cancer. Environmental Microbiology and Biotechnology, 211 234. Available from https://doi. org/10.1007/978-981-15-7493-1_10. Sajadimajd, S., & Khazaei, M. (2017). Oxidative stress and cancer: The role of Nrf2. Current Cancer Drug Targets, 18 (6), 538 557. Available from https://doi.org/10.2174/ 1568009617666171002144228. Shah, Y. M., Morimura, K., Yang, Q., Tanabe, T., Takagi, M., & Gonzalez, F. J. (2007). Peroxisome proliferatoractivated receptor α regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation. Molecular and Cellular Biology, 27(12), 4238 4247. Available from https://doi.org/10.1128/mcb.00317-07. Shimizu, Y., Nakatsuru, Y., Ichinose, M., Takahashi, Y., Kume, H., Mimura, J., Fujii-Kuriyama, Y., & Ishikawa, T. (2000). Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proceedings of the National Academy of Sciences of the United States of America, 97(2), 779 782. Available from https://doi. org/10.1073/pnas.97.2.779. Singh, M. S., & Michael, M. (2009). Role of xenobiotic metabolic enzymes in cancer epidemiology. Methods in Molecular Biology, 243 264. Available from https://doi. org/10.1007/978-1-60327-492-0_10. Sterling, K. M., & Cutroneo, K. R. (2004). Constitutive and inducible expression of cytochromes P4501A (CYP1A1 and CYP1A2) in normal prostate and prostate cancer cells. Journal of Cellular Biochemistry, 91(2), 423 429. Available from https://doi.org/10.1002/jcb.10753. Tamaki, A., Hayashi, H., Nakajima, H., Takii, T., Katagiri, D., Miyazawa, K., Hirose, K., & Onozaki, K. (2004). Polycyclic aromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibroblast-like synoviocyte line via aryl hydrocarbon receptor. Biological and

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C H A P T E R

3 Recalcitrant toxic xenobiotics and their routes of exposure to humans Introduction

salt compounds, preservatives, etc.), cosmetics and personal care products (makeup, hair dyes, soaps, perfumes), and household products (chlorine bleach, bug sprays, cleaners, etc.) are increasing in society. In addition, the beneficial role of xenobiotics as significant components of advanced technologies enables the further development of human civilization. So, looking to the progression of human civilization, xenobiotic compounds cannot be divided into straightforward groups such as good versus bad ones, which makes it increasingly difficult to eliminate the latter from the living environment (Guengerich, 2003). The primary anxieties regarding xenobiotics are due to their toxicity to living organisms and high potential to produce adverse effects on the environment on a global level. Acid rains and increasing levels of greenhouse gases enhance global warming, whereas sea pollution or soil contamination by agricultural chemicals expedite the embodiment of heavy metals into terribly toxic organic compounds, and heavy metropolitan traffic and local heating increase the level of particulate matter having polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), dioxins, etc. The classification of toxicity is defined as the grouping of compounds into common categories based on their

Xenobiotic compounds are chemicals that are considered as foreign to the biosphere and might be available to microorganisms depending on their fate in water and soil (Karn et al., 2009). There are several types of structural features of xenobiotic compounds, such as polyaromatic hydrocarbons, cyclic biphenyls, nitroaromatic compounds, aliphatic and aromatic halogenated compounds, triazines, azo dyes, organic sulfonic acid, etc. (Godheja et al., 2016). Xenobiotics are largely produced by anthropogenic activities and have been made publicly aware due to their ability to interact with living organisms. Some organisms produce xenobiotic compounds as a part of their defense system, such as mycotoxins and bacterial and herbal toxins, even though xenobiotics become hazardous after entering the food chain. Xenobiotic compounds are present everywhere in the environment, hence human exposure to xenobiotics is unavoidable. Table 3.1 shows potential xenobiotics and their sources of origin. Exposure to some xenobiotics are necessary due to their beneficial impacts to human health like drugs, antibiotics, dietary supplements, etc. Daily exposure to xenobiotics, like food ingredients (dyes, stabilizers, emulsifiers,

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00015-7

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© 2022 Elsevier Inc. All rights reserved.

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3. Recalcitrant toxic xenobiotics and their routes of exposure to humans

TABLE 3.1 Sources of some xenobiotic compounds. Source

Xenobiotic compounds

Skin care products, hair conditioners, shampoos, food additives, moisturizing oils

Hydrocarbons

Oils and foodstuffs, skin cleaners, fragrance, food flavoring agents

Alcohols/ethers

Disinfectants; flavoring substance in foodstuffs, UV Phenols stabilizer and antioxidant for hydrocarbon-based products Foodstuffs and essential oils, Fragrance

Aldehydes and ketones

Soap, emulsifier for facial creams and lotions, shaving cream formulations, mold cheese

Carboxylic acids

Fragrances, household dust, PVC (Polyvinyl chloride) floor wipes, food additive, emollient

Carboxylic acid esters

Cough syrup, dishwashing agents, body care, baby care, toiletries, artificial and natural jasmine oil, coffee, tobacco

Nitrogenous organics

Emulsifier

Deceth-3, Oleth-30, Lauric acid, Glycol distearate Ceteareth-25, Glamorous

Fragrances

Tonalide, Galaxolide, HCA, Hexyl cinnamic, aldehyde, flavors AHTN, HHCB, Styrene, Benzene-1,3-diol, p-Cresol

Plasticizer

Bisphenol-A, Butylbenzyl phthalate, Di-(2-ethylhexyl) phthalate, Dibutyl phthalate, Diethyl phthalate, Di-isobutyl phthalate, Dimethyl phthalate

Preservatives

Methylparaben, Ethylparaben, Propylparaben, Butylparaben, Bronopol, Bronidox, 5-Chloro-2-methyl-4 isothiazolin-3-one, Imidazolidinyl urea, Triclosan, Quaternium

EDCs

Bisphenol-A (BPA), nonylphenol (NP), and triclosan (TCS)

Pharmaceutical products

Acetaminophen, Salicylic acid, Hormones, Antibiotics, Lipid regulators, Nonsteroidal anti-inflammatory drugs, Betablockers, Antidepressants, Anticonvulsants, Antineoplastics, Diagnostic Contrast Media

Dyes and pigments

3,30-Dichlorobenzidine, 4,40 Methylenebis-(2chlorobenzenamine), o-Aminoazotoluene Benzidine, o-Anisidine, CI77891 (TiO2), CI77491 (iron oxides), Mica

EDCs, Endocrine disrupting chemicals.

toxic effects. These categories are mainly allergens, neurotoxins, carcinogens, mutagens, teratogens, immunotoxins, etc. Xenobiotic substances can affect the environment directly as parent compounds or indirectly as intermediates or products of their metabolic process. Oxidative stress is an important secondary

product of the metabolism of xenobiotics. The production of reactive oxygen species (ROS) by oxidative stress attacks DNA and proteins or enhances inflammation. In some conditions, an inactive conjugated metabolite is activated by enzymatic actions and leads to a tissue-specific toxic effect such as tumor promotion. Particular

Xenobiotics in Chemical Carcinogenesis

Introduction

xenobiotic compounds entering the human body downregulate the essential cellular- and organ-signaling mechanisms because they imitate the physiological substrates. Xenoestrogens or endocrine disruptors like phthalates or PCBs (DDT, dioxin) damage reproductive function, alter wildlife, and can cause sterility with a decrease in sperm count in men. Another important issue is the carcinogenic impact of xenoestrogens. The assessment of environmental exposure to xenobiotics is acomplished on the basis of evidences and their combined exposure to different xenobiotics are emphasized rather than a separate or consecutive exposure to an individual xenobiotic. Chemicals following the same mechanisms can produce additive effects. However, the interaction between chemicals might result in an inhibition (antagonism) or synergism, a highly noticeable impact than could be anticipated by addition. The predictive effects of combined xenobiotic compounds by animal experiments and computer modeling is one of the most rigorous exercises of advanced toxicology (Gillam, 2005). Xenobiotics can produce adverse effects on human health by altering or interacting with different cellular signaling pathways involved in the direct growth, development, and normal physiological functions (Godheja et al., 2016). Such compounds are highly toxic in the environment and may alter the survival of lower and higher eukaryotes. Such compounds are ubiquitous and exist in the environment for several years leading to bioaccumulation or biomagnification (Godheja et al., 2016). They also find ways into the food chains and the contents of such compounds was observed to be higher in organisms that did not come into direct contact with xenobiotics. Presently, environmental pollution is a prominent and challenging issue of modern human life (Ali et al., 2019). Expeditious industrialization and urbanization generating heavy metals leads to environmental contamination and their frequencies of mobilization and transport in the

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environment have significantly increased since the 1940s (Merian, 1984). The natural sources of such contaminations in the environment are weathering of metal-containing rocks and volcanic eruptions, and primary anthropogenic sources include industrial emissions, mining, smelting, and agricultural activities for example, use of pesticides and phosphate fertilizers. The ignition of fossil fuels also attributes to the production of heavy metals such as cadmium to the environment (Wieczorek-Dabrowska et al., 2013). Heavy metals are present in the environment, pollute food chains, and produce various health issues due to their toxicity. Mainly, the chronic exposure to heavy metals in the environment is the actual threat to living organisms (Wieczorek-Dabrowska et al., 2013). The concentration of metals higher than threshold levels influence the microbial balances in the soils and may deteriorate their fertility (Barbieri, 2016). The accumulation of toxic heavy metals in the biota of the riverine ecosystems might have negative impacts on animals and humans (Malik & Maurya, 2014). The greater concentration of heavy metals in biota could have adverse effects on the ecological health of aquatic animal species and might attribute to a decrease in their populations. Usually, heavy metals are highly effective neurotoxins in fish species. The reactions of heavy metals with chemical stimuli in fish could alter the communication of fish with their environment (Baatrup, 1991). The impact of heavy metals has been observed with fish deformities in both natural populations and in the laboratory. Primarily, such deformities have adverse effects on fish populations in their survival, growth rates, welfare, and external images. Such impairment in fish could act as great biomarkers of environmental heavy metal pollution (Sfakianakis et al., 2015). The metals of natural or anthropogenic origin are almost present everywhere in the aquatic environment, and hence unraveling their behavior and interaction with aquatic organisms, especially

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3. Recalcitrant toxic xenobiotics and their routes of exposure to humans

fish, a main source of protein for human consumption, is of potential socioeconomic significance (Ali et al., 2019). A few organic pesticides are highly widespread POPs (persistent organic pollutants) implicated in agriculture at the global level. Other POPs like volatilized industrial pollutants and pollutants from fuel combustion also contaminate wide areas due to dissemination by wind and rainfall. Non-biodegradable compounds remain in the environment and the soil acts as a wide sink for them. Such pollutants are capable of transfer to the environment and persist even in low concentrations over a long period, hence, through bioaccumulation, they produce toxic effects on organisms (Langenbach, 2013). Since xenobiotics not adsorbed by the soil can become mobile, molecules might be scattered by water or air via the biosphere that would pollute large geographical areas and affect the biodiversity of the flora and fauna. These dispersions of molecules become recalcitrant in the environment which makes them remediation inefficient. The influence of pesticides over wide areas can only be possible if their molecules undergo natural biodegradation. Mainly, man-made remediation can be employed to accidents in specific areas that are not expedient over large areas due to the high costs. The only efficient policy for remediation of recalcitrant compounds is by restricting their use or banning them altogether (Langenbach, 2013). Therefore, the dispersion of recalcitrated molecules is playing a critical role in the development of various types of cancers. This review will focus on recalcitrant toxic xenobiotic molecules and their transfer through different routes to humans.

Recalcitrant xenobiotic molecules The word “recalcitrant” is defined as difficult to manage or operate and not easy to control. Presently, it has been modified that recalcitrant means difficult, but not impossible, to degrade.

Generally, recalcitrant molecules resist biodegradation for a complete range of reasons, and some are more highly resistant than others. Several recalcitrant molecules are xenobiotic in nature, but it does not mean that all xenobiotics are recalcitrant. Even the degradation of several natural compounds and materials like lignin are challenging (Knapp & Bromley-Challoner, 2003). Prior to industrialization, the natural activities on the biosphere of earth were consistent due to the more or less balanced biosynthesis and biodegradation reactions. During periods of evolution, a large number of different chemical compounds are biosynthesized in nature and parallel microbes are exposed to these chemicals. After millions of years of exposure, microbes have developed the potential and mechanism to invade these chemicals. Of several varieties of chemical compounds made by chemists, various have identical structural and bonding properties to that of natural compounds, and can be biodegraded by microbes (Bharadwaj, 2018). Recalcitrant xenobiotic compounds have the following properties: • These chemicals are not identified by the microbes as a substrate and cannot be degraded by them. • For transportation of such molecules into the microbial cell, microbes do not have permease enzyme. • These are very complicated compounds. Hence, it is very difficult to enter inside the microbial cell. • These xenobiotic compounds are highly stable in nature and insoluble in water. So, such xenobiotic compounds become highly poisonous in nature. Types of recalcitrant xenobiotic compounds (Saxena et al., 2012).

Halocarbons Such compounds are composed of different numbers of halogens for example, CI, Br, F, or

Xenobiotics in Chemical Carcinogenesis

Routes of xenobiotic exposure

I, atoms in the place of H atoms. These compounds are implicated in several applications as solvents such as chloroform, CHCl3, as propellants in spray cans of cosmetics, paints, etc. In addition, they are also used in condenser units of cooling systems for example, freons, CCI3F, CCI2F2, CCIF3, CF4, and as insecticides (DDT, BHC, lindane, etc.) and herbicides (dalapon, 2, 4-D, 2, 4, 5-T, etc.). Chloroform and freons are volatile and dispersed into the atmosphere where they deteriorate the protective ozone (O3) layer causing increased UV radiation.

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Oil Mixtures Due to its insolubility in water, oil becomes recalcitrant, and its components serve as toxic xenobiotic compounds. However, the naturally produced oils have several such components that are easily biodegradable. The biodegradation process is usually employed to manage small oil seepage whereas large spills creating pollution becomes serious to human life. Hence, these compounds are usually recalcitrant in nature.

Other Xenobiotic Compounds Polychlorinated Biphenyls PCB compounds are covalently attached with two benzene rings containing halogens in place of hydrogen. These are widely employed as plasticizers, insulator coolants in transformers, and heat exchange liquids.

Several numbers of pesticides contain aliphatic, cyclic ring structures with replacements of nitro, sulfonate, methoxy-, amino, and carbamoyl groups in addition to halogenated groups. Such alterations in xenobiotic compounds make them recalcitrant.

Routes of xenobiotic exposure Synthetic Polymers Synthetic polymers like polyethylene, polystyrene, polyvinyl chloride, and nylons tare used as garments, wrapping materials, etc. They are recalcitrant due to their water insolubility and large molecular size.

There are mainly four routes through which a xenobiotic compound can enter the human body: inhalation, skin/eye absorption, ingestion, and injection (UNL Environmental Health & Safety, 2002).

Inhalation Alkylbenzyl Sulfonates These compounds are surface-active detergents that are formed to be superior in comparison to soaps. The presence of a sulfonate (
SO3
) group at one end resists microbial degradation, whereas the other end becomes recalcitrant if it is branched. This explains that the degree of resistance increases with increasing branching of alkylbenzyl sulfonates. The non-branched alkyl ends of alkylbenzyl sulfonates are easily biodegraded by beta-oxidation of their alkyl ends.

Inhalation is the main route for entry of those chemicals in the form of vapors, gases, mists, or particulates, etc. Once these chemicals are inhaled, they either give off or accumulate in the respiratory tract. The deposited chemical can damage the respiratory tract through direct contact with tissue, or the chemical might disperse into the blood via the lung-blood interface. After direct contact of xenobiotic compounds with tissue in the upper respiratory tract or lungs, these chemicals might produce adverse health impacts ranging from simple irritation to serious tissue

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3. Recalcitrant toxic xenobiotics and their routes of exposure to humans

damage. The compounds absorbed into the blood are circulated and transported to different organs which have an affinity for those specific xenobiotic chemicals. After that, the health effects can be observed in the particular organs sensitive to the toxic xenobiotic compounds.

Skin (or eye) absorption Skin (dermal) contact of xenobiotic compounds can produce adverse effects that are innocuous like redness or moderate dermatitis, while more serious impacts can damage skin tissue or other harmful conditions. Several toxic molecules also cross the skin barrier and can be absorbed into the blood system, which can produce systemic damage to internal organs. The eyes are highly sensitive to chemicals and hence, short exposure can generate severe negative impact to the eyes. The chemicals can also be absorbed through the eyes and moved to other parts of the body producing harmful impacts.

Ingestion Compounds that unintentionally enter the mouth and are absorbed do not usually damage the gastrointestinal tract itself until they are irritating or corrosive. The insoluble chemicals in the fluids of the gastrointestinal tract (stomach, small, and large intestines) are usually eliminated through the metabolic process. Other types of chemicals are soluble and absorbed in the lining of the gastrointestinal tract. After that, the absorbed compounds are circulated by the blood to internal organs where they can cause damage to the tissue.

After the compound enters the body, three other possible processes may occur: metabolism, storage, or excretion. Several compounds are metabolized or transformed through chemical reactions in the body. However, some chemicals are dispersed and stored in particular organs. Storage might decrease metabolism and so, enhance the concentration of the compounds in the body. Several excretory processes like exhaled breath, perspiration, urine, feces, or detoxification, liberate the body, over a period of time, of the chemical exposure. However, some chemical elimination might be a matter of days or months; for others, the frequency of elimination is too slow and they might exist in the body for a lifetime and produce deleterious impacts.

Hazards from xenobiotic molecules The effect of xenobiotic molecules is highly poisonous in nature. and their harmful impact is observed on lower eukaryotes to higher eukaryotes including human beings. The exposure of hazardous xenobiotic compounds causes specific skin diseases and prolonged exposure leads to cancer development. As hazardous xenobiotics molecules have recalcitrant characteristics and are not biodegradable, they persist for a long time in the environment and result in bioaccumulation or biomagnification. Through bioaccumulation or biomagnification, xenobiotic molecules move into the food chain and their concentration increases with increased trophic levels in that ecosystem (Bharadwaj, 2018).

Xenobiotics in carcinogenesis Injection Chemicals move into the body when skin is penetrated or punctured by contaminated materials. An adverse impact can be produced as the chemical is transported in the blood and accumulated in the target organs.

Several xenobiotic compounds stimulate carcinogenesis or cause genotoxicity by interactions with genetic factors. A multitude of procarcinogenic molecules undergo metabolic transformation to become ultimate carcinogens. The degree of carcinogenic generation is dependent on the ratio

Xenobiotics in Chemical Carcinogenesis

Removal of xenobiotics molecules

between activation and detoxification potentials. Hence understanding the interindividual variations in xenobiotic metabolizing enzymes (XMEs) have drawn more attention toward the molecular basis of diseases developed by the interaction of the genetic factors with environment. Now, researchers of molecular epidemiology appraise the prognostic value of the reported associations between the genetic variants in the genes encoding XMEs and several diseases including cancer. However, the concept of the association between the metabolic potential altered by the genetic modification in XMEs and disease developed by the metabolically activated procarcinogens was reasonable, the present meta-analyses and genomewide scans (GWAS) have revealed that the assignment would be difficult. Due to problems in recruiting the subjects, studies evaluating prognostic factors were mainly conducted on small numbers of patients. In addition, all types of cancer have specific indications for diseases with distinct etiologies, so selecting patients with different diagnoses is questionable. Sometimes, the recognition of single chemicals and levels of exposure in the studied patients is highly complicated by the long latency period from exposure to initiation in carcinogenetic activities (usually decades). Eventually, the interplay between different categories of lowpenetrance genes, like XMEs, most apparently combine the impact of associations. The main aim of molecular epidemiology is to anticipate cancer susceptibility based on interindividual variability and protect interacting exposures. Therefore, the individualized therapy of a cancer patient tailored to the XMEs overexpressed in tumor cells will be available in the future (Gillam, 2005).

Removal of xenobiotics molecules Unfortunately, xenobiotics are being largely used throughout modern society. For betterment of life, several industries manufacture various chemical compounds but are harmful and toxic for the organisms, such as the use of plastics,

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pesticides, paints, textiles and pharmaceuticals. These could not be eliminated from our daily needs, but the time has come to reduce these problematic materials. One of the most potentially useful ways to overcome of such problems is the application of microbes that can degrade these toxic compounds from the environment. Because microbes can easily grow and divide in laboratory, they may be efficient devices for the degradation of toxic xenobiotic compounds. The microbes secrete different types of enzymes that are capable to degrade such chemical compounds into harmless end products. Several types of microbes are used to remediate the various kinds of waste but unluckily, the man-made chemical compounds are not degraded by the microbes because they do not efficiently break specific chemical bonds present in xenobiotic compounds (Agrawal & Shahi, 2015). Advanced fields of the science like genetic engineering make it possible to create novel microbes that can degrade artificial synthesized xenobiotic compounds. Among such microorganisms, the Pseudomonas genus is highly implicated for degradation of such xenobiotic molecules. These bacteria contain extra chromosomal DNA (TOL plasmid) that play major roles in the degradation of toluene and xylene (Varsha et al., 2011). In addition, the combined efforts of human and microbial activities are also used to degrade such xenobiotic compounds. In this approach, recalcitrant chemicals are first split into smaller entities and then processed to microbial degradation. For example, accidental oil spilling is very harmful to life especially aquatic organisms. The combined efforts of humans and microbes have improved the survival of aquatic organisms under moderate leakages of oils; however, the area of an oil spill can be extensive, and the frequency of oil degradation by microorganisms becomes slow due to the high toxicity of oil. At present, a chemical is employed in solving such problems (Varsha et al., 2011), that is, chemical name SOT II (solid oil treatment) is an inorganic solid absorbent that is chemically inactive and

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3. Recalcitrant toxic xenobiotics and their routes of exposure to humans

spread over the oil spill area. Since SOT II is a strong absorbent, it compacts in small particles with oil and sinks to the basement of the sea. The characteristics of strong absorbent SOT II particles do not allow them to leave the oil spill. By this approach, the superficial layer of oil is separated from the water and the living organism survives when they are in direct contact with oxygen and sunlight. The compact particles of SOT II with oil move to the bottom of sea and are available as food for oil-degrading organisms, such as bacteria, algae, fungi, and protozoa etc. At the basement of the sea, this process takes place immediately and the oil degrading organisms degrade the oil within a week by producing the end products: water and CO2 (Janssen et al., 2005). This technique exhibits 99% success in the elimination of oil from the sea and ecosystem. It is know that xenobiotic compounds contain toxins and hence, the detoxification is a potential remedy to negate such toxins. During the detoxification process, the negative effect of such toxins is overcome by planning the detox diet containing 40% solids and 60% liquids. By considering the properties of a detox diet, its main aim is to eliminate such toxins from xenobiotic compounds. Solid food has some specific phytochemicals such as: indoles, flavonoids, and bromelain. Papain, a compound present in papaya, is a colon cleaner and enhances to immune system. The intake of raw food like sprouts, dried fruits, nuts, milk, etc. containing antioxidants also play critical roles in detoxification and increase the immune system of the human body (Janssen et al., 2005).

Risk assessment for exposure of humans to toxic compounds The term ‘risk’ has several meanings and explanations, although it has been considered as ‘the incident or possibility of a person being harmed or experiencing a negative health impact when exposed to a hazardous

compound. At this stage, a process known as risk assessment (RA) has been developed to decrease and/or eliminate such risks. It identifies hazardous molecules that anticipate the probability of risk to individuals or populations related with those hazard compounds (Park & Choi, 2009). Therefore, the risk could be explained by the following equation (Pedrete et al., 2016): Risk 5 Hazard 3 Exposure 3 Susceptibility According to the above equation, absence of risk (risk 5 0) means that all factors are equal to zero, but this state is impossible to achieve (Manno et al., 2010). Among the three factors of the equation, the last one, susceptibility, is very tough to appraise and hence it is generally discarded. For a RA process, awareness of the exposure assessment and toxicological characteristics of the compounds is necessary especially in the case of hazardous compounds. Exposure assessment needs the knowledge of pathways and patterns (e.g., air, water, food, soil, and workstation), rate, and periods of exposure to the hazard compounds, and assessment of any possible adverse impact on a person. This assessment is accomplished on the basis of cause-effect and doseresponse data. Even though workers or the population, in general, are exposed to a single compound randomly, they are commonly exposed to intricate mixtures that might present additive, synergistic, or antagonistic actions, enhancing the complexity of the risk assessment as well (DeBord et al., 2015). Risk identification of exposure to a xenobiotic compound involves hazard characterization, dose-response investigation, and exposure assessment. This step leads to qualitative and/or quantitative explanation under certain exposure circumstances. Therefore, it is necessary to establish risk management and risk communication procedures for developing a scientific concept to support decision making agreement in risk management. Such procedures aid in determining the

Xenobiotics in Chemical Carcinogenesis

Exposure to food carcinogens

removal or controlling exposure to a certain chemical compound (DeBord et al., 2015). To understand any structural and functional modification in an organism, various types of biomarkers have been synthesized, such as those of exposure, internal dose and biological impact, and that of susceptibility. Determining biomarkers against xenobiotic compounds can aid in delineating the continuity of procedures occurring from exposure to response time. These particular biomarkers can describe qualitative and quantitative indices of the condition of persons at several stages of the toxicological events, from exposure to disease, mainly in diseases with a long latency period such as tumorigenesis (Pedrete et al., 2016). The discovery of biomarkers from a new era’s advance technologies might result from the implication of “-omics” technologies such as genomics, proteomics, or metabolomics, and such technologies are effectively changing our understanding of medicine and biology. The authentic model-that of a continuum of molecular/genetic modification causing cancercould be analyzed using biomarkers and remains fundamentally conclusive. The various research in molecular epidemiology over the past 20 years has adopted this common model and major findings of key research are supportive (Vogelstein & Kinzler, 2004). The evidence encouraging the paradigm of cancer as a continuum with measurable molecular/genetic procedure have: (1) data of various researches establishing a correlation between external assessment of exposure and internal analysis of biomarkers of biologically active dose or initial biological response/effect for example, carcinogen-DNA or carcinogen hemoglobin adducts, in relation to exposure to PAHs, acrylamide, styrene, or 1,3-butadiene (2) studies revealing relationships between DNA or protein adduct contents and environmental exposures to carcinogens through smoking, the workplace, or the ambient air, with potential interindividual differentiation in adduct contents; (3) studies explaining the capability of specific

45

carcinogenic DNA adducts and chromosomal aberrations to assess cancer; and (4) research describing the function of particular genetic variants such as single nucleotide polymorphisms (SNPs) in modulating the risk of cancer, especially in persons/populations exposed to carcinogens (Vineis & Perera, 2007).

Exposure to food carcinogens The IARC monograph has comprised the toxic impact of xenobiotic compounds on human health that have been mentioned in Table 3.2. It has been analyzed that diet plays a major role by contributing nearly one-third of the cancer load imbalance in nutrition and enhancing the susceptibility to oncogenic impacts. The intake of food consumption with high amounts of fat, calories, and processed meat and less fruits and vegetables is related with the prevalence of various kinds of cancer such as colon, prostate, endometrium, and breast cancer (Kirsi & Kirsi, 2012). One of the main anxieties of the health risks from food is poisoning by toxic chemical, even carcinogenic components like mycotoxins, pesticides, and organochlorines or nitrites that could be converted into carcinogenic nitrosoamine (Miller, 2008). Among them, the most important mycotoxins are aflatoxins. Aspergillus flavus fungi could produce hepatotoxic chemicals and infect nuts, corn, and grain (Richard, 2007). Moreover, other mycotoxin compounds like fumonisin B, ochratoxin A and deoxynivalenol are poisonous to food materials (Bullerman & Bianchini, 2007). Nitrates are extensively used in farming but not intrinsically carcinogenic; however it could be endogenously transformed into nitrites in the stomach via digestive bacterial microflora that could be further converted into N-nitroso compounds (Tricker, 1997). In addition, some foodstuffs like Asian salted fish, have such nitroso compounds. Nitroso compounds like nitroso dimethylamine (NDMA), are very highly mutagenic components. In human beings, it has been

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3. Recalcitrant toxic xenobiotics and their routes of exposure to humans

TABLE 3.2 Carcinogenic agents classified by the IARC (International Agency for Research on Cancer)(Saxena et al., 2012) monographs. Classification Impact on humans

Name of some carcinogenic agents

Group 1

Carcinogenic to humans

Alcoholic beverages, Areca nut, Betel quid without tobacco, Opium consumption, Processed meat, Salted fish, Soot (as found in occupational exposure of chimney sweeps), Tobacco smoke, Asbestos, Afatoxins, Aristolochic acid, Sulfur mustard, Cyclosporine, Lindane, Ethanol in alcoholic beverages, Shale oils, Vinyl chloride

Group 2A

Probably carcinogenic to humans

Biomass fuel (primarily wood), indoor emissions from household combustion, Nitrate or nitrite (ingested) under conditions that result in endogenous nitrosation, Non-arsenical insecticides, Red meat, Glyphosate, DDT (4,40 -dichlorodiphenyltrichloroethane), Nitrogen mustard, Chloramphenicol

Group 2B

Possibly carcinogenic to humans

Aloe vera, whole leaf extract, Chlorophenoxy herbicides, Di(2-ethylhexyl) phthalate, Hexachlorobenzene, Catechol, Nitrogen mustard N-oxide, Aramite, Metronidazole, Magenta, Uracil mustard, Chloroform, Coconut oil diethanolamine condensate, Trypan blue, Zalcitabine, Heptachlor

Group 3

Not classifiable as to its carcinogenicity to humans

Coal dust, Coffee, Hair coloring products, Profavine salts, Tea, Paracetamol, Quercetin, Anthracene, Hydroxyurea, Rifampicin, Vincristine sulfate, Allyl isovalerate, Reserpine, Actinomycin D, Allyl isothiocyanate, Cholesterol, Aciclovir, Isopropyl alcohol, Ampicillin, Methylene blue, Hydrogen peroxide, Crude oil, Saccharin and its salts, Coumarin

suspected, but must still be clearly explained, that the intake of nitrates enhances the risk for gastric and nasopharyngeal cancers (Tricker, 1997). In addition, it has also been known that more drinking of alcoholic beverages causes various types of cancer especially in the mouth, larynx, pharynx and esophagus (Longnecker, 1995). Moreover, human beings could be exposed to Bisphenol A, a xenoestrogen implicated in plastic food containers. The carcinogenic impact of Bisphenol A has been reported in animal studies, stimulating breast (Durando et al., 2006) and prostate cancer (Ho et al., 2006). Moreover, some food carcinogens are synthesized during food processing such as by heating or frying, for example, acrylamide, PAHs like benzo(a)pyrene and heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo [45-b] pyridine and 2-amino-3-methylimidazo [4,5-f] quinoline (Miller & Miller, 1975). It has been reported that

acrylamide is neurotoxic, mutagenic, and oncogenic in animals and stimulates tumors in various sites (Klaunig, 2008). In spite of the neurotoxic impact of acrylamide, epidemiological studies on acrylamide have also suggested even less of an exposure response relationship in carcinogenic impact in human beings (Exon, 2006; Klaunig, 2008). Recently, a weak correlation between acrylamide and endometrial, ovarian, and renal cell cancers has been observed after the results of cohort studies (Hogervorst et al., 2008). A positive relationship between acrylamide-hemoglobin adducts and breast cancer after alteration for smoking behavior (Olesen et al., 2008) has also been revealted. Acrylamide could be metabolized to a more genotoxic compound, glycidamide (Klaunig, 2008). Human exposure to acrylamide occurs usually through food, where it is synthesized when heating food rich in carbohydrates like potato products to over 180 C (Wirfa¨lt et al., 2008).

Xenobiotics in Chemical Carcinogenesis

Assessment of exposure to food carcinogens

Mainly, smokers are more highly exposed to acrylamide than non-smokers (Lovreglio et al., 2011), and the carcinogenic impact from smoking is even higher than that from food (Hagmar et al., 2005).

Assessment of exposure to food carcinogens As toxic effects of compounds are dosedependent, knowledge of the quantities and time of exposure is an important aspect of the risk assessment (Greim & Snyder, 2008). While occupational exposure and exposure to chemicals at home might occur orally, dermally, and through inhalation, exposure to food carcinogens usually happens orally. The positive and negative impacts associated with the intake of food depends on how much differently metabolized ingredients are taken and what such ingredients have influenced the health (EFSA, 2005). Moreover, it is also essential to keep in mind that cancer-related risk with diet has a lot to do with the nutritional value of food as well as calories, as being overweight is a risk factor for cancer, such as breast cancer (Kulie et al., 2011). The rate and period of exposure to toxic chemicals depending on the level in the food product and the quantity consumed is very difficult to determine (Greim & Snyder, 2008). Therefore, direct measurements by biomonitoring and modeling at total exposure from the environment are not convenient standalone procedures for the analysis of exposure to toxic components of food. The method selected for exposure analysis of food toxins depends on the knowledge and availability of resources, considering the population, if the acute or chronic impacts are going to be analyzed and the intended use of the outcomes (World Health Organization (WHO), 2001). In determining the exposure to toxic ingredient in food, three areas must be considered: (1) amount of the components in food after processing the food for the final product; (2) data of the intake amount of food; and (3)

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assimilation of such elements in determining exposure (Arcella et al., 2005). These three areas have several flaws in the approaches presently applied that lead to ambiguity which may cause either over- or underestimation of actual consumptions and risk of food materials. Mainly, the dietary exposure to hazardous chemicals could be analyzed by combining data on contents in all food products with data on their consumption (Arcella et al., 2005; Kirsi & Kirsi, 2012). Even though it is neither cost-effective nor essential to garner detailed data for all compounds, a stepwise or tiered approach is usually employed to emphasize resources on the highest critical issues (Kirsi & Kirsi, 2012; Lawrie & Rees, 1996). It has been very challenging in the assessment of the concentration of toxins in food as well as in analyzing the food consumption data (Arcella et al., 2005). The condition of exposure analysis of food toxins is completely reliant on the quality of the food consumption data employed in the assessment of toxic ingredients (Arcella et al., 2005). Knowledge on food consumption can be garnered by: (1) food supply data expressing the country’s food consumption level as lost from the market, (2) data from household consumption surveys that commonly measure quantity of foods taken into the household after purchasing form the market thereby no information on manufacture protocols as well as about consumed amounts is mentioned, (3) data from dietary assessments from persons that account for the quantity of food and drink usually taken from one day up to one year of consumption or (4) a collection of duplicate diets, where the amount of foods are assessed chemically and real consumption documented (EFSA, 2006). Evidence from dietary collection amongst individuals observed is highly similar to the real consumption (Arcella et al., 2005). In the case of duplicate-diet analysis, exposure assessments are not associated with consumption and concentration of food data related to the same persons. Hence, the studies of exposure to dietary compounds need modeling to

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3. Recalcitrant toxic xenobiotics and their routes of exposure to humans

develop a likely real-life exposure condition. At present, to obtain a highly realistic result of exposure to toxic chemicals of food, a risk assessment has been highly emphasized in probabilistic modeling. The probabilistic approaches require more resources than deterministic approaches, and hence allow the identification of the variability and uncertainty in analyzing exposure to food toxins (Arcella et al., 2005). The intensity of uncertainty is being considered as a more important aspect in exposure assessment (EFSA, 2006; Heinemeyer, 2008). The main objective in the uncertainty assessment is to characterize the sources of uncertainty to reveal for decision-makers the highly important parameters in an exposure scenario. The EFSA Scientific Committee suggests a tiered approach for the assessment of uncertainties initiated with accessible data and increasing the exposure measure if it is required (Arcella et al., 2005; EFSA, 2006). EFSA is continuously exploring alternative exposure paths for the assessment of food toxins. All uncertainty might be assessed at one of three tiers: qualitative, deterministic, or probabilistic. In most conditions, uncertainties are associated with food consumption and body-weight that are main inputs in all kinds of dietary risk analysis, whereas the period of exposure is not considered in the assessment of toxins. Every year, advanced exposure models and statistical and biological monitoring techniques are being developed for the exposure assessment of carcinogenic ingredients of food (Nieuwenhuijsen et al., 2006). Knowing the limitations and requirements allows for a better understanding of the impact on the concentration of toxins by processing the food, harmonization of food intake survey procedures all over European countries, and assessment of probabilistic models (Kroes et al., 2002). Above this, the research community is still looking for the development of the European food composition database to be published and updated (EFSA, 2006). Due to these problems, it is challenging enough to assess the exposure of pregnant

women to food toxins. As to fetal exposure, one more level of intricacy must be understood: the transfer of contaminants via the placenta to the fetus. As to the human placenta, this could be experimentally modeled with human placental perfusion. However, the transfer itself is very tough to model in vitro, and several molecular pathways, such as the role of various transporter proteins, could be understood in in vitro cell cultures.

Cellular adaptation to xenobiotic compounds Cells interact with xenobiotic molecules by upregulating the production of the xenobiotic metabolism machinery such as the proteins participating in the above-mentioned stages of biotransformation. The response of adaptive cellular is greater due to the interaction of xenobiotic molecules with signaling cascades and transcriptional regulators like “xenosensors.” The xenosensors mediate the interaction between cellular structures and xenobiotics compounds in a very wide sense (Klotz & Steinbrenner, 2017). Biotransformation occurs with the production of ROS via multiple reactions both directly generating ROS as part of the respective reaction and indirectly as a result of the products made by the transformation of xenobiotic compounds (Kehrer & Klotz, 2015) (Fig. 3.1). The production of ROS is a natural process of biotransformation employing sequential redox reactions and utilizing the presence of oxygen molecules. The movement of electron to molecular oxygen is a result of the production of superoxide and derivatives like hydrogen peroxide. ROS are understood to be mediators of cellular signaling pathways by altering signaling cascades at various steps along with a level of transcriptional regulators. In addition, cells are now recognized to use the transient generation of superoxide/hydrogen peroxide as the

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Cellular adaptation to xenobiotic compounds

(A)

H 2O

(B)

O2

Cys---Fe III

N

R

R-H

H2O 2

O2 R

Cytochrome P450 (CYP)

H2 O2

O2

RNR’R” H 2O

OH

R’’

H2O

2[H]

RNR’R” Amine H2O 2 Oxidases

R’

R-OH

R-H

O2

NH2

R

Amine Oxidases

O

Aldehyde/ Xanthine Oxidases

R

O

H2O 2 NH3

O2

H 2O

(C)

(D) O2

H+

O2

NH2

R1

O HO

R3

R2

R1

[H]

R4

O.

R4

N

N

H2 N

Vicine

Glucosidase

NH2

N

NH2

Divicine

Semiquinone

2[H] NAD(P) H:quinone oxidoreductase-1 (NQO1)

OH

N

HO

R3

Quinone

OH

Glc-OH

O

R2

Glc

O

H2 O

[H]

R1 HO

R2

R4

OH

H+

O2

O2

R3

Hydroquinone

FIGURE 3.1 The critical role of xenobiotic compounds in producing ROS. ROS are produced during xenobiotic metabolism via oxidation, reduction and hydrolytic processes. (A) Cytochrome P450 (CYP) monooxygenase activity needs both electrons and the activation of molecular oxygen. Subsequently, oxygen reduction products, like superoxide and hydrogen peroxide, could leak out of the enzyme complex, which is not confirmed in how far this attribute affects xenobiotic toxicities in organisms. (B) Specific amines and aldehydes might be metabolized by oxidases which produce hydrogen peroxide. (C) Redox cycling: reduction of particular molecules leads to the formation of products which are reoxidized by molecular oxygen that is found in cells and tissues with significant concentrations. With the same process, the molecular oxygen might be reduced to superoxide that would undergo (spontaneous or enzyme-catalyzed) dismutation to produce hydrogen peroxide as shown in the case of the endogenous reduction of quinones to semiquinones and hydroquinones. NAD(P)H:quinone oxidoreductase-1 (NQO1) catalyzes the two-electron reduction of quinone substrates to produce hydroquinones and then undergo phase II metabolism to generate hydrophilic adducts. NQO1, an antioxidant enzyme generating hydroquinone, is moved on to phase II metabolism before its reoxidation through molecular oxygen. (D) Hydrolysis participates to the production of ROS: vicine of fava beans might be hydrolyzed after ingestion to produce its aglycon, divicine by action of intestinal microbes. Lastly, an o-hydroquinone might, in turn, undergo redox cycling (Klotz & Steinbrenner, 2017). ROS, Reactive oxygen species.

main components of signaling cascades along with growth factor-dependent signaling (Klotz & Steinbrenner, 2017). It can be explained that xenobiotic compounds stimulate xenosensor-dependent adaptation of xenobiotic metabolism, and in parallel, via the

xenobiotic metabolism process, attribute to the production of ROS and ROS-dependent regulation of cellular signaling processes. Cell adaptability is achieved through activation of cellular xenosensors which regulate gene expression. The generation of ROS is one

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3. Recalcitrant toxic xenobiotics and their routes of exposure to humans

of the known modulating factor of signal transduction events. FOXO (forkhead box, class O) transcription factors are critical proteins participating in the cellular response to stress along with oxidative stress elicited by the generation of ROS. In another way, FOXO activity is regulated by ROS and FOXO that target genes that encode antioxidant proteins-thereby establishing a regulatory circuit. The xenosensor molecules, such as constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2), are capable of interacting with FOXOs and ROS. The emerging image of an interaction between xenosensors, ROS, and FOXO transcription factors explains the regulatory role of ROS and FOXOs in the cellular adaptive response to xenobiotic compounds (Klotz & Steinbrenner, 2017). Exposure of cells to xenobiotic molecules occurs with the activation of xenosensors like nuclear receptor xenosensors (CAR, PXR, PPARs), AhR, or Nrf2. This is also immediately occurs with the production of ROS, that might, in turn, impact xenosensor activities.

Detection of xenobiotic-induced toxicity Systems toxicology is the combined study of classical toxicology with quantitative assessment of wide networks of molecular and functional alterations happening across different levels of biological systems with complete spectra of toxicity of xenobiotics compounds (Sturla et al., 2014). In another way, systems toxicology can be defined as studying and understanding anything and everything which occurs in a biological structure in response to its exposure to a xenobiotic molecule. Below are the main components of systems toxicology: • Absorption and dissemination of the xenobiotic molecule inside the biological organization.

• Biotransformation of the xenobiotic compound leading to the development of toxic and/or non-toxic modulators. • Interplay of the parent xenobiotic substance and/or its products with the cellular targets of toxicity. • Changes in cellular components along with genes, proteins, and lipids. • Structural modification of target organ toxicity, for instance, histological alterations. • Functional phenomena of toxicity such as deterioration of major activities in target organ(s)/organ system(s), and • Removal of the xenobiotic molecule and/or the transformation of intermediate products from the biological structure. An understanding of the systems toxicology is associated with manifestations of xenobiotic-induced toxicity, structural, and/or functional alterations, which typically occur via alterations in cellular components like genes, proteins, lipids, metabolites, etc. at cellular, tissue, organ, or individual levels (Fig. 3.2). Systems toxicology needs potential and revolutionary techniques with the ability of covering the “global” variations happening in a biological organization in response to the xenobiotic exposure. Advanced developments in biological fields, mainly molecular biology, computer science, mathematics, and bioinformatics have played a vast role in the genesis of different “omics” techniques that also play a significant role in systems toxicology. The main “-omics” techniques constitute genomics (study of the genome or DNA), transcriptomics (study of the transcriptome or mRNA), proteomics (study of the proteome or proteins), lipidomics (study of the lipidome or lipids), metabolomics or metabonomics (study of the metabolome or metabolites or small molecules), adductomics (study of DNA adducts due to xenobiotic exposure), and epigenomics (study of the epigenome), and these several “omics” techniques are

Xenobiotics in Chemical Carcinogenesis

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System toxicology maturation

Quantitative assessment

Human biomonitoring in the assessment of common population exposure to xenobiotics

Exposure

Molecular communication

Cellular responses

Organ responses

Individual responses

Population responses

Chemical structure and characteristics, internal dose, metabolic transformation

Binding to macromolecules like protein, nucleic acid

Changes in gene and protein expression, metabolic level and lipid groups

Interferences in tissues function and homeostasis

Depraved development disease, lethality

Frequencies of cancer development and mortality rate

Exposome identification

Measurement of ligand binding and adduct formation

Spontaneous Computable Biological network model

Analysis of physiological and histological alterations

Phenotypic assessment

Epidemiology

Phenotypic assessment

Epidemiology

Exposome identification

Exposome identification

Dynamic Multiscale Biological Model

Dynamic Adverse Outcome Pathway Model

FIGURE 3.2 The paradigm of system toxicology includes several events from biological network models to dynamic AOP models. The main aim of Systems Toxicology is to simulate the population-level impact of exposure through dynamic AOP models. Dynamic AOP models have three wide steps of maturity from top to bottom. The first level is causal computable biological network models which connect the system’s interaction of a toxic chemicals with the organ-level responses, and this model is employed to measure the biological effect of an exposure in the aspect of quantifiable last points like histology or physiological analysis. At the second level, as much mechanistic knowledge taken from quantitative assessment collects and links the exposure with the organ-level responses through dynamic models. Finally, the third stage of maturity is achieved by linking the exposure with population level via mathematical models which facilitate the simulation of population level impact of a chemical exposure (Sturla et al., 2014). AOP, Adverse outcome pathway.

applicable and essential in knowing the system or full toxicity of a xenobiotic compounds (Joseph, 2017).

Human biomonitoring in the assessment of common population exposure to xenobiotics A group of several chemicals from manmade and natural origins move in animal feed, human food, and water either as unwanted contaminants or as part of the ingredient of a diet. The significant anthropogenic contaminants of public and animal health have POPs such as dioxins, PCBs, brominated flame

retardants, perfluoroalkyl acids, Maillard reaction products (acrylamide, furans), phthalates, pharmaceuticals, as well as residues from production aids and compounds certified for use following a pre-marketing consent in food and feed materials like pesticides/biocides, and food and feed additives. A major group of natural contaminants is heavy metals for example, lead, cadmium, uranium, mercury, and metalloids like arsenic and natural toxins formed by bacteria, protozoa, algae, fungi, and plants (Kromerova´ & Bencko, 2019). A large population of modern societies are exposed to a broad range of environmental chemicals. Exposure to some of environmental compounds might produce negative health

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3. Recalcitrant toxic xenobiotics and their routes of exposure to humans

impact. Understanding of population exposure to such chemical is so imperative to estimate ˇ ´ et al., 2017). the related health risks (Cerna Analysis of population exposure to environmental compounds can be sorted into two methodological approaches: environmental monitoring means the assessment of toxic compounds in environmental media and determination of person exposure according to their consumption and analysis of environmental substances in human body fluids and tissues is known as human monitoring. Therefore, a combination of both approaches is suggested to assess the exposure and bodily burden ˇ ´ et al., 2017). (Cerna The National Research Council (NRC) of the United States of America (2002) has explored human biomonitoring (HBM) system to analyze human exposure to xenobiotic chemicals that are metabolised into different components in human tissues or specimens like blood or urine (Siegel et al., 2020). Hence, the HBM requires biomarkers that are detectable indicators of certain changes or process in biological construction. Biomarkers measure the content of chemical compounds and their transformed metabolites or reaction products in human tissues or specimens for example, blood, urine, hair, adipose tissue, teeth, saliva, breast milk, and sperm (Choi et al., 2017). The potential significance of using biomarkers is obvious in their nature, expressing an integrative approach of exposure to measured components viz. the internal dose as a consequence from multiple events of human exposure and also adds knowledge of toxicokinetic and individual properties like geneticallyassociated susceptibility (Kromerova´ & Bencko, 2019). It has main procedures like metabolism, bioaccumulation, and excretion (Choi et al., 2017). The use of biomarkers has advantages in monitoring exposure along with early detection of health impact (Kromerova´ & Bencko, 2019).

Challenges of human biomonitoring Both biomarkers of effect and biomarkers of exposure must be correlated closely with entire individual exposure to have an authentic measure of the intake dose or individual health risk. In using biomarkers, they must be sensitive, peculiar, biologically significant, viable, practicable, and less expensive. However, all these criteria are not followed by most biomarkers and hence they compromise with such criteria (Kromerova´ & Bencko, 2019). The concentration of biomarker differs both within and between individuals; therefore, such variations in level of biomarker detected in a population during biomonitoring assessment could not be easily interpreted. Moreover, biological media is preferred for sampling impact of biomarker level independent on other factors. Eventually, renal or hepatic diseases, in general, have an effect on biomarker alterations (Aylward et al., 2014). The advantages and disadvantages of several sample types like blood, hair, urine, or breast milk have been discussed widely (Paustenbach & Galbraith, 2006). With less tissue amounts in the ng kg21 body weight range, the measurement of biomarkers could be an analytical challenge which is also complexed by contamination and the high instability of conjugates. With urine sampled, the kind of sampling (spot urine, 24 h urine or morning void) is a critical parameter as is the use of volume-based or creatininebased urinary level. Alterations in protein/fat composition and enzyme activity affect the accuracy of human milk samples (Choi et al., 2017). The internal contents like concentrations in fluids (urine, blood) or organs inside the body, are pertinent for real exposure (Ciffroy et al., 2016). However, the HBM data does not allow for variations in exposure by source, and HBM alone could not furnish knowledge about the

Xenobiotics in Chemical Carcinogenesis

Conclusions and future prospective

origin of exposure or how long a chemical compound has persisted in the body. To express HBM data in daily exposure measure, it is necessary to have detailed knowledge of the major analytical/methodological drawbacks and the toxicokinetics of the individual compound (Choi et al., 2017). Moreover, the HBM raises critical issues on ethical and privacy concerns due to evidence which collects samples from humans and sometimes in an invasive way such as blood samples (Choi et al., 2017). The contribution of tissues or fluids by healthy individuals raises sensitive, ethical, and privacy issues. Therefore, the ethical committee as a legal authority works in Europe to ensure the rights and prestige of study individuals. One of the highly significant international references to describe and assure the fundamental human rights in the areas of biomedical research, mainly those who involving in the research activities, is the Oviedo Convention and its Additional Protocol regarding Biomedical Research. Another is the Additional Protocol, which focuses on the need of receiving informed consent and is necessary for that a research project is going to be submitted to an ethics committee for independent evaluation of its scientific novelty and interdisciplinary review of its ethical acceptability. The Data Protection Directive 95/46/EC that is now renamed by General Data Protection Regulation governs the processing of individual data within the EU. It gives accountability to organizations having personal information and provides a specific legal right to individuals. The samples and data received in an HBM study are known as sensitive personal data associated with health. Generally, the ethically approved data are not processed in principle forbidden, until some critical circumstances are met. Several issues regarding ethics and data security has also been explained by two international projects, COPHES (COnsortium to Perform Human biomonitoring on a European Scale) and DEMOCOPHES (DEMOnstration of a

53

study to COordinate and Perform Human biomonitoring on a European Scale) (Casteleyn et al., 2015).

Conclusions and future prospective Humans are exposed to different kinds of chemicals in all areas of life. Air, water, soil, and food are the most essential components of the human environment. Each of those elements regulates the quality of human life, and each of them can become contaminated. Humans are exposed to toxic or potentially toxic chemicals in various ways in our daily lives and hence, a different area of toxicology has shown great importance for society in making awareness toxic compounds. After considering this, someone may have questions like “Are all chemicals toxic?” where an answer may be “There are no safe chemicals, only their safe use” (Iovdijova´ & Bencko, 2010). Xenobiotics causing toxicity in biological systems have been classified into inorganic and organic chemicals. It has been noted that xenobiotic compounds are responsible for about 80%
90% of chemical-induced toxicity in the human population. Xenobiotics compounds are also ubiquitous environmental pollutants in both aquatic and terrestrial ecosystems. The hazard of xenobiotics compounds is a function of its environmental persistence, toxicity, and bioaccumulative potential. Toxic environmental chemicals are more hazardous due to these three properties such as persistence, bioaccumulation, and toxicity. The trophic transfer of such toxic substances through food chains/webs has important implications on human health. Hence, it is necessary to assess and monitor the concentrations of potentially toxic chemicals in different environmental segments and the resident biota. A comprehensive study of the environmental chemistry and ecotoxicology of xenobiotic compounds reveals that steps should be taken to minimize the effect of the toxic xenobiotics on human

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health. In addition, harmonization in the area of HBM is essential in acquiring corresponding markers of external exposure for addressing the impact of xenobiotic compounds playing roles in the development of various types of cancers.

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4 Incidences of crucial environmental xenobiotics for inducing cancers Introduction

altered in cancer cells. For instance, cigarette smoking has been associated with the development of various types of cancers. Therefore, ignoring cigarette smoke has been revealed to inhibit cancer risk. Other highly modifiable cancer incidence factors are food preservative chemicals, alcohol consumption, and obesity (Purohit et al., 2005). Prevention is deciphered as the decrease of cancer mortality by stopping the cancer risk. This could be achieved by ignoring carcinogenic exposure, changing lifestyle practices, and early diagnosis of cancerous lesions. Several epidemiological studies suggest that highly physically active people have a lower incidence of particular cancers than inactive persons. Not all xenobiotic components cause cancer, but some cannot be avoided. Other factors, such as family history and aging, are innate. Various factors might act simultaneously to modify a normal cell to a malignant cell (Fidler et al., 2017). The aim of this chapter is to explain the contribution of environmental xenobiotic exposure causing the development of cancers.

Biological events of cancer explain that all cancers are developed from both environmental and genetical factors, viz. several exogenous components integrated with internal genetic alterations can cause cancers. The disruption of cellular signaling and defensive mechanisms can be prevented by stopping carcinogenic exposure outside the body from any source in the environment. Hence, inhibition of carcinogenic xenobiotic exposure is still a major concern (Parsa, 2012; Sonnenschein & Soto, 2008). However, individuals with certain genetic predispositions might be more sensitive to the impact of environmental exposure than other factors. Individuals with BRCA1, BRCA2, and p53 genetic changes due to environmental factors are less capable of inhibiting the proliferation of cancer cells (Vogelstein & Kinzler, 2004). Indeed, aromatic amines lead to bladder cancer among workers employed at chemical factories. DNA methylation is highly related with histone deacetylases and histone methyltransferases, which can alter histone amino-terminal lysine and produce certain histone codes, causing inactive chromatin generation that forms the different properties of cancer cells. It has been highly understood that many numbers of genes are

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Pesticides in carcinogenesis It has been explained the global implication of pesticides and investigated the evidence of

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pesticides exposure causing to development of particular cancers in humans. A pesticide is explained as any compound or blending of substances (1) promised to protect, kill, or regulate any pest, like vectors of human or animal disease, undesired species of plants or animals causing harm during the production, processing, storage, transport, or marketing of food, agricultural commodities, wood and wood products, or animal feedstuffs; or (2) fed to animals for insect prevention, or other pests in or on their bodies (Bergesen et al., 2019). Usually, this term is not associated with fertilizers, plant and animal nutrients, food additives, and animal drugs. An extensive application of pesticides seems in agriculture and in vector control, as well as in public health programs (Townson, 1992). Relevant quantities also are employed in forestry and livestock formation. Several reports have revealed the relationship of epidemiological evidence with chemical pesticides and cancer. Animal studies have deciphered that several pesticides such as organochlorines, creosote, and sulfallate are carcinogenic whereas others like DDT, chlordane, and lindane are cancer promoters. Some pollutants in the processing of commercial pesticide might also lead to carcinogenic incidence. In humans, arsenic chemicals and insecticides employed occupationally have been categorized as carcinogens by the International Agency for Research on Cancer. However, this human data is insufficient due to a smaller number of studies that assess individual pesticides. Often, contradictions of epidemiologic studies have been associated with phenoxy acid herbicides or pollutants in them with soft tissue sarcoma (STS) and malignant lymphoma, organochlorine insecticides are related to STS, non-Hodgkin’s lymphoma (NHL), leukemia, and, less frequently, with tumors of the lung and breast, organophosphorus chemicals are associated with NHL and leukemia, and triazine herbicides are connected to ovarian cancer (Dich et al., 1997).

Therefore, more epidemiologic studies are required with enhanced exposure analysis for individual pesticides, taking into consideration work practices, implication of protective mechanisms, and other parameters to decrease incidence.

Role of environmental agents in human cancer Exposures to environmental xenobiotic compounds are pervasive. In daily life, people are exposed to several familiar toxicants and various potentially harmful compounds that have less well-explored incidences. For instance, plastic food and beverage bottles, cosmetics, sunscreen, sanitation products and garden stuffs all have chemicals. Chemical pesticides remain on various commercially produced fruits and vegetables and grain crops. In addition, many chemicals are explained as persistent organic pollutants (POPs) because of their resistance to deterioration, environmental existence, and accumulation in the food chain. They have been prohibited for decades in many countries due to the negative effects on the human health. Even still, they concentrate in soil, sediment, air, and biota due to their long half-lives, and human beings remain exposed to such xenobiotics chemicals via various pathways (Koual et al., 2020). However, the reasons of several individual human cancers due to environmental xenobiotic compounds are unpredictable, and there are indisputable outcomes that specific chemical substances, radiation, and particular biologic components are contributors to the comprehensive risk of human cancer. Intake of tobacco stuffs, mainly cigarette smoking, cause about 30% of all cancers. Some instances of chemical xenobiotic carcinogens are polycyclic aromatic hydrocarbons (PAHs), aromatic amines, benzene, aflatoxins, tobacco chemicals, and chemotherapeutic compounds. Metal

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Conclusions

carcinogens are highly linked with occupational exposures and have certain products of arsenic, nickel, and hexavalent chromium. Radiation carcinogens are ultraviolet radiation, ionizing radiation, and radon. Fibers like asbestos and specific dusts are etiologic components in lung carcinoma and mesothelioma. Also, several chemicals in the diet may cause the formation of cancer via carcinogenic or anticarcinogenic pathways (Ba´ez, 2008).

Exposure of biomarkers and assessment of human exposures More studies in the unraveling of the mechanism of carcinogenesis are open areas for the exploration of molecular biological markers which provide both disease-related exposure and/or pathways involving both exposure and disease. It is expected that the implication of molecular markers would help to explain the mechanisms of environmental xenobiotic components (mainly at low extents and in complex mixtures) in the etiology of human carcinoma. Such molecular markers can be categorized into three main groups (Groopman & Kensler, 1999; Ross et al., 1992): • Markers of exposure provide a biologically efficient amount of a carcinogenic compounds • Markers of impact suggest a diseasesignificant response to exposure • Markers of sensitiveness identify the intrinsic susceptibility of a person to a carcinogenic component (Huff, 2020; Strickland et al., 1996). The predictable and persistent interaction of a carcinogen with macromolecules was first explained by Miller and Miller in 1947, who revealed azo dye remained integrated to the liver proteins of treated rats. Further studies suggested the significance of carcinogenic alterations of DNA either directly or after

metabolic induction in the cancer progression. The evaluation of carcinogenic metabolites, carcinogen-DNA adducts, or carcinogenprotein adducts in human tissues or fluids contribute to the basis for development and implication of personal exposure assessment, molecular dosimetry research, and the elaborate study of “molecular” cancer epidemiology. The main benefit of such a method is that highly relevant analysis of individual or group doses might be obtained rather than via accounts of carcinogenic exposure in the environment or occupation (Ba´ez, 2008). Therefore, molecular studies are essential to predicting the environmental xenobiotic compounds involved in the silent progression of cancer.

Conclusions A major archetype in environmental carcinogenesis: gene-environment interactivity, a view employed to explain the complexity between individual or population genetics and reaction to xenobiotic agents-has also gone through an extensive conversion into highly contemporary knowledge of the human exposome. Hence, it is essential to know the contribution of environmental xenobiotic component agents to the several indications of cancer: perturbing the genome, resisting cell death, altering cellular energetics, assisting proliferative signals, abstaining growth suppressors, averting immune destruction, stimulating tumor inflammation, triggering invasion and metastasis, and instigating angiogenesis. Environmental xenobiotics such as pesticides, herbicides, airborne pollutants etc., play hazardous roles in the human body by interacting with cell signaling. Therefore, more studies like next-gene generation and “omics” approaches are required to explore the specific molecular targets of carcinogenic xenobiotics for cancer development inhibition.

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resistance. Environmental Health: A Global Access Science Source. Available from https://doi.org/10.1186/s12940020-00670-2. Parsa, N. (2012). Environmental factors inducing human cancers. Iranian Journal of Public Health, 41(11), 1 9. Purohit, V., Khalsa, J., & Serrano, J. (2005). Mechanisms of alcohol-associated cancers: Introduction and summary of the symposium. Alcohol (Fayetteville, N.Y.), 155 160. Available from https://doi.org/10.1016/j.alcohol. 2005.05.001. Ross, R. K., Yu, M. C., Henderson, B. E., Yuan, J. M., Qian, G. S., Tu, J. T., Gao, Y. T., Wogan, G. N., & Groopman, J. D. (1992). Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. The Lancet, 339(8799), 943 946. Available from https://doi.org/10.1016/01406736(92)91528-G. Sonnenschein, C., & Soto, A. M. (2008). Theories of carcinogenesis: An emerging perspective. Seminars in Cancer Biology, 372 377. Available from https://doi.org/ 10.1016/j.semcancer.2008.03.012. Strickland, P., Kang, D., & Sithisarankul, P. (1996). Polycyclic aromatic hydrocarbon metabolites in urine as biomarkers of exposure and effect. Environmental Health Perspectives, 927 932. Available from https://doi.org/ 10.1289/ehp.96104s5927. Townson, H. (1992). Public health impact of pesticides used in agriculture. Transactions of the Royal Society of Tropical Medicine and Hygiene, 86(3), 350. Available from https://doi.org/10.1016/0035-9203(92)90345-D. Vogelstein, B., & Kinzler, K. W. (2004). Cancer genes and the pathways they control. Nature Medicine, 789 799. Available from https://doi.org/10.1038/nm1087.

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5 Toxicokinetics and toxicodynamics of xenobiotics in cancer development Introduction

linked with anatomy, physiology, behavior, analytical chemistry, engineering, and medicine for the prevention and treatment of damaging exposures to toxic chemicals (Croom, 2016). Toxicokinetics is comprised of four main events: Absorption, Distribution, Metabolism and Excretion or Elimination (ADME). Moreover, behavior and genetics may also effect ADME. For instance, how behavior can affect the absorption of toxicants could be observed with smog exposure. Similarly, mask wearing people when going outdoors would absorb less smog particles than those who spend the same periods outdoors breathing unfiltered air. Nonetheless, the behavior could also change distribution, metabolism, and elimination of toxicants. Significant alterations in the toxicokinetic profiles of individuals have been observed based on diet and medication, such as drinking grapefruit juice or taking amoxicillin. Likewise, mutations can significantly change the toxicokinetic profiles of people. Such alterations in toxicokinetics can be attributed to variations in toxicodynamics (Croom, 2016). Toxicodynamics is also comprised of several levels: molecular, cellular, tissue and organ. Hence, the investigation of timing of exposure is associated with the formation and disappearance of molecules, cells, tissues, and organs at different stages of development. For a specific

The implication of several chemicals in our modernized society is multifarious and is increasing day by day. With the use of such chemicals or their products, it should be a pertinent balance between the profits and possible risks related to their applications. Such risks might occur to the labor force generating the chemicals, the consumers, the public, organisms in the environment, ecosystems, etc. (Blaauboer, 2003). The potential use of chemicals in commerce, the home, the environment, and medical fields have different types of harmful impacts. The nature of such effects is investigated by the physicochemical properties of the agent, its interaction capability with biological systems for example, hazard, and its potential to become integrated with biological systems viz. exposure. The main concept of toxicology is associated with a certain dose that causes poisonous or detrimental effects. Toxicokinetics explains how a toxicant arrives into the body and reaches a specific tissue. Toxicodynamics is related to changes appearing in that tissue after reaching an effective toxicant dose. Doses of toxicants that might be safe for adults could be harmful to children and destructive to embryos. Translational toxicology provides a significant knowledge of toxicants

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toxicant, it could be a limited window of susceptibility based on developmental alterations. For instance, thalidomide, if consumed early during pregnancy, led to many children to be born without limbs. However, this only happened after initial exposure during pregnancy and the mothers were never at risk of losing their already formed arms and legs (Kim & Scialli, 2011). Translational toxicology elucidates both prevention and treatment efforts. Prevention efforts include screening, security labels and properties of products, self-protection instruments, and legitimate restrictions on prescriptions and purchases. Treatment efforts are comprised of preventative and susceptible treatments. The preventive or prophylactic treatments are for a certain condition where exposures are expected but usually unavoidable. The susceptible or responsive treatments are provided after exposure of xenobiotics compounds. Hence, treatment efforts between exposure and responsive are often delayed. Such delays could be exacerbated when significant time is given in identifying the toxicant of xenobiotic substances. The estimation of toxicity data from animal model for the prediction of health impacts in humans must be noted for determining the variations in both toxicokinetic and toxicodynamic factors considered. The data from single toxicokinetic differences are not enough to describe the overall interindividual variation in susceptibility observed in exposed populations; toxicodynamic factors are also required (Hattis, 1996). Toxicokinetic and toxicodynamic factors also reveal age-dependent differentiation like very young and very old compared to adults. Furthermore, disease stages might modulate the toxicokinetic handling of a xenobiotic compound or its toxicodynamic interaction and response induction in a target site. Moreover, toxicokinetic and toxicodynamic factors cause genetic polymorphic differentiation and result in subgroups of the population exhibiting

increased risks toward xenobiotic exposures. Hence, the study of toxicokinetic and toxicodynamic variation due to age, disease, and genetic factors is critical factor in xenobiotic chemical risk assessment (Dybing & Søderlund, 1999). The fundamental concepts of the toxicokinetics and toxicodynamics of xenobiotics compounds are clinically pertinent to veterinary toxicology and must be known by veterinary practitioners, students, and other personnel who would be involved in the prognosis and therapy of small animal intoxications. The studies of toxicokinetic and toxicodynamic aspects on small animal toxicoses are most essential in various ways viz. first define different terms associated with toxicology. Xenobiotics is a common term used to explain any substance foreign to an organism or, in other ways, any compound not found within the normal metabolic pathways of a biologic system. The positive and negative impact of xenobiotics depend on the kind of compound and exposure level, where interactions with animals could be benign, therapeutic, or toxic in nature. The toxicokinetics and toxicodynamics of a toxic xenobiotic compound describe the “when,” “how long,” “what,” and “why” for the adverse impact of that toxicant (Evans, 2012). The accumulation of a xenobiotic substance is how the animal’s body responds to those chemicals following exposure. The accumulation or fate of a xenobiotic substance within the body consists of the chemical’s ADME (Plumlee, 2004). Toxicokinetics is defined as the quantification and addressing of the time period of the accumulation or ADME for a toxic xenobiotic. There are several specific toxicokinetic terms like bioavailability, volume of distribution (Vd), clearance, half-life, onecompartment model, and first- and zero-order kinetics (Lee & Kacew, 2013). The word toxicodynamic explains how a toxicant acts physiologically, biochemically, and molecularly within an animal’s body following exposure. The toxicodynamics of a toxic

Xenobiotics in Chemical Carcinogenesis

Introduction

xenobiotic is associated with the mechanism of action of that toxicant and the relationship between toxicant level and the noticed impacts of the toxicant on biological events in the animal viz. the dose-response relationship (Evans, 2012). The accumulation and toxicokinetics of a certain xenobiotic compound also play a role in finding the organs or tissues influenced by a toxicant, and the clinical presentation and time period of a toxicosis resulting from extensive exposure to that toxic compound (Croom, 2016; Evans, 2012). Safety or uncertainty components have been employed for 40 years to establish the safe consumption of food additives and contaminants associated with toxicity assessment done in animals and humans. A value of 100 has been suggested for application to animal data and accepted in the USA (Renwick, 1999) and at the second session of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) (1958). The same 100-fold default factor was implicated to a very high range of xenobiotic compounds with different chemical structures and metabolic fates, and a wide range of target organ impacts in the general test species for example, rats, mice and dogs. After implication studied over several years, it has been analyzed that the mainly 100-fold default value might not always be applicable (Joint FAO/ WHO Expert Committee on Food Additives, 1987); hence supplementary uncertainty factors have been designed to allow for discrepancies in the database (Joint FAO/WHO Expert Committee on Food Additives, 1994) and an additional “safety” component has been employed in some safety analysis, because of the nature of the adverse impact developed at high doses (Renwick, 1995). Instead of differences in nomenclature, the main events of safety guarantee/risk analysis for non-cancer impacts are almost the same over national and international organizations. The 100-fold uncertainty factor is implicated to the no-observed-adverse-effect-level (NOAEL)

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from animal research to acquire knowledge that is considered to be a “safe” daily consumption for humans being. The observing “safe” intake might be described as the Reference Dose (RfD), the Acceptable Daily Intake (ADI; for additives), or Tolerable Daily Intake (TDI; for contaminants) (Renwick, 1999). The toxic mechanisms of organic xenobiotic substances have been described on the basis of a cascade of processes initiating with exposure, proceeding via circulation and metabolism, and completion by interacting with cellular macromolecules. Such events of xenobiotic compounds are usually explained as toxicokinetic and toxicodynamic (Fig. 5.1) (Park et al., 2014). However, exploring the mechanisms of the toxic effects of xenobiotic compounds in organism, one must know the participating molecular and biochemical processes, as well as the relationship between main toxic metabolites with cellular macromolecules (Watson, 2014). Hence, sometimes an understanding of toxic mechanisms may not be easy, partially because of their inherent difficulty and partially due to the complicated interrelations among several components like different types of toxicant and cellular molecules with or without biotransformation. Important assessments, such as an ecological risk assessment, are performed for those chemicals like pesticides before they enter into the environment. Presently, this risk assessment depends on a summary of statistics collected in standardized laboratory studies. However, such statistical data consists of only limited information and relies on time course of exposure, and hence their interpretation to realize ecological aspects is inherently limited. Mechanistic effect models enhance potential events based on the toxicity for overcoming such issues. Toxicokinetic-toxicodynamic (TKTD) models are performed at the individual level for predicting the internal concentration of a chemical during time course and the pressure it develops on an organism. TK-TD

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5. Toxicokinetics and toxicodynamics of xenobiotics in cancer development

Toxicokinetics

Parents molecules

Xenobiotic compounds

Direct-acting molecules (Minor pathways)

Active forms (Electrophilic nature)

Natural decomposition

Interaction with cellular molecules

Indirect-acting molecules (Major pathways)

Phase II Reactivation Intermediate species • Electrophilic molecules • Redox-active compounds • Carbon-centered radicals

Biotransformation

Toxicodynamics

Phase I

Cytochrome 450

Dependent pathways (Major)

FIGURE 5.1

Independent pathways (Minor)

Lipid, Proteins, Carbohydrates

DNA

Reversible and irreversible toxicity

Irreversible toxicity

The schematic diagram explaining the mechanism of toxicity generated by xenobiotic compounds (Park

et al., 2014).

models are mainly fitted to determine the differences in ways of exposure between laboratory that is, constant and field (variable) aspects. Until now, limited studies have been performed to predict sublethal impacts of pesticide exposure to wild mammals in the field, even though these impacts are of specific interest with respect to prolonged exposure. Therefore, a TK-TD model has been developed based on the dynamic energy budget (DEB) theory that could be parametrized and investigated solely by applying standard regulatory studies. Moreover, this approach is also used effectively to determine the toxic effects on the body weight of rats over the course of time. Model predictions differentiate the effects of feeding avoidance and toxic mechanisms, considering which was the main

driver of growth. This knowledge is significant to the ecological risk posed by a xenobiotic chemical because in the ambient environment, alternative food sources might or might not be available to central species. This study emphasized single end point and growth, so this approach can be increased to add reproductive output. The developed framework is not complicated in its use and hence, can be a great asset for ecological and toxicological research and to risk assessors in industry and regulatory agencies (Martin et al., 2019). Flowcharts with hypothetical explanation have been designed and employed to explore the mechanism of the organic xenobiotic-induced events (Attia, 2010; Wells et al., 2005). However, the explanatory flowcharts do not reveal toxicokinetic and

Xenobiotics in Chemical Carcinogenesis

Role of toxicokinetics and toxicodynamics in risk assessments

toxicodynamic aspects, and hence are only beneficial in describing partial or limited events in the toxic processes. Moreover, full flowcharts have been emphasized for toxic processes by the indirect role of xenobiotics during biotransformation. So, the flowchart concerning toxicokinetic and toxicodynamic aspects in the presence of, or the absence of, biotransformation is essential to understanding the complete mechanism of organic xenobiotic-induced toxic events. The simplest flowchart has been designed to simplify teaching and better understand organic xenobiotic-induced pathways of toxicity. For a simple but significant explanatory flowchart, the critical steps and properties in xenobioticsinduced toxic events have been described as: direct-acting chemicals versus indirect-acting chemicals, biotransformation, cytochrome P450dependent versus cytochrome P450-independent biotransformation, reactivation, reactive intermediates, and reversibility versus irreversibility. Such an explanatory flowchart is known as the “Central Dogma of Toxic Mechanism for Organic Xenobiotics,” and has a similar approach to the central dogmas of molecular biology with slight modifications from the original version in Korean (Park, 2010). Hence, the main aim of this flowchart is again to introduce the central dogma describing important events for organic xenobiotic-induced toxicity in English. This chapter covers the kinetic and dynamic aspects of xenobiotic compounds in the development of cancer and their risk assessment by considering various factors.

Role of toxicokinetics and toxicodynamics in risk assessments A risk assessment is known as the stepwise continuous mechanism aimed at determining the likelihood, or the magnitude and probability, of adverse impacts to persons or population due to a certain chemical or group of chemicals based on qualitative or quantitative

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aspects. A summary of vital events in chemical risk assessment is described as (Dorne et al., 2011): (1) identification of hazard producing an adverse impact; (2) hazard characterization describes the negative impact in view of doseresponse and way of action; (3) exposure assessment predicting the potential, rate, and period of the exposure to a particular compound; (4) risk characterization, which combines the data of exposure and toxicity to qualitatively/quantitatively predict if an individual or a population is at risk. Risk assessments of chemicals are a method that is mainly based on data retrieved from animal testing having toxicological impact after exposure to certain compounds. The estimation of dose dependent exposure in humans would not produce toxicological impacts and can be referred to as safe dose and safe exposure. Conventional methods employ safety factors or uncertainty factors to predict from animal to man and from man to the common population and sensitive subgroups. Traditionally, a default factor of 10 is implicated to determine interspecies differentiation. It is suggested that this factor can be subdivided into a subfactor to understand the toxicokinetic views and a second subfactor for the toxicodynamics. Similarly, a default factor of 10 with subfactors has been described to explore the variations within a species. In the structure of the International Program on Chemical Safety’s (IPCS) project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals, a function has been initiated to lead risk assessors on the use of quantitative chemical specific data to determine variations in interspecies as well as interindividual in risk assessment. To understand toxicokinetic views, the core species, the pertinent internal exposure, and the metrics must be considered in the risk assessment. The qualities and availability of data, in vitro or in vivo, the path of administration, and the level of dose provide significant information for the

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5. Toxicokinetics and toxicodynamics of xenobiotics in cancer development

assessment of interspecies variations. The available experimental data from the certain population studied and the number of subjects and/or samples of the relevant group allow one to predict the population distribution such as the difference between central tendency and specific percentiles. In risk assessments, the toxicodynamic data should be explored in a similar pattern to the toxicokinetic. Instead of the identification of the active chemical species, the specific endpoint should also be considered (Gundert-Remy & Sonich-Mullin, 2002). Hence, exploring the relationship between the mechanistic views of the toxic process and the time dependency of toxicity is an unavoidable condition to undergo worthy risk assessment studies (Tennekes & Sa´nchez-Bayo, 2013). This relationship of toxicological behavior generated by hazard chemicals is basically described from a toxicokinetic and toxicodynamic views. Toxicokinetics usually explains the relationship associated with the concentration of a particular chemical to which a person is exposed, and the concentration of toxicologically active species at the site of action, intended as the organ, tissue, cellular or molecular locus where the chemicals produce adverse impacts. For instance, mycotoxins have several routes of exposure, such as skin absorption and inhalation (Fo¨llmann et al., 2016). So, considering the example of mycotoxin, variations in the ingested concentration and the concentration at the site of action have been elucidated by the LADME paradigm (Rubio et al., 2014). The frequency of the adverse impact of any food toxicant mainly depends on its bioaccessibility, which explains the fraction of toxicants liberated from the food matrix in the gastrointestinal tract during digestion and availability for the absorption (L 5 liberation). Next, a fraction of the released toxicants is absorbed (A 5 absorption) and moved to the bloodstream through which they are distributed into the distinct body tissues (D 5 distribution). The absorbed molecules involved in the metabolic process result in multiple metabolites (M 5 metabolism) at both

pre-systemic and systemic levels unless they are excreted out through renal or biliary methods (E 5 excretion). Even though dietary habits are imperative in defining exposure to food contaminants, the endurance of toxicologically active molecules in living organisms depends on ADME kinetics and the bioaccumulation event. Toxicodynamics describes the relationship of a toxicant at the site of action and the toxic impact at the level of molecule, cell, tissue, organ, or individual. The DruckreyKu¨pfmu¨ller model (Druckrey & Kupfmu¨ller, 1948) explains the dynamics of nongenotoxic molecules with a certain mode of action (Tennekes & Sa´nchez-Bayo, 2013): the dynamics of toxic activities depends on the interaction between the toxicant and certain molecular target(s), known as the “receptor(s).” It must be mentioned that during host-guest interaction, in terms of “receptor,” it is usually employed to suggest the host viz. biological target identified by the guest, such as mycotoxins, regardless of its biological function even if it is an enzyme, carrier, or receptor (Taylor et al., 2003; Wei et al., 2004). Generally, receptors are proteins, but they may also be other macromolecules for example, DNA-or RNA-protein complexes and glycoproteins. Receptor binding is the primary molecular step of nongenotoxic molecules action that addresses the molecular initiating event (MIE) (Allen et al., 2014) and is mainly linked to the toxic impacts through a cascade of molecular interactions which is referred to as the “mechanism of action” of a particular compound (Wallace Hayes & Kruger, 2014). Consequently, such a cascade of molecular process explores an array of functional and structural alterations at the level of cells, tissue, or organs, which is altogether explained as the “mode of action” (Grant et al., 2010). All linked pathways from receptor binding to the last adverse result are directly associated in describing the adverse outcome (AO) pathway (AOP) (Browne et al., 2017).

Xenobiotics in Chemical Carcinogenesis

In silico approach to risk assessment

Considering the initial step of MIE, nongenotoxic molecules build a dynamic binding with the receptors to attain steady-state equilibrium in a particular time period that depends on the kinetics of association and dissociation (Kenakin, 2017). At a molecular level, such a binding process usually explores structural modification by changing the normal receptor structure and function and causing disturbances in homeostasis. The intolerable impact of toxicity is observed if this type of perturbation exceeds a particular threshold level. The corresponding concentration of the bound receptor at the site of action highly affects the potentiality in provoking the toxic stimulus. Consequently, the relative concentration of bound receptor is associated with the concentration of toxicant at the site of action, its binding intensity, and the kinetics of association and dissociation. By considering the above explanation, it could be discussed that the potential of interaction based on the thermodynamic favor (ligand-receptor complex formation) could similarly correlate to the efficiency in provoking the initial step of toxic stimulus. So, with respect to the chemical risk assessment events, toxicodynamic exploration emphasizing receptor binding could support both processes of hazard identification and characterization by probing the core molecular steps of toxic action.

In silico approach to risk assessment It has been cleared that both kinetic and dynamic scenarios are very important to completely understand the toxicity of xenobiotic compounds, where a computational approach can develop a model for both the toxicodynamics and toxicokinetics of small xenobiotic molecules (Raies & Bajic, 2016). However, recent work has only emphasized the dynamic view of mycotoxins, deepening how the in-silico assessment of the primary molecular step plays a role in the toxic action may increase advanced knowledge in

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toxicology. Emphasizing the intricacies of the toxicological actions and the various aspects considered by the risk analysis methods, analysis of the mycotoxins-associated risks strongly needs interdisciplinary methods where molecular and cellular activities combine into in vivo evidence. In this complex view, the approaches designed in this work determine the molecular insights and, mainly, they deepen the toxicant-receptor interplay too early in the molecular cascade of the toxic action. So, such approaches can increase an understanding of the primary mechanism of toxicant activities and they might collaborate and support the experimental data of toxicological research during the initial stages of risk assessment. Actually, the computational assessment of molecules bioactivity like toxicity is associated with ligand-based and structure-based processes (Fradera & Babaoglu, 2017; Hassan Baig et al., 2016). Usually, ligand-based methods are based on the structures of compounds lacking any direct knowledge on the receptors’ structure and nature. Such approaches were generated for the first time in 1960s, where attempts to relate the structures of molecules to its bioactivity had been made using the first computer (Hansch et al., 1953). Such methods are relied on the common presumption that the bioactivity of small molecules depends on their chemical structure means from the ability to be absorbed in the gastrointestinal portion to the induction of toxic stimulus through receptor binding (Putz et al., 2016). Any chemical structure can be explained by combinations of certain molecular descriptors which are usually associated with assessable physicochemical properties. The relevant sorting of such descriptors can relate, qualitatively or quantitatively, with a particular biological function. Hence, the activity of molecules with unknown activity could be implied relying on the combination of the molecular descriptors as they are revealed. However, completely dynamic views like the receptor structure and nature and the ligand-receptor binding process could only

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partially be obtained from the ligand structure. On the contrary, structure-based methods depend on the three-dimensional information of the receptors’ structure. Such processes usually rely on the computation of the ligand receptor interaction allowing a direct assessment of the initial step of MIE. Such molecular methods are mainly calculated at an atomic level by computing the share of each atom interaction (e.g., Michel & Essex, 2010). These methods are specifically valuable to assess nongenotoxic compounds relying on the presumption that a need, even though not substantial, or condition to induce an adverse impact is the interaction with particular biological targets.

Bayesian population approach to toxicokinetic/toxicodynamic models in risk analysis Presently, physiological toxicokinetic models have been the most common approach in toxicology. By combining toxicokinetic models with toxicodynamic models, it may be possible to obtain estimates of risk related with exposure to a particular xenobiotic compound Although, for a more relevant analysis of the risk in a human population, some cross-species and/or in vitro/ in vivo studies is usually essential. The model calculation must be calibrated against experimental data to ensure that the model is appropriate for risk assessment. The fitting of physiologicallyreliant toxicokinetic models to experimental data obtained from concentration-time profiles is a critical problem. The models are complicated, and it is necessary to take previous information into account. Such information is used in the scientific article as reference values on physiological, physicochemical, and biochemical model parameters. Such reference values depend on different degrees of uncertainty (Jonsson & Johanson, 2003). Further, single concentration-time profiles are subject to both intra- and interindividual

differentiation. Such variability is an outcome of differing properties among individuals or across time within a particular individual, as opposed to uncertainty, that is mainly a lack of right information. If toxicokinetic models are calibrated against toxicokinetic data, it is of high significance that inter- and intraindividual variability is correctly differentiated from uncertainty. One easier solution to such issue is to employ Bayesian population methods.

Bayesian population methods Generally, a toxicokinetic model must be able to explain concentration-time profiles sufficiently, while not deviating too far from the older data on which this was originally based. The standard method to the parameterization of physiologically-reliant toxicokinetic models is to employ a likelihood-based criterion to analyze model function and further regulate the model parameters that are believed to be highly uncertain. In the meantime, all other model parameters have been taken from the reference article without any modification, unconcerned of prior uncertainty. Even though such events are well established and relatively easily to employ, several problems associated with this method have already been denoted (Spear & Bois, 1994). In a Bayesian method, the incorporation of earlier information is an elemental and integrated section of the modeling method. The information of model parameters prior to considering recent experimental data considered has been quantified by explaining the probability distributions and so-called “priors” to the parameters. Afterward, such distributions have been updated with respect to the data on hand and so-called “posterior probability distributions,” or “posteriors” for the time being and are compatible with both the experimental data and the priors, as the posteriors are obtained as the product of the possible data and the prior probability of the parameters.

Xenobiotics in Chemical Carcinogenesis

Systematical implication of effective biomarkers in population and occupational biomonitoring

An illustration of Bayesian population toxicokinetic-toxicodynamic modeling in risk analysis Several instances have been considered from a new article on dichloromethane (DCM) (Jonsson & Johanson, 2001). The carcinogenic impact of DCM is associated with metabolic activation regulated by glutathione-S-transferase theta 1 (GSTT1), while oxidation acts as a detoxification mechanism. In contrary to GSTT1, both 0/0, 1 /0 and 1 / 1 individuals were found by PCR genotyping coupled with phenotyping ex vivo. The in vivo GSTT1 metabolic capability has been detected to relate to genotype. In an initial step, an earlier developed population toxicokinetic model for DCM had been accumulated together with immense human toxicokinetic data from 27 male volunteers exposed to 250
1000 ppm DCM (Astrand et al., 1975) by using MCMC (Markov chain Monte Carlo) simulation. In such a way, the improved population estimates had been determined for the PBPK (Physiologically-Based Pharmacokinetic) model parameters. In a second step, more cancer risk had been calculated for long-lasting exposure to 10
1000 ppm DCM by a common Monte Carlo simulation. Ten thousand individual parameter vectors had been simulated by employing the posterior estimates of the population parameters obtained in the first step, in combination with the updated and exact estimates from the available article. The available data on the frequencies of the three genotypes in the Swedish population had been implicated to obtain a causal population distribution for the parameter regulating metabolism through the GSTT1 mechanism. An existing toxicodynamic model had been employed, where cancer risk had been implied as a direct function of amount DCM metabolized through GSTT1 (El-Masri et al., 1999). Instances of the Monte Carlo simulations have been explained by predicting the prevalence of risk in the Swedish population based

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on life-long exposures to 1 and 1000 ppm of DCM. Two considerable changes were shown between low (1 ppm) to very high (1000 ppm) exposure, mainly (1) a more average cancer risk per ppm of DCM and (2) a higher prevalence of risk, were observed. Such alterations have been elucidated by saturation of the protective oxidative mechanism causing in (1) a lower intrinsic clearance (Vmax/km) and hence availability of greater proportion of DCM for metabolism through the cancer developing GSTT1 pathway and (2) a transfer from flow-limited to capacity-limited metabolism. Hence, the comparatively low mean and narrow distribution of risk at 1 ppm reflects potential, flow-limited deactivation with a limited distribution in pulverization and also in inactivation and activation rates. However, the relatively high mean and wide distribution of risk at 1000 ppm results in saturated deactivation with a greater distribution in maximum metabolic efficiency of the protective mechanism which indicates a more distribution playing crucial role in deactivation and activation rates of risk factors (Jonsson & Johanson, 2003). At both exposure levels, the risk for 1 / 1 individuals was measured to be greater than for 1 /0 individuals at the population level, although the two groups overlap to a noticeable matter, particularly since considering the mean activity for the carcinogenic GSTT1 mechanism is doubled in the 1 / 1 group.

Systematical implication of effective biomarkers in population and occupational biomonitoring Efficient biomarkers can be employed to explain the relationship of exposure to environmental compounds and their mixtures associated with health issues (Table 5.1), though they are usually underused, as primal biological pathways are not well known. A multidisciplinary expert from the European chapter of the International Society for

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TABLE 5.1 Role of biomarkers in human biomonitoring related to exposure to certain xenobiotic chemicals (Jeddi et al., 2021). Types of biomarker

Used for xenobiotic chemicals

Outcome of health problems

Impact of biomarkers

Cancer biomarkers

Hexavalent chromium

Development of cancer

Plasma carcinoembryonic antigen: NSE; SCC; CYFRA; CA; AFP; 3-nitrotyrosine; prostate-specific antigen; high sensitive C reactive protein, CC16 (Clara cell secretory protein), SP-D, TNF-α; plasma total homocysteine

Genotoxicity biomarkers

PAHs; hexavalent chromium; acrylamide; mycotoxins

Carcinogenesis and teratogenesis

Chromosomal aberrations, sister chromatid exchange, micronucleus test

Oxidative stress

Hexavalent chromium; inorganic arsenic; PAHs; bisphenols; phthalates; PFOA; acrylamide; UV-filters

Several different outcomes including cancer, cardiometabolic diseases and adverse pregnancy outcomes

DNA damage: Urinary 8-hydroxy-20 deoxyguanosine (8-OHdG) lipid peroxidation: 8-isoprostane

Epigenetics and gene expression biomarkers

Cadmium; acrylamide; inorganic arsenic, cadmium; acrylamide

Depends on extent of exposure and the investigation of molecular targets for cancer development

Gene expression and methylation: pMAPK expression, DNA methylation levels and histone methylation levels in oocytes

AFP, α-Fetoprotein; CA, cancer antigen; CYFRA, cytokeratin fragment antigen; NSE, neuron specific enolase; PAHs, polycyclic aromatic hydrocarbons; PFOA, perfluorooctanoic acid; SCC, squamous cell carcinoma antigen; SP-D, surfactant protein D; TNF-α, tumor necrosis factor-α.

Exposure Science (ISES Europe) and the Organization for Economic Co-operation and Development (OECD) Occupational Biomonitoring activity of Working Parties of Hazard and Exposure Assessment group had worked together to design the lineal structure of biomarkers and recommended for their systematic implication. The work on a conventional framework of biomarkers has been described in three part. Part I is the available effective biomarkers and promising new biomarkers for the common population were associated with the H2020 Human Biomonitoring for Europe (HBM4EU) action. Part II provides an oversight of the implication of AOP and physiologically-based kinetic and dynamic (PBK/ D) modeling, which upgraded the recruitment and interpretation of efficient biomarkers. Part III explains the garnered expertise from the OECD Occupational Biomonitoring subtask potential

biomarkers in prioritizing exact modes of actions (MoAs) and applicable impact biomarkers (A et al., 2021). Various efficient biomarkers, in particular for implication in occupational settings, have been legitimized. It provides a direct assessment of the collective health risks based on the exposure to chemicals, chemical mixtures, and their transformed products. Promising novel potential biomarkers are evolving for biomonitoring of the common population. Attempts are being devoted to exploring the prioritization of molecular and biochemical efficient biomarkers which could explain a causal link in exposure-health outcome associations. Such mechanistic attempts have great potential in enhancing human health risk analysis. Advanced approaches like in silico approaches (QSAR, PBK/D modeling and ‘omics data) would help in such events.

Xenobiotics in Chemical Carcinogenesis

The pivotal function of xenobiotic receptors and cytochrome P450 induction in toxicokinetics and toxicodynamics

The pivotal function of xenobiotic receptors and cytochrome P450 induction in toxicokinetics and toxicodynamics The induction of cytochrome P450 (CYP) has been identified for the first time during testing carcinogenesis by several chemicals such as polycyclic aromatic hydrocarbons (PAHs) and drug resilience of barbiturates and other analogous chemicals (Hakkola et al., 2018). Explaining such outcomes in modern AOPs, CYP induction, or more accurately, the interaction of a ligand to a nuclear receptor (NR), can be recognized in several methods either as a MIE or as a modifying component of an AOP. Ligand complexation to NR is a MIE when it leads through downstream KEs to AO and such possibilities would be explained by connecting physiological roles of NRs. In other views, ligand interaction to NR is not a MIE, or an intermediary key event (KE), since it is not a part of a linear mechanism. In this case, receptor activation can be expected as an altering biological process, which is delivered to an AOP without being a part of the AOP itself. For instance, it has been widely elucidated, as in the condition of PAH carcinogenesis, that the production of a reactive carcinogen metabolite by involving a CYP enzyme and the complexation of a metabolite to DNA are major initial methods causing cancer. In such views, the DNA interaction of a DNA-reactive carcinogen metabolite and the subsequent DNA damage might be imagined as a MIE for the straight AOP scheme. The triggering of carcinogen-activating CYP enzymes by NRs changes such KE/MIE in the carcinogenic event, and hence, such induction can be referred to as a modifying factor. During barbiturate tolerance, the increase of metabolizing enzymes influences the concentration of a drug and hence its interaction (activation) to the GABAA receptor with a central nervous system (CNS) depression in an animal or in

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human being. In such aspects, the induction of CYP might not be considered as KE, as there is not a KE in the continuous events resulting from MIE to AO. In another way, an alternative method to decipher the above explained instances is to observe the activation of a nuclear receptor as a MIE and modify it as an increase or decrease in the level of the active molecule, either DNA-reactive metabolite or receptor-activating parent drug, as a downstream KE causing AO. The obstacles in incorporating metabolic events like the production of reactive metabolites are also known as part of toxicokinetic and ADME, for AOP approach (Leist et al., 2017). CYP3A4 is seemingly the highest essential CYP enzyme for metabolism of compounds, and for such reason, the induction and alteration of CYP3A4 are essential altering factors in a large number of chemical-induced toxicities, particularly, in pharmaceuticals (Cheng et al., 2011). For instance, anticancer therapyrelated adverse impact have been related with CYP3A4 differentiation due to induction and genetic polymorphisms in breast, prostate, gynecological, and colorectal cancers (De Mattia et al., 2016; Pondugula et al., 2016), and further, the interest of implication of nuclear receptor activation and target gene induction as biomarkers for exhibiting critical risks and rendering into successful treatments of diseases (Riley & Wilson, 2015).

Potential differentiation of sex in human and animal toxicology Being a female or male is explained by sex, which efficiently responds to all xenobiotic exposures, both inadvertent and deliberate, and affects their toxicokinetics, toxicodynamics, and results. Sex differences appear in behavior, exposure, anatomy, physiology, biochemistry, and genetics, assigning female-male differences with respect to

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environmental factors, diet, and pharmaceuticals with side effects of the drug. Sometimes, researchers have emphasized only one sex, adapted for sex, or avoided it. While studying occupational epidemiology to understand several toxic impacts in humans, the consideration of women is generally excluded. Instead of sex-specific organs, sex differences and sex 3 age interactions accomplish a large number of disease states and hormone-influenced conditions and drug delivery. While it has been found that women are more prone to adverse drug reactions (ADRs) than men, The Classic Sex Hormone Paradigm such as gonadectomy and replacement, exhibits relevant interactions of sex and toxicokinetic process: absorption, distribution, metabolism, and elimination. The approaches must be designed to determine sex differences, explain the pathways, and interpret these events in wide social, clinical, and evolutionary aspects by considering such phenomena that do not highly vary. Obviously, sex matters in responding to exposures, but how much of a difference is required remains challenging (Gochfeld, 2017). Sex disparities in response to chemical, physical, biological, or psychosocial pressures are easily observed, and tragic differences in how males and females act to exposures remain very challenging. It is very amazing that certain chemicals develop cancer or disease only in one sex but not another. Obviously, males and female humans have different lifestyles, experiences, and exposures, and most of them are not technically or ethically susceptible to disciplined trials. However, animal studies provide the chance to bypass such disparities and emphasize sex differences in anatomy, physiology, biochemistry, molecular biology, and nature. Instead of the sexspecific organs and sexually special hormonal axes, males and females might reveal differences in anatomy, physiology, and biochemistry of the organ systems that are in common. The typical sex hormone paradigm of agonistsantagonists-gonadectomy-replacement is highly

harnessed and has been added in the last decade by different kinds of knockout mice and by high throughput genetic sequencing leading advances in several “omics” (Carey et al., 2007). Disparities between sexes could be separated as: (1) sociocultural, (2) exposure, (3) body size and composition, (4) genetic-molecular-biochemical, and (5) hormonal and reproductive, including pregnancy. Also, some sex differences in anatomy, physiology, and pharmacology, develop from the bigger average body size and mass of males in several species than females (Nair & Jacob, 2016). Adverse drug reactions Most information related to ADRs is collected from spontaneous statements by patients or doctors to several pharmacovigilance systems in various countries (Ryu et al., 2015). This information experiences selection prejudice with highly severe ADRs more likely to be recorded. It has been reported that women have greater ADRs than men due partially to exhibitions of machismo among males and partially to reflecting real susceptibilities (Ryu et al., 2015). A Dutch study explained that possibly more women had participated than men to volunteer for a web-based pharmacovigilance survey program for humanitarian causes (Ha¨rmark et al., 2013). There has been a 50% enhanced risk of ADRs for women (Rademaker, 2001), whereas a twofold enhanced risk across “all drug classes,” (Nakagawa & Kajiwara, 2015) and women who had highly severe ADRs were more likely to need hospitalization. However, such ADR sex disparity is not as clear in childhood (Damien et al., 2016). The intensive reflection of female rats to anesthesia has been observed for approximately a century (Nicholas & Barron, 1932). Women might need more doses of certain drugs or may be highly sensitive to respiratory depression, and waking earlier. ADRs can be associated with overdose and toxicity of the certain pharmacologic impact or to adverse effects, irrelevant to the fundamental mode of action. The first condition is dose-dependent,

Xenobiotics in Chemical Carcinogenesis

The pivotal function of xenobiotic receptors and cytochrome P450 induction in toxicokinetics and toxicodynamics

the second is more likely associated with idiosyncrasies and probably dose-independent. ADRs often develop from drug interactions, and normally have more medications develop both arithmetic risk increases viz. more drugs cause more risk and a multiplicative risk that is, interaction. Hence, both toxicokinetics and toxicodynamics play vital roles in explaining ADRs. A list of several pharmaceutical impacts to males and females, separately, had been published in several articles. Women had good response to even lower doses of psychoactive drugs in comparison to men (Seeman, 2004). At the same dose of fluoxetine, women exhibited a higher cortisol than men (Bano et al., 2004). This can happen at higher concentrations of the drug at the target site that is, toxicokinetic or changed metabolic profile. Such disparities in frequencies of ADRs have several likely reasons associated with pharmacokinetics and pharmacodynamics (Anderson, 2008). Due to above reason, several FDA drugs have been banned due to production of toxic impact in women (U.S. Government Accountability Office, 2001). Hence, such adverse impacts might have been identified long ago if women had been considered as volunteers in the drug development trials. Body composition The average height and body mass of males are taller and heavier than females throughout society. Such anatomical disparities have been shown higher attention than physiological differences. Differences in body weight are employed to correct organ weights and physiological metrics or scale therapeutic doses for females (Nair & Jacob, 2016). The International Commission on Radiological Protection (ICRP) created its “reference man” to help in estimating radiation doses to organs. ICRP 89 has calculated average values for percent body composition for adult males and females

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(Valentin, 2002). The data had not been associated with physiologically-based pharmacokinetic modeling (PBPK) due to the lack of distribution parameters (Gochfeld, 2007). In clarifying morphological differences, ICRP data have been transferred into percentages of organ weight divided by body weight for example, 73 g for adult males and 60 kg for adult females, and investigated the ratio of such relative organ weights for females versus males. Maximum organs have less than a 10% difference in the weight-corrected values, although the ratio for adipose tissue was 50% greater in females. Females also had comparatively heavier pituitaries (21%), adrenals (13%), and GI tract (14%), whereas males had greater total lung capacity and vital capacity (13%), blood (11%), bone (12%), skin (15%), and specifically skeletal muscle (27%) (Valentin, 2002). There was only a 6% difference in body mass to surface area, 38.4 kg m22 for males versus 36.1 kg m22 for females. Hence sufficient differences exist even after measuring body weight. The differences in size of the physiological body between men and women are small. Such differences in forced vital capacity have been accounted for in reference standards for spirometry, although they are not in the same patterns: with excessive workouts, women have maximum ventilation frequencies (Valentin, 2002). Cardiac output is greater in women whereas men have greater blood volume (Valentin, 2002). The basal metabolic rate (BMR) of women is 52 kcal h21 in comparison to 68 kcal h21 for men, hence standardized for body mass the female BMR is 93% with respect to men, whereas weight standardized total energy expenditure is 78% of male, reflected in average calories exhausted. Risk assessors implicate a default value of 2 L day21 for adult drinking water intake, which is a good approximation of the 1960 mL day21 for females but underestimates the 2600 mL day21 for males (from Table 2.30 in Valentin, 2002).

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5. Toxicokinetics and toxicodynamics of xenobiotics in cancer development

Sex hormones and their exemplification The heterogametic sex determination in the embryo of human is a peculiar characteristic, if it is XX (female) or XY (male). The Y chromosome has the sry gene, which directs the sex differentiation and development of the fetal testes. The presence of genes on sex chromosomes directly influences brain formation and determines the hormones that indirectly exert several effects. In both males and females, androgens regulate the function of brain (Application of Toxicogenomics to Cross-Species Extrapolation, 2005). Steroids could alter gene expression, if triggering neurons to develop new or reject old synapses (Kawata et al., 1994). The estrogenic and androgenic hormones and their receptors are always changing throughout the life cycle. Even the estrous/menstrual cycle in females regulates a short-term cycle as well. Since the mid-1900s, physiologists and ethologists and, recently, toxicologists have implied the effect of estrogenic and androgenic hormone systems largely on different behavioral and physiological phenomena (Adkins-Regan, 2007). The stepwise experiment is designed as (1) determining sex differences, (2) gonadectomy, (3) replacement with same sex hormones, (4) replacement with opposite sex hormone. Afterward, such modifications have: (5) experiments with agonists and antagonists, (6) studies with genetically modified animals (knockouts), and lastly (7) segregation of genetic sex from gonadal sex by modifying the sry testes-determining gene (Arnold & Burgoyne, 2004). Some genes which have high fold differences are found on the Y and X chromosomes (Yang & Li, 2012). It has also relocated the testes-determining sry gene from the Y chromosome to an autosome through transgenic insertion (Arnold & Burgoyne, 2004). After successful breeding, XX and XY males along with XY and XX females have been generated. It has been observed that less than 10 genes differentially were expressed in XX versus XY males

and XX versus XY females suggesting some genes are controlled directly in the lack of sex hormones (Arnold et al., 2012). Organisms, like vertebrates, have separate sexes, exhibit dimorphic behavior, especially with respect to reproduction, and are regulated by sex certain brain centers, which might include new neurons or contact under hormonal regulation. These are associated with several cycles with annual photoperiodism. The prominent sex differences happen in centers regarding touch and olfaction in nocturnal mammals and vision and hearing in birds (Nottebohm & Arnold, 1976). The typical paradigm of sex hormone can be seen in renal clearance fit. For instance, perfluorooctanoic acid (PFOA) has garnered attention due to detectable residues of such persistent organic pollutant (POP) universal in human and animal tissue. PFOA is removed through an organic anion transporter (OAT) in the renal tubule, although the half-life is 70 times greater in male than female rats (Worley & Fisher, 2015). The treatment of estradiol or castration increases the elimination rate in males, whereas subsequent testosterone treatment prolongs it. Ovariectomy revealed clearance in females and estradiol restored it (Worley & Fisher, 2015). Growth hormone Growth hormone has several functions in controlling sex-dependent gene expression (Waxman & O’Connor, 2006). Maximum cyp450 genes are upregulated by growth hormone. The malefemale disparity in CYP expression might exceed 500-fold in rats and mice, so that some isoforms seem sex-specific. Identical but smaller differences are observed in humans. The timing for release of growth hormone varies throughout the life span. In human females, the growth hormone is liberated at a somewhat regular level, which induces CYP3A4 expression in the liver in response to dexamethasone, whereas pulsatile releases of

Xenobiotics in Chemical Carcinogenesis

Genotoxic and nongenotoxic mechanisms of xenobiotics in carcinogenesis

growth hormone are seen in males due to inhibitory properties (Dhir et al., 2006). Such impacts are less noticed in humans than in rats. Similarly, the CYP2C11 expression is controlled by growth hormone in the spleen and thymus (Thangavel et al., 2007). Exposure The 2007 Framework has determined the sex disparities in exposure event and link to associated behavior and occupation in the home, community, and workplace environment (Gochfeld, 2007). Behavioral differences occurring under “lifestyle” directly influence contact and intake. For instance, smoking is harmful to both sexes, although males and females smoke differently, where males draw more on the cigarette, whereas women usually hold cigarettes close to their face and feel higher side-stream smoke (Burger & Gochfeld, 1990). Apart from humans, male and female mammals and birds reveal different individual and social behavior that affect the intake of nutrients and toxicants (Burger, 2007). Sexual dimorphism, dominance, and social groupings are essential in the wild and are employed in laboratory studies. Males and females vary in locomotor and research activities and consumption of energy associated with dominance, mating, and reproduction. Endocrine disruption It has also been reported that targets of endocrine disruption also play critical roles in sex differences. The mechanism of chlorinated hydrocarbon pesticides induces hormones which destroy estrogen, hindering egg production in birds like pelicans, eagles, and falcons, and have led to the extinction of some birds within a 20 year period (Peakall et al., 1975). The great publication of “Our Stolen Future” (Colborn et al., 1996) revived and emphasized interest in endocrine active molecules in the environment influencing humans, leading to a significant study on sex differences:

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• Production and liberation of proteins and hormones • Up or down-regulation of receptors • Non-steroidal agonists that is, activation binding • Non-activating receptor binding that is, competitive inhibition • Non-hormonal imitators or antagonists that is, receptor or non-receptor mediated • Changed metabolism that is, increased or decreased breakdown • Modified transport quantity or free:bound ratios

Genotoxic and nongenotoxic mechanisms of xenobiotics in carcinogenesis The genotoxic mechanisms in the development of tumors are directly associated with mutations that lead to oncogene activation and tumorsuppressor gene inactivation. Nonetheless, it has been understood for several years that cancers could develop without direct or indirect interaction of a chemical and cellular DNA, which is, in the dearth of direct mutations. The differentiation between nongenotoxic and genotoxic carcinogens had been clearly defined following the characterization of a several kinds of nongenotoxic carcinogens by the US National Toxicology Program (Ashby et al., 1989). These contain a large number of chemicals acting by a different kind of mechanisms, like interruption of regular hormonal homeostasis in hormone responsive tissues, and peroxisome proliferation and proliferation of urothelial cells of the ureter and urinary bladder following impairment by kidney stones. Genotoxic carcinogens contribute to tumor formation in various tissues of both males and females in rats as well as mice. In contrast, nongenotoxic carcinogens generally stimulate tumor development only at high doses, in a single tissue, in a particular sex, or only in certain species. So far, the available experimental

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data does not clearly explain the presence of actual thresholds for DNA-reactive carcinogens, however small concentrations might exist for which, experimentally, the manifested tumor clinically might not be identified in the animal or human lifespan. Therefore, such concentrations could not be taken as thresholds. In particular, for those carcinogens which operate through other biological impact, the carcinogenic activity will parallel dose-response relationships of the significant biologic impacts, which is a highly pertinent aspect for human risk assessment. Treatment procedure or exposure views which do not create biological impact will not stimulate tumor development. This is because there are two main limitations: very less dose-response studies have been conducted with nongenotoxic carcinogens, and in most cases the biochemical pathways causing tumor development action are not well explored. Generally, nongenotoxic carcinogens have been comprised into two main groups. The first group contains such compounds which stimulate cytotoxicity and regenerative cell proliferation such as 2,2,4-trimethylpentane and other branched-chain hydrocarbons in the proximal tubules. The second group of nongenotoxic carcinogens trigger cell proliferation without cytotoxicity viz. they are directly mitogenic, a significant instance of such nongenotoxic group are carcinogenic hormones or peroxisome proliferators like di (2-ethylhexyl) phthalate and clofibrate. The stimulation of cell proliferation is involved in both groups of nongenotoxic carcinogens and might lead to malignant transformation by enhancing the large number of spontaneous genetic errors, so that DNA replication does not happen with 100% fidelity. Further, in frequently proliferating cells, DNA damage has a greater possibility of being transformed to heritable mutations. However, in all such cases, cell proliferation is the final outcome of an as-yet unrecognized molecular processes.

The events of genotoxic and nongenotoxic are not mutually distinct processes. However, they participate in tumor development, as could be observed with several genotoxic carcinogens. In many cases, genotoxic carcinogens stimulate tumor formation only upon implications of high doses, collectively leading to cytotoxicity, cell death, and regenerative proliferation. So, tumor formation is the final result of a complex, multistep interaction between genotoxic and extranuclear mechanisms.

Advanced approaches in the science of xenobiotic toxicology Increasing our understanding toward biological and chemical phenomena has immensely enhanced the possibility of exploring the mechanisms associated with the toxicity impacts of compounds. Such advances in understanding have increased the development of test methods underlying mechanistic events. This has been highly upgraded by an increase in technology in toxicology field. Such scientific and technological upgrades can be identified in three major areas (Blaauboer, 2002). The first area is our increasing knowledge on the fundamental physiological events in biology. The advancement in molecular biology, cell culture techniques, (neuro) physiological scales, genomics, etc., has shown more impact in toxicological fundamental studies, and would easily create their effect on testing methods (Harries et al., 2001). New test approaches usually reflect such increased knowledge of molecular biology and an advanced level of scientific implications. Hence, the events for advancement of a new approach is more highly scientifically meticulous than in the past, leading to advanced tests that can result in an advancement in the quality of risk analysis (Walker et al., 1998). An exemplary overview of several such new methods has been published by the ECVAM research group on chemicals (Worth et al., 2002), in which the

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Conclusions

ECVAM workshop reports are also accounted. Such workshops had been organized over the last decade and provide the state of the art in particular fields of in vitro approaches (see also the ECVAM internet site: http://ecvam.jrc.it). Further, a pertinent advantage of in vitro approaches is that human derived systems could be implicated for toxicological studies (MacGregor et al., 2001). The second area is the growing understanding in chemical aspects. In this case, also basis is our understanding in molecular events, generating better knowledge of the process in which chemicals might interact with each other. The identification of molecular fragments with a particular chemical activity could lead to a measurement of a chemical’s reactivity in a living system (Xie, 2010). The establishment of the relationship between the structural and biological characteristics of chemicals could be conducted into knowledge-based expert systems. The implications of such databases are usually referred to as “in silico” toxicology. DEREK is one such expert system (Ridings et al., 1996) and could be employed to analyze the relationship between particular fractions of the molecule under study and several kinds of toxicological endpoints like mutagenicity, carcinogenicity, and skin sensitization, and it is highly used in the chemical industry. Other systems, like CASE or TOPKAT, are used for statistical studies (Benfenati & Gini, 1997). Extra physicochemical properties for example, lipophilicity, hydrophilicity, and molecular weight, might be included in this relationship between chemical structure and toxicity. This approach has developed the quantitative structure activity relationships (QSARs) in a number of areas, which is still growing. However, QSARs are limited to specific chemical groups and well-organized biological events (Barratt et al., 1996). A third area of advancement is associated with computer-based modeling techniques. Over the last 15 years, the feasibility of such modeling methods has been highly enhanced

by the availability of computer techniques which offer for the simultaneous, numerical solution of differential equations (Clewell & Andersen, 1996). This method has developed PBBK models that allow for the explanation of time-courses of the tissue content of the chemical under toxicological study (Faller et al., 2001). Further, this could be observed as an advancement in the field of toxicodynamic modeling, offering an explanation of the mechanisms causing adverse impacts (Geiss & Frazier, 2001). Hence, increases in our knowledge of the process in which a chemical’s toxicity is evaluated by its own physicochemical characteristics as well as physiological events in the biological system have highly enhanced both our knowledge in toxicological processes and also our capability to analyze experimental outcomes.

Conclusions The fundamental function of most toxic xenobiotics compounds is based on cellular damage, and such damage is sometimes most dramatic in cells with high frequencies of metabolism and replication. The toxic xenobiotic molecules produce adverse effects on cells by altering their biologic microenvironment like pH or occupation of a specific receptor site, where ultimate toxicants usually interact with target sites of cells. In addition, some xenobiotic molecules imitate the function of common nutrients and endogenous hormones or neurotransmitters. Hence, certain receptors are stimulated or blocked, and the activities of enzymes are inactivated or inhibited. During the biotransformation of xenobiotic molecules, the electrophiles, free radicals, nucleophiles, and redox-active compounds are often produced, and these chemical species react instinctively with target macromolecules to produce their toxic effects. At the cellular level, the toxic chemicals can modify cellular maintenance,

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both internally and externally, by affecting membrane integrity and the capability of cells to control their volume and energy metabolism. Eventually, more exposure to toxic xenobiotic molecules through toxicokinetics and toxicodynamics leads to cellular dysfunction and injury and, often, disrepair, and such adverse effects could be addressed clinically as abnormalities in the structure and function of particular organs and tissues. The exploration of science in risk assessment/safety assurance for non-cancer endpoints is very slow with developments in toxicology and clinical sciences. Sophisticated knowledge on standard default uncertainty factors and its mechanisms of toxicity, genetics and other sources of human variability are not sufficient, unless the scientific data is contributing to the selection of appropriate uncertainty factors. Therefore, the introduction of toxicokinetic and toxicodynamic data related to the xenobiotic compound under evaluation offers the possibility of producing a compoundrelated uncertainty factor that would cover both quantified differences and remaining uncertainty. Toxicokinetic and toxicodynamic modeling are essential tools in toxicological research, and there are increasing possibilities to integrate these outcomes into hazard and risk assessment. Their application would endorse many more scientifically based approaches and better structured risk assessment that could be less reliant on animal experimentation.

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6 Mechanism of oxidative stress in carcinogenesis induced by xenobiotics Introduction

This event is irreversible with genetic instability, alterations in nuclear ploidy, and breakdown of chromosome integrity. Consequential examinations have revealed that cancer development is highly intricate process, and by using the three stages, it is understood where and how modifiers of cancer work. Based on this multistep carcinogenesis, it is clearly known that chemicals inducing cancer can work at all stages of the events in cancer development (Klaunig & Wang, 2018). Particular carcinogenic compounds underlying the oncogenic events for stimulating hepatic cancer are classified based upon molecular sites and cellular impacts, which include genotoxic (DNA reactive) and nongenotoxic (epigenetic) processes (Klaunig & Wang, 2018). Genotoxic compounds are mainly known for the direct damage of genomic DNA that lead to mutation and/or clastogenic alteration. Such groupings of chemicals are immediately activated in the target site and develop a dose-dependent neoplasm. A second group of carcinogenic compounds belonging to nongenotoxic are either non-DNA reactive or indirect DNA reactive species. Nongenotoxic carcinogens modify the proliferation of cell and cell death. Alterations in gene expression and cell proliferation aspects are predominant in the function of nongenotoxic carcinogens. Such carcinogenic compounds work

Development of cancer cells is associated with multiple events, in which a fundamental process involves genetic alteration in genomic DNA viz. development of a mutated cell, followed by a certain growth of the mutated cell. Such growth is induced by either an escalation in the rate of cell division in the mutated cell and/or a decline in the death rate that is, apoptosis of the mutated cell. Since the mutated cell further divides, other epigenetic and genetic alterations happen in the newly produced lesion. Earlier examinations identified the alterations occurring in tumorigenesis that leads to the initiation, promotion, and progression to describe cellular mechanisms (Klaunig & Wang, 2018). Initiation generates the mutation, a preneoplastic cell from a genotoxic step that is an irreversible, but dose-dependent event. Promotion has selective clonal expansion of the initiated cell via escalation in cell growth through either a stimulation in cell proliferation and/or a decrease in apoptosis in the target cell population (Schulte-Hermann et al., 1994). This process depends on dose and is reversed after removal of the cancer development stimulus. Third stage “progression” implicates the cellular and molecular alterations which are exhibited from the preneoplastic to the neoplastic states.

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during the promotion stage of cancer development (Klaunig & Wang, 2018; Kolaja et al., 1996). The enhanced replicative DNA synthesis and frequent cell division is a key event in every stage of oncogenesis (Butterworth, 1990; Kolaja et al., 1996). Two potential processes for cancer stimulation by nongenotoxic compounds have been designed. First, increasing DNA synthesis and cell division through a nongenotoxic carcinogens might develop mutations in proliferating cells via disrepair. The mutations generated by continuous cell division in preneoplastic cells would clonally grow to a neoplasm. Moreover, nongenotoxic compounds work to induce the selective clonal growth in spontaneously initiated cells (Ames & Gold, 1990). Several studies have explained a critical function for reactive oxygen species (ROS) in cancer formation (Ishikawa et al., 2008). ROS is generated from endogenous sources like mitochondria, peroxisomes, and inflammatory cell activation (Chikara et al., 2018) and exogenous sources such as environmental agents, radiation, pharmaceuticals, and industrial chemicals. Oxidative stress might cause genetic mutation and/or changes in cell growth. With neoplasm formation, reactive oxidant species could be produced from both endogenous and exogenous sources. Moreover, the chemical carcinogens abrogate the cellular antioxidant systems and DNA repair systems. Both endogenous as well as exogenous sources of ROS are capable of interacting and altering all events of carcinogenesis. The main ROS are superoxide anion radical (O2•2), hydrogen peroxide (H2O2), and hydroxy radical (•OH) molecules, which are produced through successive intracellular reductions of molecular oxygen. O2•2 is usually produced as a side product of mitochondrial respiration, since electrons are transferred by ubiquinone or semiubiquinone directly to oxygen despite successive acceptors in the respiratory electron transfer chain (Henkler et al., 2010). This side reactions also accomplish at the ironsulfur components of complex I and III. It has

been accounted that up to 5% of total oxygen depleted by mitochondria is transformed into the superoxide anion radical (Henkler et al., 2010). O2•2 is also produced by NADPH oxidases of phagocytes. Other endogenous sources have metabolizing enzymes like 5-lipoxygenase, xanthine oxidase, and to a lesser extent cytochrome P450-dependent monooxygenases (CYPs) (Novo & Parola, 2008). With respect to the mitochondrial redox-systems, an incidental electron transfer from CYPs to oxygen is less prominent due to no formation of intermediate electron carriers from CYP enzymes. Hence, O2•2 is considered as the main ROS because it has one reduction equivalent. This ROS component is short-lived and shows less capacity to transfer cellular membranes. The maximum O2•2 is converted into hydrogen peroxide (H2O2) and molecular oxygen in the presence of superoxide-dismutase (SOD). Hydrogen peroxide is slightly stable, able to pass cellular membranes and could thus be known as the central ROS in cancer development. H2O2 is converted into oxygen and water by catalases and glutathione peroxidases. It should be noted that H2O2 is highly oxidative and can be further reduced to the hydroxy radical (•OH). Although the reduction of O2•2 by SOD or non-enzymatic process is not the main pathway for the production of H2O2, it is well-known that about 80% of H2O2 is generated by peroxisomal and microsomal enzymes (Rhee et al., 2003). For instance, peroxisomes produce a maximum of H2O2 while ß-oxidation of long-chain fatty acids. The different mechanism in peroxisomal ßoxidation involves its mitochondrial counterpart as acyl-CoA oxidase stimulates the initial step, which produces trans-2,3-dehydroacyl-CoA along with H2O2 (Henkler et al., 2010; Wanders et al., 2010). The first component is immediately broken down into acetyl-CoA units through continuous oxidation cycles. H2O2 is also a side-product of other peroxisomal oxidases like D-amino acid oxidase, D-aspartate oxidase, or polyamine oxidase (Schrader & Fahimi, 2006).

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The entire activity of peroxisomal enzymes simultaneously might estimate up to 20% of the total cellular oxygen utilization in liver cells. Microsomal CYP-mediated ω-oxidation of fatty acids has also been explained as a main pathway for H2O2 production (Yu et al., 2005). Xenobiotic compounds are also responsible in the development of various kinds of cancers. Clinical examinations have explained that an altered homeostasis of intracellular iron is associated with carcinogenesis (Toyokuni, 2009). Hereditary hemochromatosis is a metabolic ailment related with accumulation of extensive iron, particularly in the liver, and consists a critical risk factor for hepatocellular cancer in developed countries (Kew, 2014). Thus, the triggering of oxidative stress by high levels of iron is considered as an important pathway associated with carcinogenic risk (Toyokuni, 2009). A pivotal mechanism underlying lipid metabolism exerting a major effect on endogenous ROS levels is regulated by peroxisome proliferator-activated receptors (PPARs) (Yu et al., 2005). PPARα is a main regulator of fatty acid oxidation and generally triggered by lipids and long chain fatty acids which endure microsomal or peroxisomal degradation (Yeldandi et al., 2000). However, organic solvents, pharmaceuticals that is, fibrate drugs, specific phthalates as a plasticizer, and other synthetic materials could substitute endogenous ligands. Target genes of PPARα have acyl-CoA oxidase, CYP4A1, and 4A6. Sustained PPAR activation increases H2O2 levels and oxidative stress (Yeldandi et al., 2000). Furthermore, a pivotal role of the sustained PPARα activation in liver carcinogenesis has been explained in acyl-CoA oxidase of mice (Fan et al., 1998). In rodents, the xenobiotic activators of PPARs have been explored as potential nongenotoxic carcinogens. Interestingly, activity levels of PPAR exhibit a huge variation in species for example, di-(2-ethylhexyl) phthalate (DEHP) works as a PPAR activator in rodents but

probably not in human cells. Hence, such matters create problems for human health, because mechanisms which produce negative impacts have not yet been widely understood (Guyton et al., 2009). In this review, the relevance of oxidative stress developed by xenobiotics compounds for development of cancer is discussed.

Oxidative DNA damage The main cause of mutations is oxidative damage in DNA that has shown 10,000 (human) to 100,000 (mouse) oxidative lesions per day in normal cells (Foksinski et al., 2004; Helbock et al., 1998) with rate of 104 lesions/ cell/day (Lu et al., 2001). The hydroxyl radical is a highly reactive ROS factor that interacts with DNA (Lu et al., 2001). Hence, immediate DNA replication is required to repair DNA damage to prevent cell death, DNA mutation, replication errors, and genomic instability (Valko et al., 2006). The most abundant oxidative DNA lesion, 8-hydroxydeoxy guanosine (8-OHdG), induces mutations in bacterial and mammalian cells (Cheng et al., 1992). 8-OHdG levels are increased in several human cancers (Diakowska et al., 2007; Weiss et al., 2005) and in the tumors of animal models (Muguruma et al., 2007). Cancer can be described as the formation of irreparable DNA damage in a specific cell with a round of DNA replication in a mutated cell. ROS trigger both single or double-stranded DNA damage, DNA cross links, and base changes. Although many produce oxidized bases, the hydroxyl radical has been widely studied for its oxidized DNA lesions (Marnett, 2000). Like the oxidative DNA adduct, the oxidation of guanine at the C8 position leads to the production of 8-hydroxydeoxyguanosine (OH8dG). The OH8dG-DNA adduct causes site-specific mutagenesis in bacterial and mammalian cells and also leads to dose-related

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increases in cellular transformation (Zhang et al., 2000). The ROS also interact with the nucleotides of DNA, particularly dGTP, to form OH8dG. So, OH8dG in the nucleotide pool is intercalated into DNA with replication leading to A:T to C:G transversions. Instead of OH8dG, other oxidative DNA lesions and uracil analogs have been shown to be mutagenic (Kreutzer & Essigmann, 1998). Apart from the ROS, reactive nitrogen species like peroxynitrites and nitrogen oxides also play major roles in the development of cancer (Ohshima & Bartsch, 1994). Peroxynitrite is able to interact with guanine forming an 8-nitroguanine adduct which stimulates G:C/T:A transversions. As shown, ROS can be generated via a multiple mechanism of xenobiotic molecules in cells. Hence, the oxidized DNA bases are able to induce mutations in neoplasia operating at the initiation stage of the cancer development.

Modification of gene expression In addition to impacts of ROS on DNA damage, the functions of ROS on epigenetic or nongenotoxic impacts have been examined (Evans et al., 2004). Exposure to ROS-stimulating agents leads to the upregulation of stress response genes, mainly those participating in antioxidant defense enzymes. The increased levels of ROS might lead to apoptosis or necrosis whereas lower levels alter expression of growth factors and proto-oncogenes (Fiorani et al., 1995) causing enhanced cell proliferation. The ROS-induced alteration in gene expression is accomplished via modification of various signaling mechanisms. ROS can stimulate kinases such as protein kinase C (PKC) that regulate cell cycle pathways (Wu, Tsai, et al., 2006) for proliferation and survival of cells associated with ROS-induced carcinogenesis. Transfer factors, mainly Nrf2, NF-kB, AP-1 and HIF-1a, on signaling pathways are activated by ROS exposure (Kensler et al., 2007;

Rankin & Giaccia, 2008). The stimulation of such transcription factors is ROS dose-dependent and hence this concentration dependence can lead to cell death or cell proliferation. Both endogenous and exogenous stressors can trigger Nrf2 (Osburn & Kensler, 2008). The activation of Nrf2 generates huge numbers of protective enzymes that also play a critical role in detoxification of xenobiotic molecules, antioxidative response, and proteome maintenance. This suggests that the lower levels of Nrf2 or entire loss of Nrf2 activity leads to enhanced ROS formation and DNA damage and predisposes cells to carcinogenesis. AP-1 has been recognized as a first transcription factor which also contributes to basal gene expression (Lee et al., 1987). AP-1 activity could be stimulated via H2O2 and is controlled by the redox state of cysteine in the cell (Klatt et al., 1999). The stimulation of AP-1 increases cell proliferation due to the enhanced expression of growth inducing genes (Brown et al., 1998). NF-kB is a nuclear transcription factor that participates in cell survival, differentiation, inflammation, and growth and thus, is also a direct target for ROS that can affect the binding potential of NF-kB toward DNA. The transcription factors are clearly activated due to induction of ROS-mediated signal transduction mechanisms. Through their potentiality to induce cell growth via regulation of apoptosis and/or cell division, transcription factors can regulate several physiological and pathological impacts of exposure ROS. Through regulation of gene transcription factors and interruption of the signal transduction mechanism, ROS is participates in the maintenance of rigorous networks of gene expression associated with neoplastic development.

Endogenous factors of ROS The primary endogenous sources of ROS are mitochondria oxidative phosphorylation, P450 metabolism, peroxisomes, and inflammatory cell activation. By mitochondrial oxidative

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pathway, about 4% 5% of molecular oxygen is transformed into ROS that is, superoxides. A superoxide is dismutated through superoxide dismutase to produce hydrogen peroxide that is converted into a hydroxyl radical (Klaunig et al., 2010). Presently, a relationship has been revealed between mitochondrial-induced ROS and tumor formation (Gottlieb & Tomlinson, 2005). ROS produced by mitochondria is higher in malignant cells than normal cells (Trachootham et al., 2006). Inflammatory cells like neutrophils, eosinophils, and macrophages are also an endogenous source for ROS. The stimulated macrophages generate several ROS, such as superoxide anions, hydrogen peroxide, and nitric oxide. Peroxisomes are cell organelles that deplete oxygen and play a role in generating cellular ROS. The formation of ROS in the peroxisome participates in acyl-CoA oxidase and xanthine oxidase that synthesize hydrogen peroxide and superoxide anions (Schrader & Fahimi, 2006). The peroxisomes in rat liver synthesis account for about 35% of all H2O2 generated from normal oxygen consumption (Schrader & Fahimi, 2006). The molecules that enhance peroxisome number viz. level of H2O2 formed like hypolipidemic drugs, phthalate esters, and halogenated solvents all lead to the formation of tumors in the liver (Moody et al., 1991), revealing a vital relationship between peroxisome proliferation-induced ROS and liver carcinogenesis (Corton et al., 2014; Felter et al., 2018).

Exogenous sources of ROS Several physical and chemical compounds that trigger the development of cancer in mammalian cells have been shown to work via oxidative stress mediated mechanisms. Ionizing radiation is identified as carcinogenic, when it works at every event of the carcinogenesis pathway (Little et al., 2008). The impacts of ionizing radiation are sometimes regulated by

ROS produced from the radiolysis of water causing DNA damage and leading to gene mutation and cancer development (Riley, 1994). Environmental agents such as non-DNA reactive carcinogens that is nongenotoxic develop ROS directly via metabolized intermediates or through induction of endogenous sources of ROS (Shi et al., 2004). The stimulation of oxidative stress and damage were detected following exposure to xenobiotic compounds of different structures and functions. For instance, chlorinated compounds, radiation, metal ions, barbiturates, phorbol esters, and some peroxisome proliferating chemicals are among the group of compounds that trigger oxidative stress and cancer (Shi et al., 2004). Therapeutic chemicals, mainly antineoplastic drugs, are also exogenous sources of ROS.

Arrays of oxidative stress It has been reported that the single nucleotide polymorphisms (SNPs) cause for the maximum genetic alterations in the human population (Shi et al., 2004). SNPs of interest participate in the mechanism of carcinogen metabolism that is, detoxification and/or stimulation, antioxidants, and DNA repair events. The metabolism of carcinogenic compounds (genotoxic and nongenotoxic) participates in both activation (phase I) and detoxification (phase II) reactions. Phase I reactions are regulated via cytochrome P450 (CYP) genes that play major roles in the metabolism of endogenous and exogenous xenobiotic compounds including therapeutic agents (Lewis et al., 2004). Cytochrome pathways use oxygen in generating their products and are capable of producing ROS. Phase II enzymes employ glutathione S-transferases (GSTs), a superfamily of phase II enzymes that catalyze the conjugation of electrophilic molecules with glutathione to protect cellular macromolecules from oxidative stress (Hayes & Strange, 2000). Antioxidant

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enzymes like superoxide dismutase, glutathione peroxidases, and catalase contain SNPs, which are related to the enhanced prevalence and susceptibility to cancer development (Conrad & Friedmann Angeli, 2018). Polymorphisms are also involved in the repair of DNA genes. Lesions of 8-OHdG DNA are usually repaired through base excision repair (BER) enzymes for example, 8-oxo guanine DNA glycosylase (OGG1), apurinic/apyrimidinic (AP), and endonuclease 1 (APE1). Various SNPs within hOGG1 have been identified (Kohno et al., 1998) and polymorphisms of OGG1 modify glycosylase activity as well as the capability of repairing oxidative DNA damage. Epidemiological studies explain the interrelationship between SNPs in OGG1 and have been related to the enhancement of human cancers (Hung et al., 2005). It has also been observed that polymorphisms in APE1 are associated with increased cancer risk (Jiao et al., 2006).

Oxidative stress linked with xenobiotic compounds in carcinogenesis A critical pathway of ROS production by carcinogenic xenobiotic compounds, such as polycyclic aromatic hydrocarbons (PAHs), participates in the transformation of such compounds into quinones. Such events happen mainly by oxidation into phenolic intermediates, which is further converted through semiquinone anion radicals into orthoquinones (Goetz & Luch, 2008). H2O2 and superoxide anion radicals (O2•2) are formed in this event. Mainly, quinones are substrates of several reductases like NAD(P)H: quinone oxidoreductase (NQO1) (Luch, 2005). While the reducing potential of cells is maintained, such compounds are converted back to hydroquinone or catechol and then are further auto-oxidized to produce H2O2 and O2•2 through futile redox-cycling (Henkler et al., 2010). Such a pathway is known as the main source for ROS in cells exposed to PAHs.

Like PAHs, Benzo[a]pyrene (BP) is a major xenobiotic compound metabolized by several pathways. The formation of BP-7,8-diol-9,10epoxide (BPDE) has been identified as the predominant pathway for cancer development, as this metabolite highly reacts with guanine or adenine residues to produce DNA adducts. As a part of this pathway, the certain effect of BP quinone production such as 1,6-BPQ and 3,6BPQ, and the subsequent formation of ROS (Henkler et al., 2010) on potential carcinogenic routes has been mainly demonstrated in breast epithelial cells (Henkler et al., 2010). The BPQinduced ROS activate the EGFR (epidermal growth factor receptor), causing increased cell growth. However, such impacts are partially attributed to stimulation of the aryl hydrocarbon receptor (AhR) triggered in parallel through both BPQ metabolites. The BP also induces H2O2 production along with UVA radiation and enhances production of 8-OHdG lesions in the DNA of epidermal cells. In HepG2 cells, BP stimulated an antioxidant response and also increased levels of GSH. However, the function of ROS in BP-induced carcinogenesis is not clear. Due to the prevalence of genotoxic events leading to the generation of bulky DNA adducts, ROS mediates minute structural damage or deterioration of cellular signaling, which becomes ambiguous and difficult to be untangled (Henkler et al., 2010). An environmental pollutant, TCDD (2,3,7,8,tetrachlorodibenzo-p-dioxin), has been recognized as a human carcinogen that is antagonistic to AhR. After activation, this receptor induces several genes playing pivotal roles in the metabolism of xenobiotic compounds. In particular, the stable stimulation of AhR is adequate in triggering spontaneous stomach tumors in mice (Henkler et al., 2010), explaining that the carcinogenic impacts of TCDD underlie this receptor. Activation of CYP1 enzymes has been designed as a pathway to ROS production, subsequent oxidative DNA damage, and finally carcinogenesis (Park et al., 1996). The potential of TCDD to

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Xenobiotic-induced ROS generation in embryos

stimulate large spectra of tumors in animals of both sexes has been highly demonstrated in several studies (Knerr & Schrenk, 2006). Interestingly, in Sprague-Dawley rats, TCDDstimulated liver carcinogenesis was mainly identified in female animals and associated with oxidative stress (Wyde et al., 2001). The next studies implied that ROS production was accomplished after initial CYP-dependent oxidation of estradiol. Such oxidation intensifies the oxidative DNA damage due to catechol involvement in redox-cycling events (Li et al., 1994). However, a predominant function of ROS-mediated mutations has still left questions of further studies in animals. Independent of gender, TCDD neither modified mutation rate nor patterns in a transgene at concentrations where ROS is produced (Thornton et al., 2001). The consequence of AhR is based on its pivotal function in the removal of xenobiotic molecules and its stimulation by several ligands that have the selected PAHs, polychlorinated biphenyls, dibenzo-p-dioxins, and dibenzofurans. It has been clearly elucidated that constant active AhR signaling is highly linked with an increased carcinogenic risk. However, despite CYP, such receptor/transcription factors also trigger expression of several other target genes like c-ras or c-fos, that promote inflammation and stress-linked signaling (Matsumura & Vogel, 2006). Other identical target genes are also stimulated by ROS and hence this signaling impacts tumorigenesis, even in the lack of noticeable oxidative DNA damage. Indeed, toxic metals and TCDD (Dragan & Schrenk, 2000) have been recognized as potential tumor promoters. However, the specific contributions of ROSinduced signaling are not clearly explained.

Xenobiotic-induced ROS generation in embryos Xenobiotic-enhanced ROS production is accomplished through many events and mechanisms. Certain xenobiotics or their hydroxylated

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metabolites involve redox cycle, where a single xenobiotic compound generates an intensified formation of ROS (Halliwell & Gutteridge, 2015). The powerful impact for this mechanism has been explained in embryo culture with no maternal attribution (Juchau et al., 1998). In general, these hydroxylated metabolites are produced and coupled with water soluble endogenous substrates such as glucuronic acid in the maternal liver, and the glucuronide-xenobiotic conjugates the excreted maternal in the urine without involvement of the embryo (Wells et al., 2005). If so, the redox cycling mechanism possibly contributes to teratogenesis if the mother has a deficiency of certain enzymes, such as UDPglucuronosyltransferases (UGTs), involved in catalyzing glucuronidation. Also, in certain conditions, the xenobiotic free radical intermediate produced while redox cycling covalently attaches to cellular macromolecules, generating a xenobiotic macromolecular adduct which modifies cellular activities. In low or negligible levels of CYPs, the embryo contains increased levels of enzymes with or related to peroxidase activities, such as prostaglandin H synthases (PHSs) and lipoxygenases (LPOs), that convert teratogens for example, phenytoin and associated AEDs, benzo[a]pyrene, and methamphetamine to free radical intermediates which then induce ROS generation (Wells et al., 2009). Particular xenobiotic compounds for example, phenytoin, structurally similar to AEDs and several antiarrhythmic compounds have been revealed to decrease embryonic heart rate, and ROS generation linked with reperfusion following revival of the normal heart rate that has been employed in the teratological pathways of such compounds. The detected embryopathies at lower phenytoin levels do not decrease embryonic heart rate, such as the reperfusion pathway for ROS production, appear to most probably be attributed to higher xenobiotic compound levels (Wells et al., 2009).

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Oxidative stress-associated mechanisms with xenobiotics in anemia cells Several xenobiotic compounds have been shown to exert increased toxicity to cells of patients with Fanconi anemia (FA) viz. a cancer-prone genetic disease (Ahmad et al., 2002; Pagano et al., 2003). The high sensitivity of FA cells is employed in FA diagnosis and is usually attributed to the incompetence of FA cells to repair DNA cross-links stimulated by xenobiotic\ molecules leading to DNA repair deficiency syndrome.

Time-dependent cellular adaptations to oxidative stress in normal cells Cells produce ROS and reactive nitrogen species (RNS) as an inevitable significance of metabolism, where they are more detrimental in intracellular signaling molecules. To secure ROS/RNS signaling events that are balanced and oxidative damage-avoided, cells have a set of antioxidant systems. Instead of those directacting antioxidants, cells are also orchestrated with indirect-acting antioxidant systems which either reduce the production of ROS/RNS or detoxify the reactive metabolites. A random enhancement of ROS/RNS with respect to antioxidant ability, known as oxidative stress, is retaliated by the cell in several processes. In this respect, the decreased glutathione (GSH) and thioredoxins (TXN) play a critical function in opposing oxidative stress, although their potential to do so is not recognized by NADPH that maintains both in a reduced state (Hayes, John et al., 2020). Importantly, the cells adapt to oxidative stress for a time being by metabolic reprogramming and for a longer duration by genetic reprogramming. After acute exposure to ROS, NADPH generation by glucose-6-phosphate dehydrogenase (G6PD) plays a critical role in

reducing oxidative stress. After achieving nontoxic threshold levels of H2O2, cells induce G6PD and reprogram glucose metabolism from glycolysis via oxidation of the pentose phosphate pathway (PPP) toward nucleotide formation, which allows enhanced reduction of NADP 1 to NADPH (Kuehne et al., 2015). Such fast reprogramming of metabolic events is due to extirpation of the negative feedback regulation of G6PD activity produced by NADPH that happens regularly under nonstressed states and is a result of acute reduction of NADPH due to ROS (Dick & Ralser, 2015). The increasing level of NADPH facilitates GSR1 and TXNRD1/2 to amplify the GSH and TXN1/2-based antioxidant systems to overcome ROS for attaining homeostatic levels. If exposed to non-toxic doses of H2O2 for a moderate time, such as 15 minutes, cells employ redox switches in glyceraldehyde 3phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2) to stop glycolysis and enhance glucose catabolism through the PPP, resulting in accumulation of upper glycolysis mediators, a spill-over of glucose-6-phosphate into the oxidative arm of the PPP, and enhanced formation of NADPH through G6PD to mitigate oxidative stress (Fig. 6.1). The redox turn in GAPDH participates in Cys-152, and PKM2 involves Cys-358. Under such circumstances, GAPDH activity is again enhanced by phosphorylation by ataxia telangiectasia mutated (ATM) as a result of production of an intermolecular disulfide bridge in ATM at Cys-2991 that also enhances flux via the PPP (Cosentino et al., 2011). The impact of ROS on GAPDH, PKM2, and G6PD functions are possibly interconnected with oxidation of Cys residues in a minimum of six protein subunits within complexes I, III, and IV of the mitochondrial electron transport chain which have Fe-S clusters, causing decreases in O2 consumption and reduced ROS formation (Van Der Reest et al., 2018). Acute oxidative stress also suppresses phosphatase and tensin homolog

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FIGURE 6.1 Metabolic processes to acute oxidative stress in cells under natural redox homeostatic states (A), glucose is usually oxidized by glycolysis to pyruvate, and through acetyl-CoA via the tricarboxylic acid cycle, with G6PD suppressed by NADPH (nicotinamide adenine dinucleotide phosphate) and minimal flux via the PPP. although, after acute oxidative stress (B), feedback suppression of G6PD by NADPH is highly reduced (i) and Cys residues in GAPDH (ii), ATM (iii), and complexes I, III, and IV of the electron transport chain (iv) are oxidized, an integration of conditions which cause the suppression of glycolysis, phosphorylation of G6PD, and enhanced metabolism via the PPP. In addition, oxidation of Cys residues in PTEN (v) leads to stimulation of PKB/Akt, causing enhanced cell survival (Hayes, John et al., 2020). ATM, ataxia telangiectasia mutated; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; PPP, pentose phosphate pathway; PTEN, phosphatase and tensin homolog.

(PTEN) by oxidizing Cys-124, which induces PKB/Akt by phosphatidylinositol 3-kinase (PI3K), upregulating antioxidant gene expression and enhancing cell survival (Van Der Reest et al., 2018). An NO-based defense mechanism against acute oxidative stress encompasses the enhanced flux via the PPP caused from Snitrosylation of PKM2 (Zhou et al., 2019). In such conditions, NOS3 activity induces proximal tubule endothelial cells after acute kidney injury, resulting in the accumulation of Snitroso coenzyme A (SNO-CoA) and Snitrosylation of PKM2 at Cys-423 and Cys-424 that leads in suppression of the kinase, deviation of glucose metabolism via the PPP, enhanced NADPH formation, and reduced ROS.

With respect to acute oxidative stress, it can be resolved by metabolic reprogramming, where adaptation to chronic oxidative stress participates in triggering of genetic programs. In the short to medium term, oxidative stress alters the abundance and/or subcellular delivery of hypoxia-inducible factor 1a (HIF-1a) that results to metabolic rerouting. In a traditional way, this participates in hypoxia and oxidation of Cys-326 in PHD2 which fastens HIF-1a and causes transcriptional alterations that lead to a switch from glucose oxidation to glycolysis (Lee et al., 2016). Specifically, in chronic oxidative stress models that participate in accumulation of endogenous electrophiles or reduction of GSH/TXN, adaptation enforces the upregulation of antioxidant genes (Chen et al., 2016).

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Impact of ROS and RNS on the tumor microenvironment The development of cancer occurs in the tumor microenvironment (TME), which participates in complementary crosstalk between neoplastic cells and the TME through ROS/RNS. The activities of cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and T cells are all influenced by ROS/RNS in the TME. Hence, both CAFs and TAMs “coordinate” with neoplastic cells by a developmental program referred to as epithelial mesenchymal transition (EMT) by aiding to the remodel of the extracellular matrix (ECM), which induces tumor cell proliferation, tumor angiogenesis, immunosuppression, and tumor invasion. Moreover, regulatory T (Treg) cells play major roles in preventing autoimmunity and inhibiting effective tumor immunity; the presence of intratumoral Treg cells is highly related to poor prognosis (Beyer & Schultze, 2006). The TME also accommodates cytotoxic CD8 1 T cells. However, they are envisaged to support the immune ravage of tumor cells, CD8 1 T cells sometimes express coinhibitory receptors like programmed death-1 (PD-1) and are understood to be terminally differentiated or “exhausted.” On the contrary, recent works have recognized a subset of stem cell-like tumor-infiltrating PD-1 1 TCF1 1 CD8 1 T cells attributed to decreased tumor progression during immunotherapy (Li et al., 2020). To impact ROS in the TME, chronic oxidative stress produced from JunD suppression has been revealed to induce myofibroblast differentiation in stroma related with mammary adenocarcinomas via stimulation of HIF-1a and enhanced formation of the CXCL12 chemokine that simultaneously activate tumor growth and vascular remodeling and decrease survival (Toullec et al., 2010). Hence, it has been thought that the transforming growth factor b (TGF-b) induced fibroblast tomyofibroblast differentiation by activating NOX4 in stromal remodeling associated with prostate

cancer and enhanced ROS formation and phosphorylation of JNK, by downregulation of the selenoproteins GPX3 and TXNRD1 (Sampson et al., 2011). Selenium supplementation reduces ROS levels and suppresses fibroblast differentiation into myofibroblasts, indicating that ROS stimulates trans-differentiation of stromal cells. Moreover, cancer cell-derived H2O2 leads metabolic alterations in CAFs with increasing glucose uptake, decreasing mitochondrial functionality, and enhancing ROS formation, but int he presence of CAFs, this leads to reciprocal metabolic alterations in the neighboring cancer cells like decreased glucose uptake and enhanced mitochondrial activity (Martinez-Outschoorn et al., 2011). Such metabolic modifications are abolished by addition of CAT, using H2O2 as the signaling factor. ROS also attribute to the pro-tumorigenic, anti-inflammatory, and immunosuppressive characteristics in TAMs that support tumor development. In malignant melanoma, formation by TAMs of mitochondrial ROS activates MAPK/ERK functionality causing the secretion of TNF-a, which induces tumor cell invasion (Lin et al., 2013). If exposed to cell-free tumor fluids, peritoneal macrophages existing in the typically active proinflammatory (M1) phenotype adopt an alternatively-induced (M2) phenotype related to immunosuppression (Ghosh et al., 2015). Further, ROS and RNS generated by TAMs inhibit T cell activities (Ghosh et al., 2015). It has been explained that, in mice, O2d produced by Nox2 activates Treg cells to dampen T cell-mediated inflammation (Kraaij et al., 2010). However, it is not well explored whether such an event is recapitulated in TAMs, if it happens then further will attribute to TAM mediated immunosuppression. Noticeably, employing oncogene-induced zebrafish models of glioma, it has been revealed that TAMs are involved in ATP-mediated coordination with preneoplastic cells at the beginning stage of tumor formation, and that reduction of TAMs or decreasing the number of such interactions significantly aggravates the

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Impact of ROS and RNS on the tumor microenvironment

growth of neoplastic cells (Chia et al., 2019). It is not confirmed if ROS plays a role in such interactions, but it is potentially considered that oncogene activation induces ROS generation. Myeloid-derived suppressor cells (MDSCs) activate antigen-specific CD8 1 T cell tolerance that consist of a critical pathway of tumor avoidance from immune inspection. Tumor-invading MDSCs form ONOO that nitrates Tyr residues in the T cell receptor-CD8 complex, hence sabotaging the binding of certain peptide-major histocompatibility complex (pMHC) dimers to the CD8 1 T cell (Nagaraj et al., 2007); mainly, implication of a ONOO scavenger aborragated MDSC-induced T cell tolerance. The therapy of cancer cells with ONOO stops the binding of processed peptides to cancer cell-related MHC, leading to resistance to antigen-specific cytotoxic T cells, while suppression of ONOO generation enhanced immunotherapy (Lu et al., 2015), using ONOO as a major regulator of the impact of cytotoxic T cells. Collectively, in myeloid cells, mitochondria, NOX, arginase-1, and NOS2 all attribute to ROS formation, thereby, moreover O2d, coordination between arginase-1 and NOS2 leads in the production of ONOO. Such combined impacts of ROS and RNS cause T cell inhibition, tolerance, and resistance to cytotoxic T cells. In T cells, ROS have a dual duty. Mitochondrial ROS require T cell induction (Sena et al., 2013), although ROS in the TME causes T cell hyperresponsiveness. In tumor-invading T cells, ROS are functionally debarred, mitochondrial function is mitigated, but are protected by enhancing mitochondrial biogenesis (Scharping et al., 2016) by employing mitochondrial ROS scavengers or high expression of CAT (Ligtenberg et al., 2016). Indeed, such modifications also recover the antitumor potential of T cells, again explaining the significance of mitochondrial functions and maintained ROS generations for T cell activity. Importantly, the increased mitochondrial function and ROS formation synergize with the tumoricidal activity of PD-1 barricade by extension of effector/memory

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T cells (Chamoto et al., 2017). Moreover, the formation of ONOO in the TME suppress T cell movement into the tumor by nitrating and deactivating the chemokine CCL2 (Molon et al., 2011) that is a chemoattractant for myeloid cells, stimulated T cells, and natural killer cells. Unlike other immune cells in the TME, the neutrophils conserve their antitumor potential under oxidative stress that are attributed to their high ROS-generating potential. Hence, tumor-associated neutrophils are revealed to inhibit the extension of the pro-tumorigenic IL17 1 gd T cells through NOX2-mediated O2d formation (Mensurado et al., 2018). In addition, IL-17-generating gd-T cells contain lower GSH levels than their IFN-g-forming gd counterparts, supporting a description for the impeccable sensitivity of IL-17 1 gd T cells to O2d and H2O2. Interestingly, Vd1 1 gd T cells, the major gd T cell subset which forms IL-17 in human cancer, also contain low GSH levels in comparison to other normal human T cell subsets, and are sensitive to ROS, indicating the clinical significances of such outcomes. The above explanations suggest that increasing ROS/RNS induces modifications in the TME which aid in carcinogenesis by altering the activities of CAFs and TAMs, and at the same time, they induce alterations in T cells which inhibit immune responses to cancer cells.

Role of oxidative stress in the treatment and prevention of cancer Anticancer drug therapy and oxidative stress Generally, treatment with anticancer regimens and radiation develops a certain condition of oxidative stress in the body, and active oxygen stimulates apoptosis through p53 and cytochrome secretion from mitochondria. The critical mechanism of action of anticancer regimens is to involve active oxygen such as anthracyclines, bleomycin, mitomycin C, and cisplatin. The redox regulation also participates in several issues associated with

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anticancer drug therapy. It has been envisaged that the high antioxidation mechanisms participate in a tumor’s acquisition of drug resistance. Thioredoxin and glutathione also have significant functions in the resistance to anticancer regimens. An approach to increase the potentiality of anticancer drugs by reducing thioredoxin expression in cisplatin-resistant cancer cells has been explained in various articles (Chikara et al., 2018). Secondary cancer based on the implication of anticancer regimens or radiotherapy is another field of examination. It has been explored that antioxidants such as vitamins C and E, uric acid, etc., in the plasma of osteosarcoma or testicular tumor’s patients after cisplatin underlying chemotherapy were decreased for a short time (Weijl, 1998). However, the main reason is shown to be the intake of antioxidants to remove the oxidative state, existing imbalance in the redox state in the body because anticancer treatment is also one of the reasons of secondary cancer related with anticancer regimens or radiotherapy. In contrast to the side effects of anticancer drugs, whether it is likely to ensure that tumor cells are more damaged than normal cells, this is beneficial in overcoming both the therapeutic dose of anticancer regimens and their adverse effects. Preventive and therapeutic potential of antioxidants The above explanations regarding the relationship of oxidative stress and cancer has assumed that the consumption of antioxidants like vitamins E and C and B-carotene is advantageous in preventing cancer development, and several related approaches have been employed (Terry et al., 2000). The suppression of inflammation by employing antioxidants has also been explored in association with the risk of carcinogenesis (Kimura et al., 1998) and such methods are envisaged to be advantageous in cancer prevention over a long period.

Relationship of ROS, ncRNA, and p53 p53 is a well known tumor suppressor factor. It has been detected in more than 50% of human cancer carrying mutations in the p53 gene and in the remaining, the pathways that p53 control are defective. p53 regulates several pathways but those associated with cell cycle arrest and cell survival are the main events (Leonard Clinton et al., 2019). The inactivated p53 leads in abnormal transactivation and disruption of downstream effector genes participating in cell cycle control, apoptosis, and DNA repair (Luengo et al., 2017). Hence p53 is nicknamed as the guardian of the cell due to its capability to regulate the expression of several genes. p53 is mutated in several cancers and many hotspot point mutations result in the activation of p53 that is, mutant p53. Rampant tumor development and appearance of drug resistance are the main results of such gains in functional mutations. Hence, these mutations have critical targets of cancer treatment. The inhibitors of heat shock protein 90 (HSP90), like 17-N Allylamino-17-demethoxygeldanamycin (17-AAG) that maintain mutant p53, have been exhibited to disrupt mutant p53. Likewise, ganetespib also integrates the inhibition of HSP90, reveal .50% of 17-AAG function (Shangary & Wang, 2009). Nutlin-3 and mdm2 have antitumorigenic and antimetastatic potential (Shangary & Wang, 2009). p53 reactivation and activation of massive apoptosis 1 and other small molecule has been revealed to regain the conformation of a mutant p53 to the wild-type form stimulating apoptosis. Other instances include 4,5-diphenyl-2-methyl picolinate (DMP), which stimulates DNA damage and accomplishes inhibition in growth of gastric cancer cells (Zhao et al., 2019). Instead of such chemically synthesized compounds, various plant-based agents also either alter mutant p53 or regain wild-type p53 that affect many alternating survival mechanisms. Over the past

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FIGURE 6.2

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Function of noncoding RNAs and ROS in p53 regulated apoptosis of cancer cells. ROS, reactive oxygen species.

decade, studies have indicated that the interactions among p53, ncRNA, and ROS aids in governing p53 regulated genes that are directly or indirectly associated with carcinogenesis (Fig. 6.2). miR-16 has tumor-suppressive activity that is downregulated in various kinds of cancer. Sanguinarine stimulates miR-16 for activation of p53 (Zhang et al., 2019). The activated p53 inhibits cell proliferation and stimulates ROS-mediated apoptosis in the HCC cells. A rank aggregation analyses have recognized many miRNAs like miR-34a-5p, miR-1915-3p, miR-638, and miR-150-3p that counter to oxidative stress in HCC cells. Among the four

miRNAs, miR-34a-5p and miR-1915-3p are controlled by p53 in oxidative stress condition. Proline oxidase (POX) is a tumor suppressor controlled by p53, which inhibits the growth of cancer cells and stimulates ROS-mediated apoptosis participating the mitochondria. The upregulated miR-23b in renal cancer directly integrates to POX mRNA and stops its tumor suppressor function. High grade serous ovarian carcinoma (HGSC), an ovarian cancer, develops from the secretory epithelial FTSE cells present at the fimbriated end of the fallopian tube. The ovulation and related inflammation are common factors which contribute to

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HGSC. The cultured primary FTSE cells reveal the enhanced ROS and upregulation of an array of miRNAs and p53 and control the activity and expression of such ROS-mediated miRNAs in FTSE tumor cells (Liu et al., 2015). Of several stress-associated miRNAs, miR-200 is controlled by p53 and overexpression of miR-200 inhibits EMT transition. p53 upregulates miR-200 in H2O2, exposing cells reversed by p53 deficiency (Magenta et al., 2011), hence explaining the ternary relationship among miRNA, ROS, and p53. The tumor suppressor miR-34c is a transcriptional site of p53. Capsaicin-stimulated oxidative damage causes stimulation of p53 in non-small cell lung carcinoma (NSCLC) cells. The upregulated p53 enhances the expression of miRNA-34a that suppresses B-cell lymphoma 2 (Bcl-2) expression for increasing cell death. In another study, the activities of miR-30 in gastric neoplasia have been investigated (Wang et al., 2017). The downregulation of miR-30 in HGC 27 expresses p53, which induces ROSmediated apoptosis. Ferroptosis is a type of apoptosis identified by iron-dependent lipid peroxidase accumulation. The P53RRA lncRNA

has tumor-suppressor potential in cells by increasing ferroptosis, cell cycle arrest, and apoptosis via p53 control in the nucleus (Mao et al., 2018). Hence, the above statement has ensures that ncRNAs, p53, and ROS interact in cancer cells as summarized in Table 6.1.

Cancer microenvironment and oxidative stress Instead of cell-autonomous events participating in genetically transformed cancer cells exposed to intrinsic oxidative stress, the significance of stromal cell populating the tumoral microenvironment has been explained. In fact, tumor microenvironment influences evolution of cancers to aggressiveness and metastatic expansion via both structural and functional bases that is, matrix composition, hypoxia, acidity, or cell-based like CAFs or macrophages (CAMs), endothelial precursors, etc. processes. Various factors like hypoxia or the occurrence of CAFs or CAMs, have already been shown to express a prooxidant environment deeply

TABLE 6.1 Signaling pathways related to ncRNA, reactive oxygen species (ROS), and p53 in cancer (Leonard Clinton et al., 2019). Noncoding RNA

Cancer type

Location with respect to ROS

Location with respect to signaling pathways

Target/function

Outcome

miR-16

Hepatocellular cancer

Upstream

Upstream

p53

Tumor suppressor

miR-34a-5p

Hepatocellular cancer

Downstream

Downstream

Oxidative stressrelated to genes

Oncogenic

miR-23b

Renal cancer

Upstream

Downstream

Proline oxidase

Oncogenic

miR-200

Endothelial cells

Downstream

Downstream

Inhibition of EMT

Tumor suppressor

miR-34

NSCLC

Downstream

Downstream

Bcl-2

Tumor suppressor

miR-30

Gastric cancer

Upstream

Upstream

p53

Oncogenic

P53RRA

Breast and lung cancer

Upstream

Upstream

p53

Tumor suppressor

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FIGURE 6.3 Oxidative stress in the tumor microenvironment. In this microenvironment, oxidative stress develops by either intrinsic or extrinsic factors. Certain stromal factors directly form ROS. CAMs produce ROS via stimulation of NOX2 and RNS via iNOS, whereas hypoxia forms oxidant species by alteration of the complex III of mitochondrial electron transport or by NADPH oxidase activity (Condeelis & Pollard, 2006; Guzy et al., 2005). In studying extrinsic or intrinsic oxidative stress, CAFs become induced and form cytokines and proteases which influence cancer development (Cat et al., 2006; Giannoni et al., 2011). Moreover, the microenvironment or aging-stimulated oxidative stress causes secretion of the “Senescent Activated Secretory Pathway” (SASP) by senescent fibroblasts impacting both stromal and malignant cells to stimulate cancer development (Coppe´ et al., 2010). Eventually, cancer cells perturb the oxidant environment by intrinsic generation of oxidative stress via downregulation of Jun D or increased NOX-4, LOX-5 and/or COX-2 activity (Sampson et al., 2011; Weinberg & Chandel, 2009). CAFs, cancer-associated fibroblasts; CAMs, cancer-associated macrophages; ROS, reactive oxygen species.

influencing tumor development and metastasis expansion in various cancer models (Fiaschi & Chiarugi, 2012) (Fig. 6.3). CAFs, generated either by local fibroblasts or by circulating mesenchymal stem cells (Pietras & ¨ stman, 2010), are induced in response to O tumor-mediated factors via a mesenchymal mesenchymal transition (MMT) transforming them into “induced fibroblasts” similar to myofibroblasts (Hinz et al., 2007; Pietras & ¨ stman, 2010). Fibroblast stimulation is highly O triggered by oxidative stress in both neoplastic and fibrotic ailments (Bocchino et al., 2010).

There are two ways to generate oxidative stress in cancer: either intrinsically or extrinsically. In fact, in skin cancer models, TGFβ1 enhances the intracellular ROS level in stromal fibroblasts, which incudes the MMT and subsequential alterations in gene expression, causing the release of hepatocyte growth factor, interleukine-6, and vascular endothelial growth factor resulting in proinvasive signals for cancer cell circulation (Cat et al., 2006). Moreover, a relationship has been established between myofibroblasts accumulation and the oxidative stress in diverse pathophysiological situation viz. JunD-lacking animals, HER-2

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amplified breast carcinoma (Toullec et al., 2010), further emphasizing the significance of oxidative stress in CAFs activity. Further, in the affected prostate stroma, MMT underlies Tumor Necrosis Factor β1-originated oxidative stress via NOX4 stimulation which leads to downregulation of ROS-scavenging enzymes like glutathione peroxidase 3, thioredoxin reductase 1, and the selenium transporter selenoprotein P plasma 1 (Sampson et al., 2011). Eventually, senescence is another factor highly influencing stromal oxidative stress. DNA damage accumulation linked with aging plays a role in the deregulation of ROS production and decline of antioxidant defences. The senescent fibroblasts create an inflammatory environment via the release of proinflammatory cytokines and proteases senescence-activated secretory pathways (SASPs) (Davalos et al., 2010). SASPs include soluble signaling factors, chemokines, insulin-like growth factor-1, released proteases, tissue-type plasminogen activators, the uPA receptor, and the plasminogen activator suppressors, that support to the conversion of senescent fibroblasts into proinflammatory cells to promote tumor development (Davalos et al., 2010; Laberge et al., 2012). CAMs stimulated with CAFs induce a prooxidant environment and have produced various types of cancer via several mechanisms (Condeelis & Pollard, 2006). Initially, the continuous production of ROS by activation of macrophage NOX-2 and Nitric Oxide Synthase directly support invasion and metastasis via CAFs recruitment or MMPs stimulations. However, CAMs release proinflammatory cytokines that interplay the inflammatory reflection in adjacent stromal and cancer cells, causing cancer cell circulation (Karin, 2005; Marnett, 2000). Decreased oxygen pressure that is, hypoxia is associated with an increase of intracellular/mitochondrial ROS which synergizes with another impacts through hypoxia to enhance tumor development (Ushio-Fukai & Nakamura, 2008). Mammalian cells reflect hypoxia through activation of stress signals that induce hypoxia-

inducible factor (HIF-) 1 and -2 transcription useful for adaptation and survival in adverse conditions (Semenza, 2000). If cells face hypoxia, the hydroxylation of the α subunit of HIF is inhibited, leading to the stabilization of the protein and inducing its transcriptional potential. HIFα stabilization brings about ROS generation from electron transport chain failure or NADPH oxidase (Murphy, 2009). In fact, the pharmacological and genetic data indicate the ubiquinone cycle of complex III responsible for ROS production, while hypoxia stabilizes HIF1α protein (Chandel et al., 1998; Semenza, 2000). Intratumoral hypoxia develops various and distinct impacts on tumor cells, ranging from metabolic reprogramming to a glycolytic phenotype, overexpression of ABC transporters, recruitment of mutated cells whose apoptotic process is lacking, or protection from apoptotic modulators. Hypoxic cancer cells are highly invasive and resistant to apoptosis, chemotherapy, and radiation treatment (Harris, 2002; Semenza, 2004). In addition, increasing evidence suggests that hypoxic cancer cells endure exposure to oxidative stress, whereby making adaptive plans to survive in adverse conditions. Noticeably, hypoxic cells increase their antioxidant ability and hypoxia acts as a promoting factor for such activity, with potential interactions with resistance to therapy (Wu, 2006). This point is very significant and indicates that the adaptive strategies are really the reflections of antioxidant and that an antioxidant phenotype might cause enhanced aggressiveness. Presently, it has been explained that aggressive cancer cells point to hypoxia involving a motogenescaping plan, underlying redox stabilization of HIF-1 and stimulation of the Met protooncogene, supporting a proteolytic motility increasing metastatic expansion to lungs (Comito et al., 2011). By considering the critical role accomplished by ROS in sensing the impact of hypoxia, it has been described that the antitumorigenic impact of antioxidants as N-acetyl cysteine and vitamin C in murine models of Myc-mediated tumorigenesis actually depend on HIF-1 (Gao et al., 2007).

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Impact of ROS and RNS on the tumor microenvironment

Hence, the adaptations to neighboring stromal cells, simultaneous with the intrinsic metabolic reprogramming of cancer cells cause significant changes in ROS generations and long-term oxidative stress in cancer cells. Due to such alterations, the oxidant-sensitive transcription factors such as Hypoxia Inducible Factor-1 (HIF-1) or Nuclear Factor κ-B (NF-κB) are activated and participate as major factors in procuring promigratory and proinflammatory reflection in cancer tissues (Wu et al., 2009; Yang et al., 2008). Moreover, human prostate CAFs develop their propelling activity for EMT in stern dependence on cycloxygenase-2 (COX-2), NF-κB, and HIF-1 because COX 2mediated generate ROS is necessary for EMT, stemness, and circulation of cancer cells (Giannoni et al., 2011; Sohal & Orr, 2012). In the same way, such responses elicited by various factors of cancer cell microenvironment, for example, CAFs, hypoxia, or acidity, embrace increased motility, survival to stressful environment, and reprogramming of metabolism. The motile impact is usually identified as EMT, an epigenetic transcriptional event causing cells to lose epithelial characters and gain mesenchymallike motility (Boyer et al., 2000; Polyak & Weinberg, 2009). EMT has been associated with the generation of stem-cell like properties as enhancements in the ratio of the expression of CD44 and CD24, stimulating CD133 expression, anchorage-independent growth, and spheroid generation, as well as the recruitment of tumorinducing cells capable of migrating metastases (Blick et al., 2008). Further, both EMT and stemness have been explained as redox-sensitive and able to utilize the prooxidant environment to achieve metastatic expansion and resistance to chemotherapies in various carcinoma models (Ahmed et al., 2010). Instead of involvement of stromal cells in cancer development, EMT is also elicited by intratumoral hypoxia working in a biphasic way. Hypoxia-induced dissemination has a new mitochondrial delivery of ROS, causing

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stimulation of cell polarization and directed circulation; further, there is a second late phase, where ROS acts on HIF-1α stabilization and VEGF expression for potential motility (Novo et al., 2012). Moreover, stromal factors of tumor microenvironment control EMT and stemness via enhanced hypoxic inducers. In this way, CAFs are capable of imitating hypoxic inducers, leading HIF-1 expression due to their oxidative stress, although without the actual requirement of oxygen deficient. In fact, exposure to reactive stromal fibroblasts involves an HIF-1 and NF-κB-mediated transcriptional reflection driving EMT, although that does not require hypoxia. Indeed, the intratumoral hypoxia may exacerbate such EMT events, increasing motile reflection. Presently, the generation of oxidative stress in ovarian carcinogenesis has been related with a stress signature in two miR-200 family members, miR141 and miR200a, previously employed in the regulation of EMT and stemness (Gregory et al., 2008). Particularly, high-grade human ovarian adenocarcinomas accumulate miR-200a containing increasing levels of ROS that are related with increasing survival of patients after treatment and suggest that even oxidative stress stimulates tumor growth and sensitizes tumors to treatment (Mateescu et al., 2011).

Oxidative stress and ER activity Instead of DNA damage, the other two main impacts of excess ROS generation for proteins that affect ER mechanism and the endocrine responsiveness of ER positive breast cancer are that isdirect oxidative injury to protein structure and ROS-stimulated kinase signaling. Intracellular proteins most sensitive to direct oxidant damage are redox-sensitive nuclear transcription elements like ER35 and SP, whose zinc finger cysteine residues are promptly oxidized and inhibit their DNA-binding activity (Benz & Yau, 2008). In ER-positive breast cancers, impairment of SP1

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DNA-binding potential has been related with aging, underlying enhanced levels of the oxidative stress marker phospho-ERK5 (extracellular signal-related kinase 5) in cancer (Quong et al., 2002). However, full loss of the DNA-binding activity of the ER in primary human breast cancers has not been particularly correlated to aging, such loss has been appeared to happen in onethird of all ER-positive primary breast cancers associated with impairment of progesterone receptor (PR) expression (Scott et al., 1991). Since the DNA-binding and transactivating potential of both ER and SP1 are required for inducing optimal estrogenic genes like PR and BCL-2, ERpositive breast cancers which have been provided to certain levels of oxidative stress will be envisaged to reveal suppressed expression of PR, BCL2 and other estrogen-inducible genes. The second main impact of oxidative stress is its relationship with kinase-dependent signal transduction. Apart from their activity in the mediation of growth factor receptor signaling, ROS directly suppresses protein tyrosine phosphatases and induces SRC, Janus kinase, Ras family members, protein kinase C, and MAPK signaling. Such induced kinase mechanisms modulate the ER function (Levin, 2003) and are employed in endocrine resistance (Kirkegaard et al., 2005; Nabha et al., 2005). Mainly, more MAPK signaling in ER-positive breast cancer cells damages estrogen-inducible gene transcription (Oh et al., 2001) and stimulates a profile of gene expression similar to that of ERnegative breast cancer cells (Creighton et al., 2006). Hence, oxidative stress highly changes the phenotype of an ER-positive breast cancer, and in some conditions, the endocrine responsiveness of the tumor is completely lost.

Quantitative determination of oxidative stress in cancer cells via gene expression Quantitative analysis of intracellular oxidative stress condition is a major issue since it is the basis for explanation of the basic reasons of

metabolic alterations in diseased human cells, mainly cancer. However, this problem has been shown to be highly challenging to figure out in vivo due to the complex mechanism associated with the problem. Hence a computational approach is revealed for prediction of the quantitative level of the intracellular oxidative stress in cancerous tissue. So, the study of genomic mutation as a fundamental predictor is highly useful in analyzing the intracellular oxidative stress level. According to genomic mutation analysis, a statistical assessment is performed to determine an array of enzyme-encoding genes, where synergistic expression levels explain the frequencies of mutation in particular cancer tissues in the TCGA database (Liu et al., 2020). In a study, the rates of point-mutations in coding regions per genome over all cancer genomes for every 14 cancer types were determined. Among all, LUAD had the highest average mutation rate at 347.20/genome, whereas KICH was the lowest at 19.75/ genome. The average numbers of other 12 cancer types in the decreasing order as: 288.95 mutations in LUSC, 272.02 in COAD, 257.50 in STAD, 234.71 in BLCA, 213.26 in HNSC, 124.59 in ESCA, 147.65 in LIHC, 303.75 in BRCA, 111.14 in KIPR, 113.94 in KIRC, 138.75 in PRAD, and 134.18 in THCA (Liu et al., 2020). Quantitative analysis of the intracellular oxidative stress was validated to be a precious tool for the explanation of the prospective reasons of several alterations in cancer cells with a wide metabolic reprogramming. However, issues related to quantitative analysis proved to be highly challenging because there are several contributors to both the total oxidizing power and the anti-oxidizing potential in human cells. Earlier, several studies emphasized the oxidative stress stimulated by certain molecular species, like H2O2 or lipid radicals, instead of the entire oxidative stress level. Based on the above work, it can be said that a computational approach is one of the best tools

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Quantitative determination of oxidative stress in cancer cells via gene expression

for explaining oxidative stress level. The fundamental premise of this tool is that the genomic mutation level is highly related to the entire intracellular oxidative stress condition. The second premise is that several enzymes have antioxidation capacity, as explained by several researchers (Rajput et al., 2013). The outcome of the regression analyses of genes in two EC classes, EC 2. (transferases) and EC 3.- (hydrolases), mainly four subclasses of these two, could be employed to decipher the mutation rate in all cancerous cells through a linear combination of their expressions with high statistical consequences. This highly demonstrates that all enzymes encoded by such genes are involved in cellular antioxidation, which is a great discovery and permits further examination. Moreover, several cancer types contributing to a different combination of genes from four

subclasses of enzymes highly indicate that such cancer types might confront several types of oxidative stresses, thus implicating several combinations of antioxidation enzymes. This also permits further study relating why genes in distinct enzyme classes exhibit great coordination with mutation rates in various cancer types, so as to unravel the elaborate mechanisms of their antioxidative activity for various kinds of oxidants (Liu et al., 2020). As explained above, oxidative stress develops from various molecular species like ROS, RNS, reactive lipid species, and several free radicals. Distinct molecular species may be utilized to consume certain kinds of oxidizing compounds. It has been explained that three independent classes of molecules have statistically significant correlation coefficients with general-purpose predictors of oxidative stress (Table 6.2) (Liu et al., 2020).

TABLE 6.2 Correlation between oxidative-stress predictor and expression of different genes in several kinds of cancers (Liu et al., 2020). Name of cancer

Gene expressions Fatty acid synthesis

Mucin synthesis

Glutathione synthesis

BLCA

FASN

MUC15

GCLM

BRCA

ACAT2

MUC20

GCLM

COAD

ACAT1

MUC5B

GSS

ESCA

ACAT2

MUC17

GCLC

HNSC

MCAT

MUC3A

GCLM

KICH

ACAT2

MUC12

GCLC

KIRC

ACAT1

MUC16

GSS

KIRP

ACAT1

MUC12

GSS

LIHC

FASN

MUC20

GCLC

LUAD

ACAT2

MUC22

GCLM

LUSC

FASN

MUC4, MUC20

GSS

PRAD

FASN

MUC6

GCLC

STAD

MCAT

MUC7

GCLM

THCA

ACAT1

MUC15

GCLC

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6. Mechanism of oxidative stress in carcinogenesis induced by xenobiotics

The availability of such computational tools creates a new avenues for the exploration of the effect of oxidative stress on different chronic inflamed diseases such as cancer, including (1) explanation of entire metabolic events, especially reprogrammed metabolisms detected in cancer and other diseases, which are statistically related with the level of oxidative stress, thus providing a new ability for determining the possible reasons of several modified metabolisms, and (2) systematic assessment of several classes of enzymes in terms of their antioxidative functions that can bring potentially influential and new targets for curing several chronic diseases, including cancer. Therefore, the predictor would prove to be a potential tool for the explanation of reasons of different systematic changes with metabolic reprogramming to garner in-depth knowledge of why certain metabolic events are reprogrammed and particular cellular activities tend to be repressed or hyper-activated in cancer disease.

Conclusion and future prospective This chapter has summarized that oxidative stress contributes to carcinogenesis by generating ROS associated with the exposure to xenobiotic compounds. Generation of oxidative stress acts as a carcinogenic risk factor due to two major events, production of hydroxy radicals causing oxidative DNA damage and continuous alteration in redox homeostasis, which are related to chronic proinflammatory signaling-causing cancers by inducing proto-oncogenes or antiapoptotic factors. However, a main role of ROS to oncogenesis has been widely explained, where eventful adverse impacts are frequently suppressed by alternate genotoxic or epigenetic pathways being stimulated in parallel. Moreover, the adverse impacts of radicals are counterbalanced by alterations in the cellular antioxidant response (Henkler et al., 2010).

In addition, the mechanism of oxidative stress has been employed as a therapeutic target. Hence, potential anticancer regimens could be developed by this mechanism without generating adverse effects to normal cells. Therefore, it necessitates a new and larger way of running clinical trials to substantiate the therapeutic efficacy and selectivity of potential anticancer agents through oxidative stress events. The above explanations will lead to exploration of the mechanism of oxidative stress as oncogenic factors associated with xenobiotic molecules causing cancer, and the screening and/or synthesis of anticancer drugs targeting oncogenic factors in the future.

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7 Genotoxic and non-genotoxic activities of xenobiotics in carcinogenesis Introduction Exposure of carcinogenic agents is an unavoidable consequence of modern society. On the basis of the mechanism of action, chemicals are classified as non-genotoxic and genotoxic. International Agency for Research on Cancer (IARC) has classified 121 agents as carcinogenic to humans (Group 1), 89 agents as probably carcinogenic to humans (Group 2A), 315 agents as possibly carcinogenic to humans (Group 2B), and 497 agents are not classifiable as to their human carcinogenicity (Group 3) (https://monographs.iarc.who.int/ agents-classified-by-the-iarc/). The characteristics of genotoxic and non-genotoxic carcinogens have been considered for risk assessment. Nongenotoxic agents are also classified as tumor promoters having diverse underlying mechanisms. Thus, existence of a threshold concentration or no-effect level is conceived for nongenotoxic agents. However, genotoxic agents, their DNA reactive metabolites, and metabolic precursors are assumed to characterize risk factors at all concentrations since DNA lesions (even one or few) may induce mutations and consequently enhance tumor risk. Other substances might enhance instability in a genome by indirect mechanisms, such as interfering

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00002-9

cellular response to DNA damage (Fig. 7.1) (Hartwig et al., 2020). The genotoxic potential of most classified carcinogenic chemicals is reflected in various genotoxicity tests such as micronucleus tests (in vivo) or the Ames test (Braakhuis et al., 2018; Herna´ndez et al., 2009). Most genotoxic carcinogens directly interact with DNA by the formation of covalent bonds resulting in DNA adducts. These adducts lead to different types of DNA damage such as formation of chemical bonds between adjoining bases, crosslinks between helices, cleavage of DNA strands, and DNA hydration (removal of bases). All of these damages alter the information stored in the DNA. Such mutations can be fixed by DNA repair mechanism. If DNA replication occurs before the action of repair mechanisms, there is a possibility for mutations to become permanent that eventually develop tumors. However, 10% 20% of the chemicals grouped by IARC (Group 1, Group 2A, and Group 2B) are analyzed to lack genotoxic potential (Herna´ndez et al., 2009). Non-genotoxic carcinogens have no direct DNA-damaging effects. They can stimulate cancer by other events such as disrupting cell structures, altering the rate of cell proliferation, or enhancing genetic error, epigenetic mechanisms or oxidative stress. Moreover, some genotoxic carcinogens may develop tumors by non-genotoxic

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FIGURE 7.1 Strategies based on the assessment of key events are important for the characterization of the mode of action of genotoxic carcinogens (Hartwig et al., 2020).

mechanisms. Increased cellular proliferation is the main event of non-genotoxic mode of action. Increased cellular proliferation can be stimulated by sustained cytotoxicity, disruption of signaling pathways, induction of oxidative stress, or mitogenic stimulus through receptor binding.

How to identify the mode of action of carcinogenic chemicals? Generally, combinations of genotoxicity tests have been used for evaluation of genotoxic potential of a chemical covering all probable mechanisms leading to tumor initiation. In addition standard mutagenicity and clastogenicity tests

including Ames, mouse lymphoma, HPRT, micronucleus or chromosomal aberration tests, and new test systems are under development to provide more inclusive mechanistic reports on important events and toxicological fingerprints causing genotoxicity or mutagenicity in in vivo or in vitro conditions. Further, studies are required to differentiate indirect and direct genotoxicity. The stimulation of genomic damage (chromosomal mutations, chromosomal and DNA lesions) is a preliminary event in a sequence of steps that ultimately induce tumor formation. In recent years, the capability of accurate identification and quantification of DNA lesions has been remarkably increased. The exposure to minute traces of

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How to identify the mode of action of carcinogenic chemicals?

genotoxic agents in food and other consumer media induce DNA damage. Presently, dosimetry of these genotoxic hazards can be accomplished with advanced instrumental analysis. In addition, DNA is also damaged by endogenous processes by the action of reactive oxygen species generated as leakage from the electron transport chain during respiration and other electrophiles that are produced in physiological metabolism as intermediates. This may drive measurable steady state levels of DNA lesions (alkylation products and oxidized bases) in all groups of cells and tissues. There are various defense mechanisms that may counteract/prevent the initiation of DNA damage. Therefore, it is crucial to measure steady state levels of DNA damage in vivo conditions that account for both detoxification of chemicals or its reactive metabolites prior to their interaction with DNA and for DNA repair. Furthermore, no increases in steady state levels of background DNA damage or endogenously stimulated DNA lesions (base alkylation, base deamination, base loss, base oxidation, base dimerization, single strand breakage etc.) indicate no increases in mutations and accordingly no prominent threat for malignant transformation at that exposure level. For practical applications, statistical analysis of the respective observations must be executed to quantify the remaining threats. If human exposure is below the level at which a substantial rise in the frequency of DNA lesions can be eliminated statistically, genotoxicity at this level may be evaluated inappropriately and of low precedence for further carcinogenic concern. In case of very reactive chemicals (formaldehyde or acetaldehyde), background levels of chemicals as well as their local levels at the entry site in the body should be considered, for example, nasal tissue and gastrointestinal tract might be relevant in cases of inhalation and oral exposure, respectively. Although DNA lesions may be repaired, mutations involve irreversible changes in DNA depending on the affected nucleotide position

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or gene that might have substantial relevance of the carcinogenicity process. Hence, measuring mutations instead of DNA damage would be highly advantageous. However, this would involve very sensitive mutagenicity tests under in vivo conditions that are not presently available. Moreover, the PIG-A test could be a promising approach that may be applied in repeated-dose toxicological studies because only small amounts of blood samples is required for this test (Olsen et al., 2017). Genotoxic compounds inducing the same types of DNA damage may be grouped together. The basal levels of the specific lesions in human cells or tissues have been identified and the additional DNA modifications induced by the exposure of a particular xenobiotic compound can be employed for the evaluation of additional risk associated with the exposure. Information about frequency and type of biological effects is an important requirement for such a risk assessment approach. These biological effects, especially mutations and malignant cell transformations, have appeared possibly after inducing respective DNA lesions. The induction and disappearance kinetics of DNA lesions require specific attention regarding fixation of mutations. However, quite different dose response relationships are followed by induced mutation. At high concentrations, some other important effects such as enhanced cell division and proliferative responses (within target cells or tissues) should be taken into account. In addition to the preferred targets (dosimetry) of DNA lesions, tracking blood protein adducts can provide complementary information related to internal exposure of electrophilic agents produced by defined exogenous exposure. Techniques are well established to assess internal exposure using quantification of protein adducts for serum albumin and hemoglobin as dosimetry. Although protein adducts are considered as exposure markers, they are not fixed, in contrast to DNA lesions. Thus, these lesions indicate

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prominent exposure generally without any relevance for the carcinogenic process. The dosimetry of mercapturic acids or other metabolites are used to check short term exposures that are unable to induce measurable changes at adduct levels in blood protein. Reference parameters such as Biological Reference Value (German DFG MAK Commission) can help in the assessment of such biomonitoring results. The Biological Reference Value depends on the relevant biomarkers reflecting background exposure of unexposed reference population at a working age. Moreover, protein adducts and/or body/urinary fluid biomarkers like mercapturic acids may integrate or replace the determination of external exposure to environmental and dietary genotoxins. In addition, toxicogenomic approaches can provide more inclusive mechanistic information. Relevant toxicogenomic data including dose response behavior to toxicity-related classical apical end points must be linked. Such studies are informative if properly used to upgrade our understanding of low dose relationship and as a consequence of biological thresholds. However, such an approach has some limitations because a definite level of DNA damage is required by the onset of transcriptional responses that may be converted into mutations even at low concentrations having the capability to control the sensitivity of such approaches. In addition, signatures or patterns of biomolecules should be employed to reveal the mode of action along with identification of important events relevant to adverse outcome pathways. Unique options are provided to make models that reflect the human situation along with interindividual differences in combination with physiologically-based kinetics. Furthermore, reactions under sensitive low dose administration can be anticipated. This may furnish information about dose response relationship of DNA reactive metabolites apparently effective at doses that are not accessible experimentally. Moreover, structural activity relationships include various in silico procedures specially designed to uncover

relationships between biological activity and chemical structure of compounds. Such novel approaches may provide a wide range of data from compounds for which in vivo studies are accessible to those compounds having limited or completely absent toxicological records. The resultant mechanistic profile from such records could be envisaged to provide information of importance of unfavorable outcome routes for improved risk analysis.

Background DNA lesions The exact identification and measurement of DNA lesions in body fluids and tissues has increased in recent years. The application of advanced instrumental analysis facilitates the consistent dosimetry of DNA lesions related with exposure of food or other consumer sources having minute traces of genotoxic chemicals. However, endogenous metabolic processes produce genotoxic agents that may leak out and come in contact with the cell. These genotoxic agents include ROS and other endogenous substrates such as acetaldehyde, formaldehyde, ethylene and its epoxide, products of lipid peroxidaion, acrolein equivalents, etc.

Formation of DNA adducts in endogenous processes Aldehydes, products of lipid peroxidation, form DNA adducts such as malondaldehyde, ethanol, and propanol adduct. Malondialdehyde give rise to deoxyguanosine adducts including pyrimido[1,2-a]-purine-10(3H)-one and to a lesser amount, deoxycytidine and deoxyadenosine adducts (De Bont & van Larebeke, 2004). The large number of etheno adducts (3,N4-ethenodeoxycytidine and 1,N6-ethenodeoxyadenosine) have been detected in samples of the human lung. These etheno adducts are produced in the reaction of DNA bases with epoxyaldehydes formed in

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different oxidative processes of 4-hydroxynonenal, crotonaldehyde, and acrolein (De Bont & van Larebeke, 2004; Swenberg et al., 2011).

Alkylating compounds arising from endogenous processes In addition to lipid peroxidation products and ROS, numerous other reactive molecules produced in the metabolic process of an organism tend to react with DNA. S-adenosylmethionine, a methyl group donor, is necessary for endogenous methylation and is also involved in methylation of DNA bases, such as 3-methyldeoxyadenosine, 7-methylguanine, or O6-methyldeoxyguanosine. The most common product of alkylation is 7-methylguanine, which does not modify DNA coding. On the other hand, O6-methyldeoxyguanosine is a premutagenic agent leading to mismatches in DNA replication (Nakamura et al., 2014). Ethylene generated in metabolic processes can result in ethylene oxide that interacts with guanine to form N7-(2-hydroxyethyl) guanine. Even though 7-methylguanine and N7-(2-hydroxyethyl) guanine are not premutagens, they facilitate basic sites in DNA by depurination that could lead to mutation if still unrepaired (Swenberg et al., 2011). Formaldehyde is generated as an intermediate in the metabolic process from different substrates. It can stimulate formation of DNA adducts (N6-hydroxymethyldeoxyadenosine, N2-hydroxymethyldeoxyguanosine and N4-hydroxymethyldeoxycytidine) that may result in DNA crosslinks. These DNA adducts are considered as promutagens that may cause double strand breaks (Lai et al., 2016; Swenberg et al., 2011).

Carcinogenic mode of action In the near future, strategies based on the assessment of key events important to critical outcomes may allow further characterization of the mode of action of genotoxic carcinogens

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and also identify practically safe doses in a few cases. For example, the first step in such a strategy may be to characterize genotoxic compounds on the basis of their mode of action. The observation of increased incidence of cancer at certain doses may mostly indicate DNA damage. Further, they may employ promotional activity or affect the process of DNA modifications. For differentiation of three groups, in vitro studies have provided important information about mode of action including dose-response relationships with induction of DNA damage and mutagenicity. The risk assessment of substances having genotoxic and additional promoting activity (Group 2A and 2B) would be beneficial through the reliable quantification of cancer risk at doses below the initiation of promoting activity (i.e., the border between low dose range and high dose range). However, mostly incidences of tumor are too low in this range, making their assessment difficult through experiments or from epidemiological data. In such cases, the start of promotional activity may be evaluated and enumerated by appropriate biochemical parameters (acetaldehyde, formaldehyde, ethylene and its epoxide, products of lipid peroxidation, acrolein equivalents, etc.). Group 3 compounds that act through indirect mechanisms (e.g., inactivation of DNA repair processes) to increase DNA damage and mutagenicity, exhibit thresholds in the absence of other direct genotoxic action as the effects may be caused by the induction of ROS and/or interactions with proteins. On the other hand, special attention should be given to this mode of action because the relevant interactions may appear mostly at low concentrations. This could aggravate repair deficient conditions that may increase frequency of mutation in each cell division by the accumulation of DNA lesions induced by exogenous factors and endogenous DNA damage. As the inhibition of DNA repair may increase clastogenicity and mutagenicity, the no effect concentrations (a basis for low limit value setting) may be quantified in vivo under steady state

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conditions by the absence of elevated levels of DNA damage, chromosomal damage and/or mutations. In the low dose range, quantitative evaluation of genotoxicity is required for all the groups in a similar mode. Most incidences of tumor are too low to be detected experimentally at low dose/concentration, and only an upper limit for the additional tumor occurrence can be evaluated from the animal and population studies data. In recent years, the ability for exact measurement of DNA damage in body fluids and tissues has been remarkably increased. In the low dose range, the quantification of target endpoints like protein adducts may provide additional information about DNA lesions in target cells. Subsequently, two types of genotoxic agents can be categorized on the basis of endogenous background levels of the identical or like DNA lesions (1) exogenous exposure of compounds on the preeminent component of endogenous background exposure such as ethanol or acetaldehyde; and (2) compounds with unknown endogenous exposure applying lifestyle-related unavoidable exogenous background exposure such as benzo[a]pyrene, aflatoxins, allylbenzenes, heterocyclic aromatic amines, pyrrolizidine alkaloids. The endogenous background level of same/similar DNA lesions induced by the same or similar xenobiotic agents (acetaldehyde, ethanol and ethylene oxide) is considered for the determination of potential limit. The next step for compounds lacking comparable endogenous background lesions such as aflatoxin, benzo[a]pyrene, or allylalkoxybenzenes would be the evaluation of carcinogenic risk at concentrations within a low dose range and calculation of exposure edge.

validated in vitro assays. In vitro cell transformation assays (CTAs) that mimic different stages of in vivo tumorigenesis process have been reported for detection of non-genotoxic carcinogens. Bhas 42 CTA is superior to other CTAs because it is capable of detecting promoter activities without treatment of initiator (Hwang et al., 2020). Non-genotoxic carcinogens exhibit epigenetic effects that are long lasting and induce cell proliferation/sustained cellular dysfunction or hyperfunction, target lesions, and neoplasm in animals (Hayashi, 1992). Non-genotoxic carcinogens have broad varieties of mechanisms of action for cancer induction such as tumor promotion, receptor/non-receptor mediated endocrine modulation, inducers of inflammatory responses and tissue specific toxicity, immunosuppressants, etc. The identification and characterization of non-genotoxic carcinogens is very challenging because of the diverse modes of action, tissue specificity, and absence of genotoxicity.

Mode of action for endocrine modifiers Maximum non-genotoxic carcinogens are receptor-regulated endocrine modifiers which interact to receptors like progesterone receptor, estrogen receptor, thyroid hormone receptor, or aryl hydrocarbon receptor (AhR). Estrogen hormones, like 17β-estradiol, interact with estrogen receptors with hydroxylated metabolites (2-hydroxyestradiol and 4-hydroxyestradiol) to stimulate mitogenic impacts.

Endocrine modifiers How to identify the mode of action of non-carcinogenic compounds? Non-genotoxic carcinogens are traditionally identified in a 2-year rodent bioassay’s in vivo conditions due to non-availability of accurate or

Several human non-genotoxic carcinogenic agents are endocrine modifiers by interacting with receptors like estrogen receptors (estradiol), progesterone receptors (progestins, medroxyprogesterone acetate), AhRs (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,4 dichlorobenzene), or

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How to identify the mode of action of non-carcinogenic compounds?

thyroid hormone receptors (“non-dioxin-like” polychlorinated biphenyls). Estrogenic hormones like 17b-estradiol (E2), along with its hydroxylated metabolites, 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2), interact to the estrogen receptor (ER) and strong high mitogenic impact by changing ER-regulated genomic or/and non-genomic events. In the genomic events, estrogen produces homo- or heterodimers complexes with ERa and ERb, and further binds such complexes to estrogen response element (ERE) sequences in the promoter site of estrogen-responsive genes. Moreover, ERa and ERb can also control the transcription of certain genes independent of ERE by interplaying with another DNA-bound transcription components (Chen et al., 2008). In the non-genomic event, estrogen can interact with ER present in the plasma membrane, or another non-ER plasma membrane-related estrogen-binding proteins causing the stimulation of cellular reflections like enhanced extent of calcium or nitric oxide and the stimulation of different intracellular kinase cascades like mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, protein kinase A, and protein kinase C (Chen et al., 2008). Estrogen’s capability to regulate transcription components plays a role in controlling cellular events like proliferation, differentiation, cell motility, and apoptosis is assumed to be the propulsive force for cancer development in humans (Chen et al., 2008). In humans, breast and endometrial carcinoma are estrogen-related cancer tumors (Rosen et al., 2005), and for this cause, estrogenic hormones are known as human nongenotoxic carcinogens (IARC, 1987). In certain cases, different receptors can be regulated by nongenotoxic carcinogenic agents like in the condition of dichlorodiphenyltrichloroethane (DDT). DDT is a pesticide which perturbs the endocrine system, triggers hormonedependent pathology (Kavlock et al., 1996), and stimulates CYP2B and CYP3A in a sex-associated

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mode suggestive of a plausible function of cytochrome P450s in endocrine perturbations (Sierra-Santoyo et al., 2000) DDT is a xenoestrogen which interacts with the ER to induce estrogenic activities (Jaga, 2000) and 1,1-dichloro2,2-bis(p-chlorophenyl) ethylene (p, p0-DDE), the main metabolite of DDT, which is related with breast cancer progressions (Aube et al., 2008). Instead of binding to the ER, DDT isomers are also able to suppress the androgen receptor role leading to significant androgenic antagonistic functions (Maness et al., 1998). The capabilities of compounds to interact with different receptors requires focus to assess the mode of action of xenobiotics carcinogens. DDT also decreases gap-junctional intercellular communications (GJICs) in rat and mouse hepatocytes (IARC, 1999a, 1999b). In humans, increased risks of nonHodgkin’s lymphoma and lung cancer in laborers exposed to DDT (IARC, 1999a, 1999b) has been observed. The carcinogenic impact(s) of progesterone and curative agent progestins (medroxyprogesterone acetate) in breast tumor development and progression is not well explored. Progesterone and therapeutic progestins interplay with another steroidal receptors like the androgen receptor, the mineralocorticoid receptor, and the ER (Druckmann, 2003). Further, the progesterone receptor (PR) is stimulated by estradiol in several target sites (Druckmann, 2003), and they are beneficial prognostic markers of breast cancers plausible to counter anti-estrogen receptor treatments (Lange et al., 2008). Recently, it has been suggested that protein kinases are critical regulators of PR action and the interactions between PR and membrane-induced signaling pathways control mitogenic inducers in hormonally responsive normal tissues. Deregulation of such interactions might develop breast cancer in humans (Lange et al., 2008). TCDD is a human carcinogenic agent that interacts with and induces the AhR, a liganddependent transcription component, by synthesizing a heterodimer with the Ah receptor nuclear

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translocator (ARNT). The Ah-TCDD-ARNT complex interacts to functional sequences and changes their expression (Whitlock, 1993). The implication of TCDD has been based on enhanced expression of ras, erbA, c-fos, c-jun, and other cyclindependent kinases (Knerr & Schrenk, 2006). Furthermore, TCDD has been shown to stimulate CYP1A1, glutathione-S-transferase Y a subunit, aldehyde dehydrogenase, and quinine reductase (Whitlock, 1993). In order to carcinogenicity, TCDD activates cancer in the liver, thyroid, oral cavity, and lungs in rats, and in the liver, thymus and skin in mice (Knerr & Schrenk, 2006). Human epidemiological studies explain an elevated incidence in lung cancer, soft tissue carcinoma, non-Hodgkin lymphoma, and various other cancerous neoplasms in herbicide manufactures exposed to TCDD (IARC, 1997). The detected impacts due to “coplanar” “dioxin-like” polychlorinated biphenyls are alike to the impact produced by TCDD and associated halogenated aromatic hydrocarbons (Knerr & Schrenk, 2006; Loaiza-Perez et al., 1999). Non-dioxin-like PCBs play as “‘phenobarbitalstimulators”’ independent of the AhR. These PCBs are CYP inducers, mainly in human CYP1A2 (Landi et al., 1999) and CYP2B1, 2B2 or 3A leading to the toxic impacts (Knerr & Schrenk, 2006). “Non-dioxin like” PCBs and polybrominated biphenyls (PBBs) regulate the endocrine system by interacting directly to thyroid hormone receptors (TRs), suppressing deiodinase, or replacing T4 from the serum-binding protein transthyretin (Zoeller, 2007). The hepatic DNA adducts have not been observed in mice (Whysner et al., 1998) but the production of ROS and stimulation of lipid peroxidation in rat hepatocytes has been elucidated (Gurer-Orhan et al., 2006). Moreover, “non-dioxin-like” PCBs suppress GJICs in WB-F344 rat epithelial cells (Knerr & Schrenk, 2006; Machala et al., 2003) and the same thyroid impact has been determined with hexachlorobenzene (Loaiza-Perez et al., 1999). It has been suggested that by irregulating estrogen, progesterone, or thyroid hormone

homeostasis coupled with cytotoxicity, that regenerative hyperplasia and suppression of GJICs might be major pathways that cause stimulation and promote the development of cancer. Non-receptor regulators endocrine modifiers Many anti-thyroid drugs like 6-propyl-2 thiouracil, 6-methyl-2-thiouracil, and thiourea elevate the risk of thyroid cancer in rodents by perturbing the biosynthesis or production of thyroid hormones. Goitrogenic agents/drugs like central nervous system-acting drugs (phenobarbital), calcium channel regulators (g1,2,3,4,5 hexachlorocyclohexane), chlorinated hydrocarbons (chlordane), polyhalogenated biphenyls (polybrominated biphenyls), and enzyme stimulators enhance the peripheral metabolism of thyroid hormones. The extent of thyroid hormone could also be perturbed by xenobiotics which suppress the 50 monodeiodinase, an enzyme involved in the conversion of T4 in peripheral sites like the liver and kidney, to biologically active T3. The suppression of 50-monodeiodinase causes decreased circulating T3 levels with a concurrent compensatory enhancement in the production of thyroid stimulating hormone (TSH). Greater concentration of TSH might stimulate follicular cell hypertrophy and hyperplasia and follicular cell cancer in 2-year cancer bioassays in rats (Capen, 1994), and might play a significant role the development of thyroid cancers.

Tumor promotion Several non-genotoxic carcinogenic agents have cancer promoting potential, although other events like cytotoxicity, regenerative hyperplasia, or stimulation of oxidative damage are important for cancer development. In particular, PCBs, cancer promotion, cytotoxicity, and regenerative hyperplasia, and suppression of GJICs have been

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explained to be primary mechanisms in PCB-stimulated cancer (Safe, 1989). Similar nongenotoxic mechanisms have been observed with dimethylarsinic acid and monosodium methane arsenate thereby cancer promoting activity (Wang et al., 2002), cytotoxic and regenerative hyperplasia (Cohen et al., 2006; Xie et al., 2004), modifications in DNA methylation (hyper- or hypomethylation), suppression of DNA repair (Salnikow & Zhitkovich, 2008) and impeding of GJICs (Budunova & Williams, 1994) drive the carcinogenic event. The induction of the cell cycle development, mainly the G1/S transition, along with the suppression of p53 explains that cells exposed to arsenic might be involved in the cell cycle with unrepaired DNA lesions (Salnikow & Zhitkovich, 2008). The suppression of DNA repair and the escalated G1/S transition form arsenic compounds, prime cancer inducers. Importantly, arsenic itself stimulates deletions, chromosomal abnormalities, aneuploidy, and sister-chromatid exchanges, while certain arsenic chemicals like dimethylarsinic acid and monosodium methane arsenate are assumed to act in a non-genotoxic event; however, dimethylarsinic acid has exhibited lower genotoxic impacts at extensively high doses, mainly in the presence of oxygen (Kenyon & Hughes, 2001). Such dual events of cancer progression and cytotoxicity have also been observed with 1,4-dioxane (Stickney et al., 2003), hexachloroethane (IARC, 1999a, 1999b), polychlorinated biphenyls, and the chlorinated hydrocarbon insecticide and flame retardant mirex (Meyer et al., 1993). Cancer development and oxidative stress are considered as major mechanisms of nongenotoxic carcinogens. Pentachlorophenol as a herbicide and insecticide is a wood preservative that produces ROS when metabolized, especially via formation of the hydroxyl radicalderived 8-oxodeoxyguanosine in mouse and rat liver (Dai et al., 2003; Lin et al., 2002). This information has suggested that pentachlorophenol is involved in cancer promotion, but not activity initiation (Umemura et al., 1999).

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Further, it has been explained that the stimulation of oxidative stress is responsible for cancer promotion by triggering hepatocellular proliferation (Umemura et al., 1999). Mitogenic activity stimulated by lead acetate interacted with renal cytotoxicity due to the formation of ROS and regenerative hyperplasia might be a leading cause for cancer development (Calabrese & Baldwin, 1992). The participation of oxidative stress in lead neurotoxicity has been elucidated by the amplification of glutamate-stimulated oxidative stress, likely via the induction of protein kinase C (Naarala et al., 1995) and the MAPK cascade. Cytotoxicity associated with the stimulation of oxidative damage has been determined with nitrobenzene (Han et al., 2001), 1,4-dichlorobenzene (Butterworth et al., 2007), and catechol (Oikawa et al., 2001). Conclusively, it has been explained that cancer promotion alone might not be enough for cancer development but the involvement of cytotoxicity and regenerative hyperplasia, or oxidative stress might be major mechanisms for cancer development by nongenotoxic carcinogens.

Toxicity and inflammation at the tissue level The stimulation of tissue-specific toxicity causing inflammation and regenerative hyperplasia might be significant ways to activate certain non-genotoxic carcinogens. For example, renal cytotoxicity activated by chelating components like nitrilotriacetic acid and nitrilotriacetic acid trisodium monohydrate have been accomplished by alterations in the Zn21 and Ca21 ions in renal cells leading to regenerative hyperplasia and renal carcinoma (Nesslany et al., 2008). Beryllium-activated tumors might be associated with chronic beryllium disease, a granulomatous lung problem identified by the accumulation of berylliumtargeted CD4 1 T cells in the bronchoalveolar lavage (Fontenot & Amicosante, 2008). The

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stimulation of an immune reaction and regenerative hyperplasia, the overexpression of cancer-associated genes, and the suppression of genes participating in DNA synthesis, repair, and recombination might all be crucial for the stimulation of beryllium-induced carcinoma (Joseph et al., 2001). Other significant instances based on gallium arsenide are cytotoxicity, immune response regulation, and inflammation for cancer promotion, and vanadium pentoxide associated with chronic inflammation and interstitial fibrosis is responsible for the development of lung cancer (Ress et al., 2003). The above explanations suggested that the additional events in tumor promotion are required for cancer development, and the same has been seen with cytotoxicity due to the inflammation, regenerative hyperplasia, and/ or immune response modulation is essential to induce carcinogenetic events by non-genotoxic carcinogenic agents.

Cytotoxicity and immune inhibition The stimulation of cytotoxicity and immune inhibition might be major mechanisms in the induced cancer by non-genotoxic carcinogens. Cyclosporine; a lipophilic cyclic polypeptide and an immunosuppressant drug generates calciumdependent suppression of transcription of interleukin-2 and various other cytokines like T-helper lymphocytes. Post-transplant malignancy is assumed to have defective immune surveillance of neoplastic cells and inhibited role of antiviral immunity (Buell et al., 2005). Treatment of adenocarcinoma cells with cyclosporine A produces in the stimulation of phenotypic alterations like the aggression of non-transformed cells whereas treatment with monoclonal antibodies for transforming growth factor-b (TGF-b) suppresses such phenotypic alterations and decreases the number of metastases. Such outcomes indicate that immunosuppressant drugs such as cyclosporine A could elicit direct cellular impact which may

cause for the promotion of cancer, independent of immune reactivity. Furthermore, the cyclosporinestimulated production of TGF-b is assumed to be a significant mechanism in cancer development (Hojo et al., 1999). Phenytoin is an antiepileptic drug which is capable to develop cancer in mice. The human peripheral blood mononuclear cells of healthy volunteers have been exposed in vitro to phenytoin led to a relevant inhibition of natural killer cell function, depression of interferon enhancement of natural killer cell cytotoxicity, and of antibody-dependent cell regulated cytotoxicity. These outcomes are evocative of conspicuous immunosuppression of natural killer cell and antibody-based cell-regulated cytotoxicity functions in patients having antiepileptic treatment like phenytoin. Neoplasm formation might result from the direct action with cellular DNA and/or an indirect event by immunosuppression (Margaretten et al., 1987).

Suppression of gap-junction intercellular communications Gap junctions encompass proteinaceous, plasma membrane channels that connect the interiors of neighboring cells and permit the candid exchange of small molecules (,1000 Da) and ions. Such transmission between cells is significant in the balancing of homeostasis by regulating cell differentiation and proliferation (Yamasaki et al., 1996). Several other non-genotoxic carcinogens reveal an inhibition or reduction in GJICs. For instance, chlordane, a hydrocarbon insecticide and a strong inhibitor of GJICs, is sometimes implicated as a positive regulation for the determination of GJIC suppression (Rivedal & Witz, 2005). TCDD has been revealed to suppress GJICs in MCF-7 breast cancer cells by elevating the phosphorylation of connexin-43 through the protein kinase C-alpha signaling mechanism (Gakhar et al., 2009). A unique mode of action has been detected in human mammary

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epithelial cells thereby TCDD changed the position of connexin-43 from the cytosol to the perinuclear membrane (Gakhar et al., 2009). The non-genotoxic carcinogens that show suppression of GJICs are DDT, pentachlorophenol, phenobarbital, polybrominated biphenyls, butylated hydroxyanisol, peroxisome proliferators (Wy-14643 and DEHP), acetamide, phenytoin, mirex, nickel and arsenic chemicals (Cowles et al., 2007; Sai et al., 2001).

Other mechanisms There are many compounds that are different or not completely explored modes of action. For example, the model nongenotoxic carcinogen carbon tetrachloride (CCl4); a hepatotoxicant which stimulates fatty degeneration, fibrosis, hepatocellular death, and carcinogenicity. CCl4 is stimulated by CYP2E1, CYP2B1 or CYP2B2, and likely CYP3A, to produce the trichloromethyl radical, CCl3*. This radical could interact with nucleic acids, proteins, and lipids and perturb the major cellular mechanisms. DNA-CCl3* adducts are considered to be significant in the formation of hepatic cancer. Oxygen radicals like the trichloromethylperoxy radical CCl3OO*, are very highly reactive and might induce lipid peroxidation reactions and degrade polyunsaturated fatty acids. CCl4 is always positive in triggering recombination and aneuploidy in fungi and activating liver DNA adducts for oxidative and lipid peroxidation (Eastmond, 2008). CCl4 also activates hypomethylation, impedes protein synthesis, and stimulates tumor necrosis factor-a, nitric oxide, and transforms growth factors a and b in the cell (Weber et al., 2003). Instead of such evidence, certain nickel compounds exhibit lower genotoxic potential; however, most nickel (II) compounds are considered to stimulate cancer through non-genotoxic events. Epigenetic events evoked by nickel compounds like nickel sulfate hexahydrate, nickel (II)

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oxide or nickelocene have stimulated DNA hypermethylation, the Hypoxia Induced Factor1a transcription factor, hypoxic stress, suppression of histone acetylation, changing in iron homeostasis, reduction of ascorbate, and suppression of GJICs. Gene silencing of tumor suppressor genes like p53, Fhit, and p16 through hypermethylation of its promoters might be significant in the activation of nickel-induced tumor. Nickel compounds may also play as cancer promoters by increasing the cytotoxicity and genotoxicity of DNA-damaging components via the suppression of DNA repair, particularly nucleotide and base excision repair mechanisms. Perchloroethylene (PCE) is a typicallyimplicated solvent in the dry-cleaning industry and in industrial degreasing functions. The proof for increasing the risk of any kind of cancer in human epidemiological studies is not clear. Many epidemiological studies have elucidated the increased incidences for esophageal cancer, non-Hodgkin’s lymphoma, and cervical cancer. Significant species variations exist, suggesting that humans might be comparatively less sensitive to the cancer-producing impacts of PCE than rodents. The carcinogenic impact of PCE is likely because of the production of the metabolite trichloroacetic acid (TCA). In mice and rats, TCA stimulates hepatocellular peroxisomes, whereas humans are comparatively insensitive to such chemical and other peroxisome proliferators. Peroxisome proliferation is known to stimulate cancer; however, the certain pathway of this induction is still unexplored (Wernke & Schell, 2004). Though PCE is known to stimulate peroxisome proliferation in mouse liver, a poor quantitative correlation has been observed between peroxisome proliferation and cancer development in the liver upon consumption of PCE via inhalation. The stimulation of leukemia in rats is symptomatic of a different way of carcinogenic activity (Diodovich et al., 2005). Butylated hydroxyanisole, a food antioxidant, is transformed into tert-butylhydroquinone (TBHQ) and tertbutylquinone (TBQ) in the liver through different

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metabolic events. The carcinogenic events are not yet known though possible agents contain oxidative damage activated by TBQ and gapjunction impacts (Williams et al., 1999). Even though CCl4 and certain nickel compounds change gene expression by stimulating hypo/hypermethylation and also perturb the stability of genomic constituents, more studies are required to unravel the events of CCl42, nickel, PCE-, and butylated hydroxyanisolestimulated cancer.

Conclusions

positive outcomes in the in vivo transgenic rodent gene mutation assessment. Non-DNA damage, like spindle poison or inactivation of topoisomerase, sometimes causes positive outcomes in cytogenetic genotoxicity assessment like chromosome abnormalities assessment or the micronucleus assessment. Hence, more mechanistic studies associated with cancer formation based on genotoxicity assessment are required to differentiate genotoxic and non-genotoxic carcinogenic agents.

References

Exposure to xenobiotics chemicals is an unavoidable result of modernized society in which certain compounds are toxic to human health. The impacts of carcinogenic xenobiotics are a major burden in several countries, and international organizations like the World Health Organization have defined guidelines for controlling such xenobiotic substances. Presently, carcinogenic agents have been classified into two groups, genotoxic and non-genotoxic carcinogens, that are subject to several administrative guidelines. Genotoxic carcinogens are compounds which produce carcinogenic impacts through the generation of mutations. Due to the interactive potential of DNA, it has been envisaged to show no secure exposure threshold or dose. Genotoxic carcinogens are controlled under the inference that they cause cancer in humans, even at very low quantities. While non-genotoxic carcinogens that stimulate carcinogenicity via mechanisms other than mutations like hormonal impacts, cytotoxicity, cell proliferation, or epigenetic alterations, are considered to have a safe exposure threshold or dose; hence, their implication in society is authorized until the exposure or consumption extent exceeds the threshold. Genotoxicity assessments are a significant approach to categories of the two group of carcinogens. Certain carcinogens give negative outcomes in in vitro bacterial mutation assessment but provide

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Lange, C. A., Sartorius, C. A., Abdel-Hafiz, H., Spillman, M. A., Horwitz, K. B., & Jacobsen, B. M. (2008). Progesterone receptor action: Translating studies in breast cancer models to clinical insights. Advances in Experimental Medicine and Biology, 630, 94 111. Lin, P. H., La, D. K., Upton, P. B., & Swenberg, J. A. (2002). Analysis of DNA adducts in rats exposed to pentachlorophenol. Carcinogenesis, 23, 365 369. Loaiza-Perez, A. I., Seisdedos, M. T., Kleiman De Pisarev, D. L., Sancovich, H. A., Randi, A. S., Ferramola de Sancovich, A. M., & Santisteban, P. (1999). Hexachlorobenzene, a dioxin-type compound, increases malic enzyme gene transcription through a mechanism involving the thyroid hormone response element. Endocrinology, 140, 4142 4151. Machala, M., Blaha, L., Vondracek, J., Trosko, J. E., Scott, J., & Upham, B. L. (2003). Inhibition of gap junctional intercellular communication by noncoplanar polychlorinated biphenyls: Inhibitory potencies and screening for potential mode(s) of action. Toxicological Sciences: An Official Journal of the Society of Toxicology, 76, 102 111. Maness, S. C., McDonnell, D. P., & Gaido, K. W. (1998). Inhibition of androgen receptordependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells. Toxicology and Applied Pharmacology, 151, 135 142. Margaretten, N. C., Hincks, J. R., Warren, R. P., & Coulombe, R. A., Jr. (1987). Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro. Toxicology and Applied Pharmacology, 87, 10 17. Meyer, S. A., Moser, G. J., Monteiro-Riviere, N. A., & Smart, R. C. (1993). Minimal role of enhanced cell proliferation in skin tumor promotion by mirex: A nonphorbol ester-type promoter. Environmental Health Perspectives, 101(5), 265 269. Naarala, J. T., Loikkanen, J. J., Ruotsalainen, M. H., & Savolainen, K. M. (1995). Lead amplifies glutamate induced oxidative stress. Free Radical Biology & Medicine, 19, 689 693. Nakamura, J., Mutlu, E., Sharma, V., et al. (2014). The endogenous exposome. DNA Repair, (Amst), 19, 3 13. Nesslany, F., Simar-Meintieres, S., Watzinger, M., Talahari, I., & Marzin, D. (2008). Characterization of the genotoxicity of nitrilotriacetic acid. Environmental and Molecular Mutagenesis, 49, 439 452. Oikawa, S., Hirosawa, I., Hirakawa, K., & Kawanishi, S. (2001). Site specificity and mechanism of oxidative DNA damage induced by carcinogenic catechol. Carcinogenesis, 22, 1239 1245. Olsen, A. K., Dertinger, S. D., Kruger, C. T., et al. (2017). The Pig-a gene mutation assay in mice and human cells: A review. Basic & Clinical Pharmacology & Toxicology, 121(3), 78 92.

Ress, N. B., Chou, B. J., Renne, R. A., Dill, J. A., Miller, R. A., Roycroft, J. H., Hailey, J. R., Haseman, J. K., & Bucher, J. R. (2003). Carcinogenicity of inhaled vanadium pentoxide in F344/N rats and B6C3F1 mice. Toxicological Sciences: an Official Journal of the Society of Toxicology, 74, 287 296. Rivedal, E., & Witz, G. (2005). Metabolites of benzene are potent inhibitors of gap-junction intercellular communication. Archives of Toxicology, 79, 303 311. Rosen, E. M., Fan, S., & Isaacs, C. (2005). BRCA1 in hormonal carcinogenesis: Basic and clinical research. Endocrine-Related Cancer, 12, 533 548. Safe, S. (1989). Polychlorinated biphenyls (PCBs): mutagenicity and carcinogenicity. Mutation Research, 220, 31 47. Sai, K., Kang, K. S., Hirose, A., Hasegawa, R., Trosko, J. E., & Inoue, T. (2001). Inhibition of apoptosis by pentachlorophenol in v-myc-transfected rat liver epithelial cells: relation to down-regulation of gap junctional intercellular communication. Cancer Letters, 173, 163 174. Salnikow, K., & Zhitkovich, A. (2008). Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: Nickel, arsenic, and chromium. Chemical Research in Toxicology, 21, 28 44. Sierra-Santoyo, A., Hernandez, M., Albores, A., & Cebrian, M. E. (2000). Sex-dependent regulation of hepatic cytochrome P-450 by DDT. Toxicological Sciences: an Official Journal of the Society of Toxicology, 54, 81 87. Stickney, J. A., Sager, S. L., Clarkson, J. R., Smith, L. A., Locey, B. J., Bock, M. J., Hartung, R., & Olp, S. F. (2003). An updated evaluation of the carcinogenic potential of 1,4-dioxane. Regulatory Toxicology and Pharmacology: RTP, 38, 183 195. Swenberg, J. A., Lu, K., Moeller, B. C., et al. (2011). Endogenous vs exogenous DNA adducts: Their role in carcinogenesis, epidemiology, and risk assessment. Toxicological Sciences: an Official Journal of the Society of Toxicology, 120(1), S130 S145. Umemura, T., Kai, S., Hasegawa, R., Sai, K., Kurokawa, Y., & Williams, G. M. (1999). Pentachlorophenol (PCP) produces liver oxidative stress and promotes but does not initiate hepatocarcinogenesis in B6C3F1 mice. Carcinogenesis, 20, 1115 1120. Wang, J. P., Qi, L., Moore, M. R., & Ng, J. C. (2002). A review of animal models for the study of arsenic carcinogenesis. Toxicology Letters, 133, 17 31. Weber, L. W., Boll, M., & Stampfl, A. (2003). Hepatotoxicity and mechanism of action of haloalkanes: Carbon tetrachloride as a toxicological model. Critical Reviews in Toxicology, 33, 105 136. Wernke, M. J., & Schell, J. D. (2004). Solvents and malignancy. Clinics in Occupational and Environmental Medicine, 4, 513 527.

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Further reading

Whitlock, J. P., Jr. (1993). Mechanistic aspects of dioxin action. Chemical Research in Toxicology, 6, 754 763S. Whysner, J., Montandon, F., McClain, R. M., Downing, J., Verna, L. K., Steward, R. E., 3rd, & Williams, G. M. (1998). Absence of DNA adduct formation by phenobarbital, polychlorinated biphenyls, and chlordane in mouse liver using the 32P-postlabeling assay. Toxicology and Applied Pharmacology, 148, 14 23. Williams, G. M., Iatropoulos, M. J., & Whysner, J. (1999). Safety assessment of butylated hydroxyanisole and butylated hydroxytoluene as antioxidant food additives. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association, 37, 1027 1038. Xie, Y., Trouba, K. J., Liu, J., Waalkes, M. P., & Germolec, D. R. (2004). Biokinetics and subchronic toxic effects of oral arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid in v-Ha-ras transgenic (Tg. AC) mice. Environmental Health Perspectives, 112, 1255 1263. Yamasaki, H., Ashby, J., Bignami, M., Jongen, W., Linnainmaa, K., Newbold, R. F., Nguyen-Ba, G., Parodi,

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S., Rivedal, E., Schiffmann, D., Simons, J. W., & Vasseur, P. (1996). Nongenotoxic carcinogens: Development of detection methods based on mechanisms: A European project. Mutation Research, 353, 47 63. Zoeller, R. T. (2007). Environmental chemicals impacting the thyroid: Targets and consequences. Thyroid: Official Journal of the American Thyroid Association, 17, 811 817.

Further reading Knerr, S. , D. (2006). Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models. Molecular Nutrition & Food Research, 50, 897 907. Lu, H., Guizzetti, M., & Costa, L. G. (2002). Inorganic lead activates the mitogen-activated protein kinase kinasemitogen-activated protein kinase-p90(RSK) signaling pathway in human astrocytoma cells via a protein kinase C-dependent mechanism. The Journal of Pharmacology and Experimental Therapeutics, 300, 818 823.

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C H A P T E R

8 Modulation of the epigenome by xenobiotics in cancer Introduction Epigenetics is defined as the study of heritable change in gene expression that can happen in the paucity of alterations in genome sequence. It can be differentiated with genetics, which explains the transmission of information underlying changes in the DNA sequence. The main event of epigenetic regulation is the methylation of DNA at cytosines to generate 5-methyl cytosine (5-mC). DNA methylation is used in several biological mechanisms, although the molecular events through which it controls genome activity have only recently been discussed (Bombail et al., 2004). Hence, it is confirmed that cytosine methylation has an important function in gene silencing, X chromosome inactivation, genomic imprinting, and embryonic formation (Grewal & Moazed, 2003; Jaenisch & Bird, 2003). It has been linked with epigenetics activities, such as cancer, neurological ailments, and diabetes (Feinberg et al., 2002). DNA methylation is mainly an epigenetic process that controls chromosomal stability and gene expression. However, the abnormal DNA methylation patterns have been explored in several human cancers, such as breast, prostate, colon, thyroid, stomach, uterus, and cervix. It has been observed that exposure to different

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00008-X

xenobiotics during critical periods of mammalian development change DNA methylation and lead to negative biological impacts like aberrant gene expression. Hence, such epigenetic processes might depend on the enhanced risk in adulthood of various chronic diseases such as cancer, in response to xenobiotic exposures early in life. It has been studied relative to the impact of perinatal diethylstilbesterol (DES) exposure on the methylation process of the promoters of various estrogen-responsive genes related with the development of reproductive organs. Perinatal DES exposure stimulates epithelial cancer of the uterus in mice and is related with different reproductive tract irregularities and enhanced vaginal and cervical cancer risk in women is a clear instance of how estrogenic xenobiotic exposure over a certain period of organ development can abnormally demethylate DNA sequences and likely enhance cancer risk. Moreover, nutritional factors and stress might also change DNA methylation during the early stages of life and moderate the risk of cancer in adulthood. It has been explained that DNA methylation status might be affected by environmental exposures early in life, resulting to enhanced risks of cancer in adulthood (Li et al., 2003). Epigenetic modulation by environmental factors such as nutrition, xenobiotics, physical

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activity, stress, etc., plays a critical function in cell differentiation in early life as well as over a whole life span because it regulates gene expression in cell- and tissue-specific patterns. DNA methylation is a major epigenetic process involving gene expression (Gabbianelli, 2018). The methylation of CpG islands in a promoter site is responsible for progressive switching off of the gene and the presence of methyl groups needed for methylation underlying a folaterich diet and adequate amounts of B12 and B6 vitamins (McGee et al., 2018; Naninck et al., 2017). Deficiencies of such micronutrients in early life have led to enhanced risks of cardiovascular, metabolic, and neurological disorders later in life (Menendez-Castro et al., 2018). Moreover, other lifestyle factors like smoking, alcohol, stress, and food pesticides have been shown to enhance the risk of disease in adulthood due to genetic alterations (MenendezCastro et al., 2018). For instance, alcohol hinders the methyl donor transfer from folate to methyl tetrahydrofolate, hence disturbing the onecarbon metabolism that is, folate mechanism (Nakhoul et al., 2017). Importantly, epigenetics is an operative regulatory process occurring during the whole life of human beings. For instance, lower levels of folate, B6, and B12 in an adult diet might decrease the level of methyl groups for adenosylmethionine that is implicated by DNA methyltransferases to methylate CpG islands. It has been reported that the epigenome is highly altered in cancer through hypermethylation and genome-wide hypomethylation (Gerhauser, 2013). Hypermethylation of CpGenriched sites related to genes participate in tumor suppression and DNA repair leading to their inactivation, whereas hypomethylation induces the genes causing oncogenic activation and chromosomal volatility (Gerhauser, 2013). Histone alteration is the second significant epigenetic process that plays a role in chromatin remodeling. Functional groups such as acetyl, methyl, and phosphate, formed by the

catabolic mechanism of macromolecules, might transfer heterochromatin-silencing of genes to retain normal gene activity (Gabbianelli, 2018). Environmental pollution along with predisposing genetic factors determine short and long-term negative impacts on human health. Thus industrialized countries have given priority to research in the determining of etiology associated with diseases of environmental factors. In context, it has been highly explained that several chemical compounds like endocrine disruptors, are capable of changing the epigenetic properties of a human being. Recently, several studies have explained that the paradigm “genotype is highly related with a phenotype” is changing in support of the view that a phenotype is explained by a “genotype and by an epigenome.” Hence, there is no change in genotype of all cells related to the epigenome that alters gene expression without changing the nucleotide sequence of the genome by altering DNA methylation, histone, and the mechanism of small noncoding RNAs. The epigenome is readily affected by several factors like perturbation of normal epigenetic mechanisms which might be caused by environmental factors associated with exposure to xenobiotics, social behavior, and nutritional deficiencies. Hence, epigenetic alterations are a biological reflection of environmental factors and might be transferred to the progeny. After removal of the environmental factor, epigenetic modifications are reversed, which indicates that it is not involved in the natural selection mechanisms. However, epigenetic alterations affect gene expression with interference in stability and survival of cells as well as the inactivation of onco-suppressor genes. Hence, it has drawn attention to explore the apparent elements of stimulation of epigenetic mechanism for implementing prevention protocols. In addition, gene expression screening via high throughput techniques, such as microarrays, are seen as a new tool for identifying new epigenetic indicators to monitor the initial

Xenobiotics in Chemical Carcinogenesis

Introduction

biological impact on the population exposed to xenobiotic compounds (Ficociello et al., 2010). Lifestyle and longer exposure to xenobiotic compounds like pesticides, detergents, industrial chemicals, organic solvents, and polycyclic aromatic hydrocarbons (PAHs) can remodel the epigenome and alter gene expression to enhance disease susceptibility (Mazambani et al., 2019). PAHs are usually present in cigarette smoke, diet, and several industrial chemicals that pollute air and water (Zelinkova & Wenzl, 2015). During the metabolic process, the intermediate products of PAHs are mutagenic and synthesize DNA adducts to stimulate cancers, and thus exposure to PAHs is of certain reason. Hormonally active xenobiotic compounds are estrogenic that might stimulate the transcription of estrogen genes to induce the development of breast cancer (Brody & Rudel, 2003). The genetic revolution has emphasized an understanding of the sequence of the genetic constituents of humans and other organisms. It has been usually understood that the sequence provides confidential information for the phenotypic diversity of humans and to which diseases they are prone. Such genomic sequences also lead to determining the potential health hazards of several agents. The fundamental presumption in the field has been that the interindividual alterations in reflection to xenobiotics compounds are explained by genetic modifications and that the main hazard expected at the genomic level from xenobiotics is mutagenesis or physical aberration to DNA. According to the above fundamental hypothesis, the main emphasis of attention in pharmacogenetics has been on determining the polymorphisms in genes encoding drug metabolizing enzymes and receptors (Szyf, 2007). New xenobiotic compounds have been traditionally investigated for their genotoxic impacts. However, it has been cleared that epigenetic programming shows an equally significant function in developing interindividual

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phenotypic variations that can affect drug action. In addition, the rising thought of the influential nature of the epigenome and its reflectivity to several cellular signaling mechanisms explains that it is highly vulnerable to the impact of xenobiotics compounds not only during certain periods of development but later in life also. Hence, nongenotoxic compounds may interfere with gene functionality via epigenetic processes in a stable and longterm pattern with consequences that might be identical from the influence of physical damage to the DNA. Epigenetic programming can exist and even be transgenerationally transmitted (Naughton, 2006), and such a possibility develops a certain challenge in the toxicological study of safety of xenobiotics compounds. Presently, the efficiency of xenobiotic compounds in altering gene expression has been widely studied. Field toxicogenomics explains molecular events by measuring changes in messenger RNA (mRNA) expression, which is associated with adverse impacts of toxic compounds (Miousse et al., 2015). These disturbances might further cause changed protein expression and function, while developing the intracellular response to the xenobiotic compounds. Currently, it has been emphasized in understanding the changes of epigenetic modification in gene regulatory sites which regulate gene expression. In this regard, substantial epigenomic data sets of several tissues and disease conditions have been produced since the last decade which explore the peculiar epigenetic modifications at the cellular level developing several diseases including cancer (Sproul & Meehan, 2013). Data collections explains that epigenetic markers and/or the molecular events controlling them might be disturbed by exposure to several environmental, chemical, and biological stressors (Thomson et al., 2014). From a chemical toxicity viewpoint, it has been explained that such a mechanism of action is linked with intermediate exposure to an inducer to greatly stable cellular perturbances

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such as changes in gene expression. Thus epigenetic aspects are considered as biomarkers of exposure to toxic xenobiotic compounds responsible for cancer (Alyea et al., 2014; Laird et al., 2013). However, significant knowledge on epigenomics data identifying toxic xenobiotic compounds is not well explored. Apart from this, there is a lack of data agreement related which epigenomic alterations have adverse vs those that are likely reactive to an inducing chemical. This increases a wide interest to analyse toxicant efficiency by measuring sensitiveness and molecular alterations in adverse outcome pathways (AOPs) within the environmental regulatory agencies that is highly significant to exploring which epigenomic modifications would be beneficial for analysis and in which aspects. Substantial studies have been made by extrapolating lifetime rodent carcinogenicity to humans (Terranova et al., 2017). When xenobiotic exposure in animals is observed to be linked with either cancer stimulation or early indicators of neoplastic toxicity, then a weight of evidence-based cancer risk analysis is usually suggested. A major participating factor to the weight of evidence methods for xenobioticstimulated nongenotoxic carcinogenesis (NGC) is the assessment of a pathway or way of action as this imparts an entry point for continuous determination of efficient human significance (Van Der Laan et al., 2016). On the basis of molecular studies, species-specific, NGC has been designed for several compounds (Cohen & Arnold, 2016; Van Der Laan et al., 2016). However, the wide range of xenobioticinduced cancer which are mainly found in animal carcinogenicity studies, showing tissue-, gender-, strain- and/or species-specificities, show difficulties in determining pathways and analysis of significant changes to humans. Further, it does not have enough data on the significant relationship of xenobiotic exposure with nongenotoxic carcinogenesis in humans because of latency, low incidence, and

problems in deconvoluting environmental from intrinsic factors for cancer development. Although, some insights could be achieved from somatic mutational signatures of human cancers which are related with known mutagenic exposures (Alexandrov et al., 2013); however there would naturally be overlap between intrinsic and extrinsic events. Instead of such challenges, it is required for attentive analysis for cancer risk in human due to toxic xenobiotic compounds (Thomas et al., 2016). Exploring the molecular mechanisms based on xenobiotic-induced, NGC provides significant data of industrial, environmental, and regulatory factors with novel tools for revealing carcinogenic hazard and risk assessment. This is explained by phenobarbital-induced hepatocarcinogenesis, whereby constitutive androstane receptor (CAR)-mediated induction of mouse hepatocyte proliferation reveals a way of action which was not observed in human hepatocytes in vitro (Hirose et al., 2009). However, the humanized rodent models in which mouse livers were devised to express human CAR support proliferative reflections and cancer promotion exposure to PB (Braeuning et al., 2014; Luisier et al., 2014). In contrast, human hepatocytes had not supported hyperplastic effects to the phenobarbital (PB) in chimeric mice with humanized liver (Yamada et al., 2014). Hence, exploring such opposing results of these models would require further identification of: (1) quantitative exposure response relationships; (2) the effect of human nuclear receptor-mouse gene regulating protein interactivity; (3) the impact of mouse host cellular environment on transplanted human hepatocytes; and (4) comparability at the molecular, biochemical and cellular extents of designed or transplanted hepatocytes to human donor-derived liver tissue. Noticeably, PB stimulates alterations in the mode of chromatin modification across the regulatory sites of CAR target genes in mouse liver (Terranova et al., 2017; Thomson et al., 2013), and hence, it is

Xenobiotics in Chemical Carcinogenesis

DNA methylation in development of cancer

appreciable that variations in the genetic and epigenetic structures of PB effector genes play a significant role in assessing species-specific susceptibility to CAR-mediated hepatocarcinogenesis. Considering the above descriptions in various aspects, this chapter will provide an overview on the role of xenobiotic compounds in cancer development by modulating the epigenome.

DNA methylation in development of cancer About 3%
5% of the cytosine residues in mammalian genomic DNA are found as 5-methylcytosine formed from a covalent integration of methyl groups to the cytosine residue (Li et al., 2003). Methylation is catalyzed in the presence of DNA methyltransferases that incorporate methyl groups from S adenosylmethionines to C5 positions of cytosines. The enzymatic apparatus for DNA methylation consists of three DNA methyltransferases (DNMTs) (DNMT1, 3A, and 3B) (Li et al., 2003; Xie et al., 1999). The notable presence of DNMT1 among DNMT is mainly expressed and is needed for the maintenance of comprehensive methylation after DNA replication. It implicates hemi-methylated DNA as a preferential template (Bouchard & Momparler, 1983). In this respect, DNMT3 family genes seem to be developmentally regulated and exhibit de novo DNA methyltransferase functionality in vitro. DNMT3 could methylate hemimethylated and unmethylated DNA with the same potential (Xie et al., 1999). DNA methylation basically accomplishes CpG dinucleotides that are highly congregated in sites of approximately 1
2 kb in length, named CpG islands, in or close to the promoter and first exon sites of genes (Jones & Laird, 1999; Laird, 1997). DNA methylation is a silenced gene transcription either by arresting/facilitating protein binding or by indirect events participating in the alteration chromatin formation. Regulation

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of DNA methylation leads to controlling aspects of development, tissue-specific gene expression, and expression of imprinted genes, and silencing of transposable elements. Unmethylated CpG islands are based on housekeeping genes, whereas the islands of several tissue-specific genes are methylated or unmethylated, which depend on their expression in particular tissues (Jones & Laird, 1999; Tremblay et al., 1995). DNA methylation accomplishes a major function in mammalian embryonic development, a process which has distinctive gene expression or successively turning on and off several genes to form a stable phenotype (Kafri et al., 1992). Some studies in methyltransferasedeficient mice reveal that mouse embryos expressing less DNMT1 do not develop to term and die at 5
20 somite events depending on the level of the enzymes (Li et al., 1992). DNA methylation also participates in genomic imprinting, a mechanism in which constant silencing of a gene from only single parent is accomplished (Razin & Kafri, 1994). Gene imprinting could be determined in the DNA regions which encode the insulin-like growth factor (IGF)-2 and H19 genes. The expression of H19 gene occurs in maternal chromosome and methylation accomplishes on the paternal chromosome only, whereas the IGF 2 gene is paternally expressed and is methylated on the maternal chromosome only. DNA methylation also plays a critical role in inactivating the X chromosome (Riggs & Pfeifer, 1992). The modified DNA methylation participates in the development of cancer and certain developmental disorders (Robertson & Jones, 2000). Global hypomethylation is highly prevalent in cancer tissues in comparison to normal tissues. Alterations in DNA methyltransferase are also highly observed in cancerous tissues (Mizuno et al., 2001). Therefore the alterations in DNA methylation might involve the development of cancer through distinct paths such as:

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1. hypomethylation of promoter sites causing overexpression of oncogenes; 2. hypermethylation of promoter regions causing inhibition of tumor suppressors; and 3. hypermethylation resulting in an enhanced risk of deamination of 5-methylcytosine to thymine, causing C-to-T point mutations in tumor suppressor genes and/or oncogenes. For instance, hypomethylation triggers increased expression of oncogenes, like, c-myc (Tao et al., 2000b). Reciprocally, a distinct tumor suppressor gene is downregulated or totally silenced due to hypermethylation of promoter region. These have p16, E-cadherin, estrogen receptor, and the mismatch repair gene hMLH1 (Kulis & Esteller, 2010). These changes in methylation are commonly known as an early mechanism of cancer development (Lim & Maher, 2010).

Regulation of the epigenome by xenobiotics Epigenetic modification owing to environmental factors such as nutrition, xenobiotics, physical activity, stress, etc., plays a vital function in cell differentiation while early life and across the life span because it highly influences gene expression in a cell- and tissue-specific way (Gabbianelli, 2018). It has been observed that the epigenome is highly altered in cancer. As previously discussed, the hypermethylation of CpG-enriched regions inhibits tumor suppression and DNA repair, whereas global hypomethylation induces genes for oncogenic activation and chromosomal instability (Gerhauser, 2013). Another significant event of epigenetics pathway is related with histone modification involves in chromatin remodeling. Functional groups like acetyl, methyl, and phosphate formed during catabolic mechanism of macromolecules can shift heterochromatin-silencing of genes to balance normal gene activity.

More attention must be given to food quality, because xenobiotic (pesticides and metals) residues which are employed in pest management are observed in foods (Karmaus et al., 2017; Teodoro et al., 2019). Several studies on animal models and also humans working on farms reveal enhanced levels of pesticide metabolites in urine (Gabbianelli & Damiani, 2018). Such chemicals have an adverse effect on gene expression and epigenetic events (Skinner, 2016). For instance, pesticide residues in foods are capable of increasing the risk for neuronal damage (Nasuti et al., 2014) and obesity (Alonso-Magdalena et al., 2016) due to genetic and epigenetic alterations which might be inherited in the unexposed progeny (Bordoni et al., 2015; Gabbianelli & Damiani, 2018). In this respect, encouraging the consumption of organic foods might be beneficial, especially during the sensitive window of epigenetic plasticity like early life, to inhibit the risk for developing neuronal damage (Collotta et al., 2013; Gabbianelli & Damiani, 2018). Occupational and environmental exposure to pesticides is also responsible for adverse impacts on human health by stimulating the development of a number of disorders. The most recent hypothesized mechanisms are oxidative stress and epigenetic alterations, although biological impacts appear to be regulated specifically by genetic polymorphisms. The susceptibility to exposure could be investigated by exploring the most peculiar polymorphisms of genes participating in the metabolism of organophosphorus compounds such as: cytochrome P450, glutathione transferase, acetyltransferases, or paraoxonase 1 (Table 8.1) (Teodoro et al., 2019).

Carcinogenicity of Ochratoxin A through complex network of epigenetics Ochratoxin A (OTA) is a mycotoxin synthesized by Aspergillus and Penicillium fungal

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DNA methylation in development of cancer

TABLE 8.1 Genetic polymorphisms associated with human diseases in pesticide-exposed populations (Teodoro et al., 2019). Pesticides

Polymorphic gene

Types of cancer

Pesticide mixtures (carbamates, organophosphates, pyrethroids and organochlorines)

PON1, SOD2, OGG1, XRCC, XRCC4

Breast cancer, prostrate cancer

Organochlorine

CYP

Breast cancer

Pyrethroid

GSTM1 and GSTT1

Melanoma

Organophosphates/organic copper/triazines/biological insecticide (abamectin)

PON1, OGG1, XRCC1, XRCC4

Cancer/ oncohematological cancer

Organophosphates (Chlorpyrifos, trichlorfon, parathion and malathion)

PON1

Brain cancer, leukemia, sarcoma

Organochlorine

GSTM1 and GSTT1

Urinary bladder cancer

species in food commodities such as cereals, coffee, wine, spices, dried fruits, beer, grape juice, and animal products. Owing to its widespread presence in food, the human population is constantly exposed to OTA. OTA leads to several toxicological impacts in animal models like nephrotoxicity, nephrocarcinogenicity, teratogenicity, neurotoxicity, and immunotoxicity (Marin-Kuan et al., 2008). Several studies have emphasized the mechanisms employed in OTA toxicity (Schilter et al., 2005). As multiple experimental approaches have been generated, several, often inconsistent, data have been observed. The high dependency of the explored pathways and influences upon cell kinds, dose amounts, and treatment periods has caused a vital problem in this field. Moreover, several mechanistic studies have implied cell line models that might not always exactly reflect the conditions in vivo. Hence, new approaches have been taken to garner the available knowledge as a network of interacting events (Fig. 8.1). It could be designed a possible chain of mechanism responsible for OTA carcinogenicity. Increasing the cellular level of OTA can possibly stimulate the generation of oxidative stress causing macromolecular lesions for example,

DNA damage that could lead to mutations and cancer initiation. Oxygen radicals either develop from reactions directly participating in OTA (with Fe3þ, quinone) or indirect outcomes of the OTA-induced reduction in cellular antioxidant defenses, where both mechanisms work together and reinforce each other (Marin-Kuan et al., 2008). Instead of oxidative stress, in vitro and in vivo data suggest that OTA stimulates a multiple set of biological impacts in the modulation of several transcription factor activities and the induction of specific cell signaling mechanisms. Of the regulatory mechanisms affected in vivo, changes in HNF4a function and the induction of the MAPK-ERK cascade consist of major effectors in the way of OTA cancer development and progression. In fact, earlier they have been related to cell proliferation and cancer development in renal tissue (Marin-Kuan et al., 2008). However, the peculiar molecular pathways responsible for the OTA-mediated induction of MAPK-ERK cascade have not yet been explored. Though, on the basis of preliminary in vivo data, an interaction with the IGF-1 system seems as an appreciable and facilitating possibility which requires further attention.

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FIGURE 8.1 The designed diagram for OTA carcinogenicity with an intricate network of interacting epigenetic pathways. OTA stimulates the generation of oxidative stress causing DNA damage and mutations. The enhanced generation of reactive oxygen species is possibly to synthesize reactions directly participating OTA and as an indirect result of the suppression of Nrf2-regulated antioxidant gene expression. Moreover, OTA stimulates an array of complex biological impacts linked with cell proliferation and cancer development. They play a vital role in inhibiting the transcription factor HNF4αactivity and the induction of the IGF-1
MEK
ERK cell signaling cascade. Such impacts could be stimulated directly by OTA or indirectly, via the OTA-regulated enhanced oxidative stress and/or protein synthesis suppression (Marin-Kuan et al., 2008). OTA, Ochratoxin A.

Moreover, OTA-mediated generation of oxidative stress and suppression of protein synthesis might also play a significant role in carcinogenesis. In reflection to several chemicals, earlier studies have revealed that both effects, the blocking of protein synthesis (Laskin et al., 2002) and the generation of oxidative stress (Klaunig & Kamendulis, 2004), had induced MAP kinase cascade.

Alteration of the epigenome by chemical carcinogens Several studies have suggested that environmental factors like xenobiotic exposure and diet, could alter DNA methylation extents in rodents, sometimes at particular gene loci. A

cancer stimulating dose of the nongenotoxic hepatocarcinogen, PB, decreased the amount of liver DNA methylation in a cancer-sensitive (B6C3F1) mouse strain (Bombail et al., 2004). Such modification was temporary: methylation levels reverted to normal after a 4-week recovery duration. Notably, the same dose of PB had not changed global methylation extents in a high cancer-resistant strain (C57BL/6); however, the component enhanced the growth of hepatocytic cells in both strains. In another study based on a PCR technique, it has been observed that DNA methylation mainly alters GC rich sites of the mouse genome (Watson & Goodman, 2002). In such regions of the genome, exposure to PB led to an increase in the methylation in dosed animals in

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comparison to control animals. Further, the change was highly observed in cancer-prone C3He and B6C3F1 strains with respect to the less sensitive C57BL/6 strain. By employing the SENCAR mouse model of tumor initiation/promotion, another carcinogenic agent such as cigarette smoke condensate (CSC), showed global alteration in methylation in GC-rich site that was associated with doseand time-dependent modes (Watson et al., 2003). In this approach, CSC treatment stimulated tumor formation in response to dimethylbenz[a]anthracene (DMBA), and alterations in the methylation of GC-rich sites were highly observed in tumors in comparison to normal tissues (Watson et al., 2003). The initial CSCstimulated methylation alteration were reversed following recovery time. Further studies have shown that chemical carcinogens can change the methylation level of certain genes. Rodent hepatocarcinogens, trichloroethylene (TCE), dichloroacetic acid (DCA), and trichloroacetic acid (TCA), stimulate the liver mRNA and protein expression of the proto oncogenes c-jun and c-myc within 100 minutes of exposure (Tao et al., 2000a). Such increased expression has been occurred by demethylation of CpG dinucleotides in the regulatory sites of both genes within 5 days of exposure to above chemicals. Above studies clearly explain that specific carcinogenic compounds induce modifications in DNA methylation, and that strain variations in the extent of such alterations could reflect relative sensitivity to the carcinogenic compounds.

Epigenetic impacts of ethanol on liver and gastrointestinal system The increasing network of epigenetic regulatory events also covers ethanol-induced alterations in the gastrointestinal (GI)-hepatic system over the past few years and number of evidence have explained that alcohol alters

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various epigenetic parameters in the GI tract and liver. The affected mechanisms have DNA methylation, several site-specific alterations in histone proteins, and microRNAs. Ethanol metabolism, cell-signaling cascades, and oxidative stress are responsible for such responses. Further, ethanol-stimulated fatty liver (steatohepatitis) and development of liver cancer (hepatic carcinoma) might be causes of the modified epigenetics. Alterations of gene and/or protein expression through epigenetic modifications also might be involved in the cross-talk among the GI-tract and the liver as well as other organs also. Hence, epigenetic impacts of ethanol have a pivotal function in the several pathophysiological responses stimulated by ethanol in different organs and mediated through the liver-GI axis (Shukla & Lim, 2012). Alcohol-stimulated epigenetic modifications in the liver and gastrointestinal tract It has been explained initial evidence for the ethanol-stimulated epigenetic alterations in histone H3 and explained H3 acetylation in primary cultures of rat liver cells. Other researchers have explained that ethanol alters methylation of histone H3 at two lysine residues (lys-4 and lys-9) and that phosphorylation of histone H3 at two serine residues (ser-10 and ser-28) is enhanced in ethanol-exposed hepatocytes (Lee & Shukla, 2007). Furthermore, substantial studies have also explained that such alterations are accomplished not only in cultured hepatocytes but also in vivo in the liver as well as in other organ. Outside of ethanol, alcohols can also be observed as contaminants in adulterated alcoholic drinks which can also alter histones (Choudhury & Shukla, 2008). Eventually, with alterations of singlecarbon metabolism, ethanol might potentiate the epigenetic impacts of toxins secreted by particular bacteria in the GI tract like lipopolysaccharide or endotoxin. Such toxins stimulate methylation of histone H3 at lys-4 (Ara et al., 2008) that can, in turn, induce the progression of alcoholic liver disease (ALD).

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Ethanol-stimulated histone alterations are based on the changed expression of various genes, including encoding the ethanolmetabolizing enzyme alcohol dehydrogenase (ADH), the cancer-inducing gene (oncogene) c-jun, and the gene encoding a protein called plasminogen activator inhibitor 1 (PAI-1) that participates in the dissolution of blood clots and in several diseases such as fibrosis and specific kinds of cancer (Table 8.2). Changes in miRNAs miRNAs are RNA molecules that do not act as templates for protein formation although have regulatory mechanism (Shukla & Lim, 2012).

So far, hundreds of miRNAs have been expressed (Shukla & Lim, 2012) which might be changed by several factors leading to changes in internal or external conditions. For instance, chronic ethanol feeding causes for up- or downregulation of 1% or higher of the identified miRNAs in the liver of mice (Dolganiuc et al., 2009) and rats (Dippold et al., 2013). Owing to ethanol exposure in rat liver, the upregulated miRNA were miR-34a, miR103, miR-107, and miR-122 (Dippold et al., 2013) that have been employed as regulatory factors in lipid metabolism (Lee et al., 2010; Shukla & Lim, 2012), iron (Castoldi et al., 2011), and balancing glucose levels (i.e., glucose homeostasis)

TABLE 8.2 Epigenetic factors modified by ethanol in the gastrointestinal system (Shukla & Lim, 2012). Factors

Molecular changes

Impacts

DNA

DNA methylation through DNA methyl alcohol DNMT enzymes

ADH, genes for folate metabolism

Histone

Kinds of alterations Acetylation

ADH, LSD

Methylation

LSD (lysergic acid diethylamide)

Phosphorylation

C-jun, plasminogen activation inhibitor 1 (PAI-1)

Altered enzymes HATs HDACs

Micro-RNA

Upregulation

Lipogenesis

mir 03,20,21,29a,34a,101,103 mir107, 122, 132,148, 152, 155 mir 212, 217, 349, 705, 1224 mir 1256 Downregulation

Immune response

mir 19b, 135, 182, 183, 200b mir 199a-3P ADH, Alcohol dehydrogenase; DNMT, dehydrogenase transferase; HATs, histone acetyl transferases; HDACs, histone deacetylases.

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(Trajkovski et al., 2011). In contrast to above miRNAs, the extents of miR-200b and miR-19b had been downregulated under the same experimental state (Dippold et al., 2013). Similar outcomes had been achieved in mice, thereby chronic ethanol feeding with a liquid Lieber-DeCarli diet caused to upregulation of miR-705 and miR-1224 and downregulation of miR-182, miR-183, and miR-199a-3p in the liver. However, the biological sites of such miRNAs with respect to alcohol consumption must still be explained (Dolganiuc et al., 2009). However, alterations in miRNA contents could impact the expression of enzymes playing roles in other epigenetic changes, which confirms, in parallel, that expression of miRNAs themselves could be subjected to regulation by histone alterations and/or DNA methylation at DNA sites that control miRNA expression such as at their promoters. For instance, ethanol-stimulated expression of miR-155 appears to be controlled by employing a regulatory protein called nuclear factor κB (NFκB) to the miR-155 promoter (Bala et al., 2011), presumably occurred by epigenetic alterations related with gene activation. In other studies, elimination of methyl groups from cytosine nucleotides at the promoters of miR-29a and miR-1256 related with upregulation of such miRNAs in prostate cancer cells (Li et al., 2012). However, it has not yet been explored if miRNAs regulated by ethanol might also be controlled by DNA methylation, where such studies intrigue the possibility of cross-talk among molecular factors participating in several kinds of epigenetic alterations. Mode of alterations in DNA methylation Ethanol can also change the mode of methylation of DNA in liver influencing gene expression. For instance, gene-encoding enzymes participating in ethanol metabolism such as ADH, are controlled by DNA methylation (Dannenberg et al., 2006). Hence, it is likely that decreased levels of DNA methylation (hypomethylation) caused by

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ethanol would interfere with the transcription of such genes. Such impacts are significant in patients with late-stage ALD, thereby ethanol participates in the induction of hepatic cancer. Alterations in miRNA expression, alcoholstimulated modification in DNA methylation, have also been determined in other organs instead of the liver. For instance, chronic ethanol feeding in rats impacts methylation of genes in controlling absorption of the vitamin folate in the intestine (Wani et al., 2012). Folate is a significant cofactor in single-carbon metabolism; so, its deficiency, in turn, can influence the methylation reactions in several other organs, like the liver.

Epigenetic effect of cadmium Cadmium (Cd) is a toxic nonessential metal that causes health risks in both humans as well as animals. It is naturally present in the environment as a pollutant which comes from agricultural and industrial sources. Exposure to cadmium is usually accomplished via the ingestion of contaminated food and water and, to a certain amount, via inhalation and cigarette smoking. Cadmium assembles in plants and animals with a higher half-life of approximately 25
30 years. Epidemiological data explains that occupational and environmental cadmium exposure might be associated with several kinds of cancer such as breast, lung, prostate, nasopharynx, pancreas, and kidney cancers (Genchi et al., 2020). Epigenetic alterations are also stimulated by environmental factors like kind of nutrition and exposure to xenobiotics, owing to the dynamic condition of the epigenome (Szyf, 2007). Cadmium exposure might change gene expression profiles and interfere with epigenetic factors in three ways: DNA methylation, histone posttranslational modifications, and miRNAs. However, DNA methylation levels depend on the time of exposure to cadmium. Indeed, Cd exposure for a short-term (24 h
1 week)

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stimulates hypomethylation, whereas longer periods (8
10 weeks) trigger hypermethylation (Henkler et al., 2010). In vitro exposure to cadmium of TRL1215 rat liver cells for only oneweek suppressed DNA methyltransferase function, ending in DNA hypomethylation, whereas longer exposures to Cd (10 weeks) of the same cells led to DNA hypermethylation due to an increase in the activity of DNA methyltransferase. It has been reported that Cd-stimulated DNA hypermethylation is accomplished because of malignant transformation of human prostate epithelial cells (Benbrahim-Tallaa et al., 2007). Mainly, Cd develops an opposite impact in association of acute vs chronic exposure, as chronic heavy metal intoxication stimulates an adaptive pathway to external stress. Indeed, since the cells have been exposed for a shortterm to high doses of Cd that is, acute exposure, it might enter into apoptosis and have declined metastatic efficiency, whereas chronic exposure results to malignant transformation of normal epithelial cells as adaptation methods identified by apoptosis resistance, enhanced invasion potential, dedifferentiation, and self-renewal properties (Zimta et al., 2019).

Epigenetics modification in lung cancer of smokers The Multiethnic Cohort approach has explained that African Americans and Native Hawaiians have a higher risk of lung cancer because of cigarette smoking than Whites whereas Latinos and Japanese Americans have a less risk. Such outcomes are consistent with other epidemiological studies in the literature. African Americans contain higher amounts of nicotine in their urine than Whites per cigarette whereas Japanese Americans take up less. There are equal differences in the consumption of tobacco smoke carcinogens for example, tobacco-specific nitrosamines, PAH, 1,3-butadiene, and other toxic volatiles. The intake of lower

nicotine by Japanese Americans is clearly associated with the prevalence of low activity of the primary nicotine metabolizing enzyme CYP2A6 in such ethnic group, causing highly unaltered nicotine in the body and hence lower smoking intensity. However, the comparably elevated risk of Native Hawaiians and the low risk of Latino smokers for lung cancer have not been demonstrated by such factors. Outcomes of such published studies might provide a clue of the components for lung cancer in cigarette smokers; hence, identifying biomarkers which could determine those persons at highest risk so that preventive approaches could be started at an initial stage of the lung cancer development process (Murphy et al., 2018). Smoking is a well-known contributor to the epigenome such that distinctively methylated DNA regions from smoking might act as a marker of tobacco smoking and smokingrelated lung cancer risk, as well as aid in identification of the genes participating in lung cancer development. Generally, blood samples are used to study DNA methylation of blood leukocytes in tissues for epigenetic alterations by smoking. It has been reported that at least 20 EWAS of smoking characters from blood leukocytes of adults with .2600 CpG regions in .1500 genetic sites characterized to be distinctively methylated by smoking condition. In contrast, the EWAS of smoking in other tissues such as buccal mucosa and nasal epithelium are limited (Murphy et al., 2018; Wan et al., 2015). The frequent replication in smokingrelated distinctively methylated CpG regions are the hypomethylation of: cg03636183 in the coagulation factor II (thrombin) receptor-Like 3 (F2RL3) gene; cg05575921, cg14817490, cg21161138 and cg25648203 in the aryl-hydrocarbon receptor repressor (AHRR) gene; cg05951221, cg21566642, and cg01940273 in 2q37; cg19859270 in the G protein coupled receptor (GPR15) gene; and cg06126421 in 6p21.33. The importance of such known smokingassociated hypomethylated CpG regions and

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others are not clear yet. However, several such genetic sites are related with cell signaling, metabolism of xenobiotics, and generation of cancer. Cg03636183 in F2RL3 had been identified as the first smoking-related distinctively methylated regions recognized by EWAS. F2RL3 codes for thrombin protease stimulated receptor 4 (PAR-4) that is expressed in several tissues and plays a vital function in activating the platelet and cell signaling. Cg05951221 in 2q37 is found closer to various alkaline phosphatase genes such as alkaline phosphatase genes placental (ALPP), placental-like (ALPPL2) and intestinal (ALPI) that are involved in the dephosphorylation of proteins. Total seven genes within the 100 kilobases flanking cg06126421 at 6p21.33 code for proteins involving in cell cycle check-points such as HLA-B associated transcript (BAT3). Genetic variants in BAT3 were related with lung cancer risk in a GWAS (Wang et al., 2008). However, the investigating epigenetic modes in GWASrecognized candidate genes in lung tumors located in DNA methylation modes in 6p21.33 have not been observed to be significantly distinctive in nonsmall cell lung cancer tissue in comparison to adjacent normal tissue (Scherf et al., 2013). GPR15 a membrane-localizing protein related with higher GPR15 RNA expression in smokers. The AHRR genetic site is plausibly the most consistently and potentially distinctively methylated gene, with .35 CpG regions within the body of the gene which have been observed differentially methylated in smokers in comparison to nonsmokers. Differential methylation modes of cg05575921, the most consistent replicated probe, found in the intronic site of AHRR, were also related with multiple smoking traits such as CPD, serum cotinine, cumulative level smoked (pack-years), and time since quitting. AHRR is a component of the aryl hydrocarbon receptor (AhR) signaling cascade; which mediates dioxin toxicity and is participated in controlling of cell growth and in

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differentiation and modulation of the immune system. AHRR acts as a negative feedback regulator of the AHR that is major in the metabolism of PAH. However, the process by which AHRR methylation changes AHRR gene activity is not cleared. Even if the treatment of alveolar cell lines is accomplished with cigarette smoke condensate, enhanced hypomethylation of transcriptional inducers markers found adjacent to cg05575921 was observed, indicating the cg05575921 and other regions in AHRR might participate in the stimulation of gene regulatory factors (Murphy et al., 2018). It has been elucidated that the status of DNA methylation from smoking is vigorous (Ambatipudi et al., 2016; Murphy et al., 2018). The highest study of DNA methylation alteration because of smoking cessation (n 5 745 women) observed that regions with higher distinctive methylation in present smokers were more likely to remain distinctively methylated even after .35 years of smoking cessation such as cg05575921 in AHRR and cg03636183 in FRL3 (Guida et al., 2015). Since distinctively methylated regions could provide more knowledge above self-reported smoking history, they might act as efficient long-term biomarkers of tobacco smoking exposure in earlier smokers. DNA methylation approaches across race/ ethnicity are scarce, and most studies of nonEuropean ancestral populations have been performed in African Americans (Elliott et al., 2014; Murphy et al., 2018; Philibert et al., 2012). The regions with potential effect sizes in European ancestral populations such as AHRR and F2RL3, were more likely replicated in African Americans. A systematic assessment of the generalizability of distinctive methylated regions by smoking characteristics across race/ ethnicity will aid in determining the effects of smoking on the epigenome over populations. The South all And Brent Revisited (SABRE) cohort in the United Kingdom, the only multiethnic study had differentiated the smokinglinked DNA methylation modes of cg05575921

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in AHRR by race (South Asian and Whites) in present smokers, observed that Whites had lower DNA methylation status than South Asians. Instead, the large number of studies in blood, tissue specific-DNA methylation must also be taken for further study. Differentiation in DNA methylation were also determined within blood cell lines from smokers and nonsmokers; for some of the well-known smokinglinked regions, hypomethylation in present smokers was higher in granulocytes followed by monocytes and B-cells (Su et al., 2016). In an EWAS of pack-years in buccal cells, the higher relevant results had been determined for the well-known distinctive smoking linked to DNA methylation regions such as AHRR and F2RL3. In another way, in an EWAS of present vs. earlier smoking condition in buccal cells of chronic obstructive pulmonary disease cases and controls, only intermediate associations had been determined with the well-known regions and the most relevant outcomes had been observed in regions early not linked with present smoking status, with the exclusion of cg02162897 in cytochrome P450 1B1 (CYP1B1). Relationships for the well-established regions had not been observed in one EWAS of smoking status in nasal epithelial cells and in one EWAS of smoking pack-years in lung tumor cells (Freeman et al., 2016). Hence, the nasal epithelium might provide better feedback of the alterations in the bronchus as identical genes are expressed in the nasal epithelium and bronchus and the changes in such genes in several airway diseases seems continuous in both tissues (Murphy et al., 2018; Sridhar et al., 2008). DNA methylation results has also been employed to compute biologic age. The present smokers and ever smoking lung cancer cases have been observed to remain at older biologic ages. At current, three EWAS of lung cancer risk employing blood cells had been performed in populations of European ancestry (Baglietto et al., 2017; Murphy et al., 2018). All three studies observed cg05575921 in AHRR, cg03636183 in

F2RL3, and cg06126421 in 6p21.33 to be linked with lung cancer risk, after regulating the smoking status and pack-years. Another study also determined the links with cg21566642 and cg05951221 in 2q37.1 and cg23387569 in 12q14.1. The next regions had been earlier observed to be only slight association with smoking status. Two studies observed that the involvement of any one of the three markers (cg05575921 in AHRR, cg03636183 in F2RL3 or cg06126421 in 6p21.33), upgraded the lung cancer risk prediction (Baglietto et al., 2017). In another study, the involvement of methylation data from cg05575921 in AHRR and cg03636183 in F2RL3 was liable for the impact of smoking on lung cancer risk. Such outcomes elucidate that the known smokinglinked DNA methylation regions might have utility in lung cancer risk measurement as they might give significant knowledge that has not been covered by self-reported smoking history. More studies are required to analyze the heterogeneity of impacts by race/ethnicity, compile the outcome across tissue types, and explore the functional activity of distinctively methylated regions in respect to disease generation. Even though there are large amounts of data on differential methylation by smoking status, further examinations of the effect of smoking dose, potentiality, and period on the epigenome of smokers are still required. Finally, with the formation of newer methylation events, particularly the MethEPIC Chip that contains B400K more CpG regions, predominantly in inducer sites, it can be expected that novel distinctively methylated CpG regions will be detected. These data might give additional insights into the effect of smoking on the epigenome and determine genetic sites suitable for smoking-linked lung cancer measurements (Murphy et al., 2018). Epidemiological studies have apparently revealed ethnic/racial variations prone to lung cancer in cigarette smokers. For the same number of cigarettes smoked, particularly at low and intermediate levels of smoking as determined by

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CPD, African Americans and Native Hawaiians have the highest risk for lung cancer, Whites have a moderate risk, whereas Latinos and Japanese Americans have the lowest risk. However, other factors are also important in such ethnic/racial differences; the present examinations emphasize epigenetics and the activity of inflammation and oxidative damage in altering lung cancer risk among these ethnic/racial groups.

Xenobiotic-induced epigenetic remodeling Epigenetics, or regulation of gene expression independent of DNA sequence, does not establish the any relationship between genotype and phenotype. Epigenetic memory, mediated by histone and DNA alteration, is regulated by a set of specific enzymes, metabolite availability, and signaling events. This is an important aspect associated with how subtoxic exposure to different xenobiotics during certain developmental pathways modify the epigenome and lead to the causes of disease phenotypes later in life. Further, it has been explored that exposure to low-dose xenobiotics accomplish epigenetic remodeling in the germ line and lead to enhanced disease risk for future generations that is, impact of multigeneration and transgeneration (Jime´nez-Chillaro´n et al., 2015). Molecular pathways of epigenetic remodeling by xenobiotics Modifications in epigenetics regulate the gene expression which appear when fetal development disrupts the normal sequence of events. Such disruption triggers developmental flaws or more complicated alterations that mechanistically lead to late onset diseases of adulthood. The stability of epigenetic impressions over maximum periods of the lifespan reduce the degree of modifications caused from exposure to toxicants. In addition, the significance of xenobiotic exposure with respect to epigenetic toxicity might cause more problems

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if epigenetic reprogramming is in its highest flux viz gametogenesis and early embryogenesis (Migicovsky & Kovalchuk, 2011). Apart from this, epigenetic impressions could also be remodeled after birth, but an acute and low dose exposure to a toxicant might have a greater epigenetic impact in comparison to higher dose exposure in an adult (Ho et al., 2012). The enzymes involved in inducing and perpetuating epigenetic pathways depend upon metabolic cofactors. Several xenobiotics produce free radicals influencing a cell’s redox condition. In other ways, metabolic cofactors are involved in their removal or use reducing components for their detoxification. Some might have connections with the circadian clock to alter epigenetic modification. It has been explained that through each of these aspects, xenobiotics disrupt the epigenetic mechanism of gene expression while development by affecting the functions of enzymes is involved in epigenetic pathways (Fig. 8.2).

Altering donors for epigenetic remodeling Cellular and mitochondrial events synthesize precursors that are employed by the epigenetic machinery to acetylate, methylate, or phosphorylate targets in DNA and histones. Acetyl coenzyme A (Acetyl-coA), acetylcarnitine, ATP, and s-adenosyl-L methionine (SAM), among others, are employed by the epigenetic apparatus as acetyl, phosphate, or methyl donors. All of them are generated by cellular metabolism, with the mitochondrion being a fulcrum of metabolic events because of its role in nutrient and redox sensing (Wallace & Fan, 2010). Xenobiotics disturb the cellular metabolism, mainly mitochondrial function, and might alter the supply of substrates to the epigenetic apparatus. As explained in the above on environmental pollutants, such as PAHs, maternal exposure to PAH leads in hypermethylation of IFNg47 and ACSL family member three genes in cord blood DNA.

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FIGURE 8.2 Impacts of xenobiotic-stimulated redox changes on epigenetics. (A) During embryonic development, xenobiotics might enhance the generation of ROS in the embryo, exposing proliferating cells to enhanced oxidative stress. The shunting of sulfur from the methionine cycle is responsible for generating GSH under an oxidized state. Moreover, the oxidative stress also suppresses the activity of SAM synthetase. Hence, xenobiotics interplay with cellular redox balance altering the SAM availability to control the epigenotype of dividing cells. (B) Cellular redox balance also interacts with demethylation enzymes, like the JmjC superfamily and TET1, and with prolyl hydroxylases/ HIF systems, modifying the epigenetic machinery while development for changing the gene expression. (C) Oxidation of methylated CpG regions because xenobiotics produce either 5hmC or 8-OG and change the MBP (maltose-binding protein) binding kinetics, interacting with gene expression and re-methylation of the daughter DNA strands after cellular division. GSH, Glutathione; HIF, hypoxia-inducible factors; ROS, reactive oxygen species; SAM, s-adenosyl-L methionine.

Amazingly, exposure to PAH exists in house dust which leads to reduced mitochondrial DNA level in the blood in the winter (Pieters et al., 2013). The relationship between reduced mitochondrial DNA and epigenetic changes and the efficiency to influence future generations had not been studied, deserving further examinations on this and other cases.

Modifying DNA or chromatin remodeling enzyme function and expression The epigenetic apparatus has a large array of primary enzymes and regulators that are not

only regulated by substrates and targets but also via various signaling mechanisms. Suppression or induction of such players by epigenetic pharmacology is usually common and, in fact, is a proposed therapy against several cancers (Ahuja et al., 2014; Campbell & Tummino, 2014). The function of DNMT enzymes is usually modified by xenobiotics either by impacts at the protein or mRNA level. For instance, dichlone, a pesticide/fungicide, imitates the DNMT inhibitor 5-azacytidine (Ceccaldi et al., 2013) or the aquatic pollutant 2,4-DNP that enhances DNMT expression and stimulates DNA hypermethylation in goldfish.

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DNA methylation in development of cancer

As explained lifestyle-derived epigenetic regulators: environmental tobacco smoke and ethanol consumption, cigarette smoking interferes with epigenetic regulation. Maternal tobacco smoking leads to placental DNA methylation that is directly linked with the gestational age (Maccani et al., 2013). Enormous studies revealed that changes in DNA methylation appear from in utero exposure to cigarette smoking. Indeed, DNA methylation is considered as an authentic marker of exposure to tobacco smoke (Shenker, Ueland, et al., 2013) that has the capacity to be screened in the offspring and also in future generations. Instead of direct DNA damage, cigarette smoking or its constituents also regulate DNMT1 mRNA, protein and function in several biological models, for example, murine neurons, human bronchial epithelial cells and in various human tumors (Kwon et al., 2007). Further, cigarette smoke has acrolein that synthesizes adducts with histone proteins and reduces histone acetylation (Chen et al., 2013).

Xenobiotic epigenetic toxicity and the circadian clock It has been clearly shown that interactions exist among the epigenome, metabolism, and circadian clocks (Aguilar-Arnal & Sassone-Corsi, 2013). The reflection to xenobiotic compounds is controlled by the circadian clock at distinguished levels. In the case of hepatotoxicity of ethanol, it is clearly controlled by the clock gene Per1, since removal of it reduces toxicity (Wang et al., 2013). In particular, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) changes the clock genes Bmal1 and Per2 in the ovary, disturbing AhR circadian expression (Tischkau et al., 2011). Other instances have diethyl nitrosamine (DEN)-stimulated cytotoxicity on mouse primary hepatocytes that is highly associated with the Clock gene system, and a role for hypoxia and HIF-1a in modulating AhR signaling through AhR nuclear translocator (ARNT)

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downstream of polychlorinated biphenyl (PCB) exposure (Vorrink et al., 2014). Similar to Clock and other period-modulating proteins such as HIF-1a, ARNT and AhR are PAS (period circadian protein-ARNT-single-minded protein) domain-having proteins. A relationship between metabolism and the circadian clock is apparent in the explanation of Clock-deficient (Clock 2 / 2 ) mice modified acetylation of liver mitochondrial proteins, leading to differentiation of metabolites over the circadian cycle (Masri, & Patel, EckelMahan, et al., 2013). Such differentiation of metabolites and gene expression with the circadian rhythm (Eckel-Mahan et al., 2012) might effect epigenetics via alterations in metabolites and enzyme expression (Eckel-Mahan et al., 2012). In addition, it is hardly astonishing that Clock, a major transcription component for the circadian apparatus, regulates histone acetyl transferase (HAT) function that is thwarted by the circadiancontrolled activity of Sirt1 (Masri & Sassone-Corsi, 2013). From these examples, it could be speculated that xenobiotics interplay with the Clockcontrolled apparatus might have a downstream existing impact on metabolism and gene expression via epigenetic remodeling. This is highly significant when considering that xenobiotic exposure while major fetal epigenetic remodeling windows might be agitated by the reality that the circadian clock is working from an initial stage of development of miRNAs and epigenetic transgenerational transmission of xenobiotic-stimulated epigenetic remodeling. miRNAs are small, noncoding RNA molecules, and smaller than 25 nucleotides that can negatively control gene expression (Ranganathan & Sivasankar, 2014). Such kinds of conserved RNA are mainly generated from the nucleus; however, some updated data explaining that miRNA might also be present in the mitochondrial matrix, where they are taken from mitochondrial DNA (Bandiera et al., 2013; Duarte et al., 2014). Whereas xenobiotics can make changes in miRNA expression acutely or chronically, variations in miRNA expression could

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change the intra-cellular level in nuclear receptors and metabolizing enzymes such as CYP1B1 and CYP2E1 systems. The next impacts could modify the host reflection to xenobiotics (Yokoi & Nakajima, 2013), and modes of alterations in miRNA have been investigated in vivo after exposure to various pollutants such as 2,3,7,8Tetrachlorodibenzo-p-dioxin (TCDD), tamoxifen, arsenic, and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) (Zhang & Pan, 2009). The association of miRNA pattern remodeling and its physiological impact is not well explored. However, it seems that prenatal exposure to chemical components could enhance the sensitivity to disease of future progenies in part by regulating miRNA expression profiles. For instance, TCDD leads pre-natal changes in miRNA expression as ways of influencing as many as 15 pathways downstream associated with inflammation, renal and urological diseases, cell death, and carcinogenesis (Singh et al., 2012). However, miRNA-regulated impacts describe the possible enhanced risk of chronic diseases in adulthood, which does not frequently demonstrate how the enhanced miRNA pattern changes could translate into a transgenerational transmission. miRNA-regulated transgenerational transmission has been designed in the aspects of circulating miRNA that will link somatic changes with epigenetic reprogramming in germ cells (Sharma, 2014). Cigarette smoking changes miRNA expression in human spermatozoa, hence helping in exploring the plausible transmission of obscured gene expression to the progeny; however, such alterations have not been explained in future generations (Marczylo et al., 2012).

Model systems and biomarkers to assess epigenetic effects Various authentic model systems and biomarkers for determining epigenetic impacts have been elucidated, in which some of the selected topics are explained in this portion (Fig. 8.3).

FIGURE 8.3 Environmental factors at a single point in life lead to epigenetic reprogramming that modifies phenotype and responsiveness to toxic xenobiotic compounds.

Natural genetic variation and interaction with the epigenome at the population level It seems that a relevant knowledge gap in the field is the assessment of the natural differentiation in the epigenome among populations. As one moves further in linking epigenetic modes with a disease, it is necessary to detect the limits of what epigenetic marks might be taken as “normal.” A main hurdle in association of epigenetics for toxicological analysis is the current uncertainty around what makes a normal, adaptive reflection to an exogenous inducer and what is an adverse, diseaseassociated modification. Examination of dynamic differentiation in the epigenome among animal strains, sexes, and ages are hence a starting point to explore the natural differentiation. Whereas the studies accomplished in a single strain of inbred mice are extensively beneficial in understanding the fundamental mechanisms, they reveal relevant demerits in terms of explaining the breadth of variability observed in the human population. Present endeavors to reduce such limitations

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DNA methylation in development of cancer

include the mouse Methylome Project led by the National Institute of Environmental Health Sciences (NIEHS) and National Toxicology Program (NTP). The main scope of this project is a comparative study of the methylomes in the livers of males and females in three different inbred mouse strains with the aim of generating a novel knowledge of the relationships between allele-specific methylation patterns, regulation, and changed expression in reflection to environmental factors. Data garnered through such cross-disciplinary endeavors would have relevant information on the methylome, genome, and transcriptome of paternal strains and F1 progeny. These outcomes would also provide views on epigenomic inheritance to offspring and how the epigenetic landscape may vary among genders, siblings, and strains (Miousse et al., 2015). The study on population-based rodent models provides a relevant and interactive relationship between genetic sequence differentiation and epigenetic alterations with respect to a xenobiotic result. A similar type of model is the multiple outbred, a mouse population with genetic sequence dissimilarities which is highly extensive in comparison to human populations. Recently, the implication of diversity outbred mice as a device to place a benchmark dose for benzene-stimulated micronucleus synthesis in genetically different populations has been explained (French et al., 2015). The authors showed that genetically sensitive individuals will appear in a high conservative benchmark dose in comparison to genetically homogeneous B6C3F1/J mice that are the standard mouse model for the National Toxicology Program. Whereas the model gives a relevant paradigm for determining the negative impacts of xenobiotics components in a different population, until now there are not any reports associated with genetic variation to epigenetic alterations based on the diversity of outbred mice. Likewise, the same endeavors are being followed by many other public/private consortia or partnerships

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that is, recent European Chemical Industry Council (CEFIC) Long-range Research Initiative (LRI) to explain the “normality of the rodent epigenome” along with outbred strains (http:// cefic-lri.org/projects/c3-ed-a-comprehensive-epigenomic-profile-of-livertissue-from-rat-andmouse/). With the emergence of inclusive human tissue-specific epigenome maps, EWAS of human populations and patient cohorts possibly provide more relevant views on mechanisms and biomarkers associated with xenobiotic impacts. For instance, cigarette smoking is associated with certain CpG methylation modifications in the AhR repressor gene in blood cells obtained from both adult smokers and newborn babies posed to maternal smoking in utero (Miousse et al., 2015; Shenker, Polidoro, et al., 2013). Hitherto, EWAS studies are being highly employed to identify human disease condition and explore the efficient epigenetic risk components (Liu et al., 2013; Miousse et al., 2015). Eventually, the EWAS may assist in proposing transgenerational studies in humans based on the pattern of inheritance (Miousse et al., 2015). Nonrodent models for epigenetic assessment Above, considerable concern and dispute surrounding the potential for xenobiotics to produce adverse impacts in successive generations has been discussed. The same concerns can be relevant to targeted therapies for epigenetic modulators. Hence, it has been important to have improved methods for analyzing the possibility that certain groups of xenobiotics may create delayed effects which impact subsequent generations. As explained above, multigeneration approaches up to the F3 generation are essential to exploring transgenerational impacts. However, these studies are long and costly to proceed in mammalian species, and fit poorly into safety analysis development paradigms. The period of such studies can be reduced by the implication of nonmammalian models, such as zebrafish, which recapitulate

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the cell migration and mode of inherent formation in the mammalian conceptus in an entire organism. Zebrafish are highly employed in toxicological studies and the species has currently achieved attentiveness as an attractive model for transgenerational impacts of xenobiotics because of the strong conservation of gene and protein structure and activity between zebrafish and humans (Mudbhary & Sadler, 2011). There are many other benefits, such as ease of genetic manipulation, use in high quality imaging, and the comparatively short time frame of breeding and development. Moreover, chemical exposure to zebrafish embryos could be surveilled and standardized more successfully than rodent embryos which are subject to maternal metabolism and variations in parity. Increasingly, zebrafish are used in highthroughput assays emphasized at analyzing developmental morphology endpoints (Truong et al., 2014). Moreover, the zebrafish is a novel model for RNAi studies and provides the benefits of more rapid screening in comparison to the generation of knockout rodent models (Gayta´n & Vulpe, 2014). Various publications have reported that transgenerational adverse impacts could be explained in zebrafish employing many chemical treatments such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), androgens, and perfluorononoate (Miousse et al., 2015). Stem cells and reprogramming Stem cell models might be used to analyze the impacts of chemicals on the specific process, as proteins working in epigenetic mechanisms are highly expressed in embryonic and adult stem cells and participate in modulating the major pathways while stem cell selfrenewal, differentiation, and tissue senescence (Miousse et al., 2015). In embryonic stem cells, regulation of these proteins is linked with embryonic and developmental toxicity. Adult stem cells are found in most adult mammalian tissues as partially altered progenitor cells and

play a vital role in balancing tissue homeostasis and assist with regeneration and repair while tissue damage (Nascimento-Filho et al., 2019). Owing to stem cells in each tissue depending on several transcription and epigenetic components to balance their own certain stage of differentiation (Chen et al., 2012), modulation of epigenetic protein targets can cause stem cell exhaustion, bone marrow inhibition, immune suppression, GI toxicity, and damaged tissue regeneration and repair. However, the impact of regulation of epigenetic targets on functional adult stem cell could be modeled in vitro, it is not practically possible to design assays which could completely cover several adult tissues. Hence, a more common screen underlying human/rodent embryonic or stimulated pluripotent stem cells (hESC/hiPSC) might act as a surrogate for adult progenitor/ stem cells. Undifferentiated hESC/iPSC can be dosed with compounds and assessed for a number of differentiated and also epigenetic endpoints. Novel epigenetic biomarkers for safety assessment The implementation of advance molecular and “omics” technologies into regulatory conclusions has gained high potential to ameliorate risk and product safety assessment processes. One novel mechanism is the characterization of epigenetic markers of chronic toxicities such as carcinogenesis in rodent studies which may finally be translated into surrogate markers of an adverse reflection in humans (Laird et al., 2013; Miousse et al., 2015). Epigenetic marks can act as potential biomarkers before chemical exposure, which may influence the epigenome in an authentic and dose dependent manner. Here, there are relevant gaps in the knowledge of epigenetic impacts led by xenobiotics which would require bridged epigenetic signatures and biomarkers could be employed into risk analysis scenarios.

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References

Conclusions and perspectives From the last decades, several research studies have explored epigenomic events by xenobiotic compounds in the development of various types of cancers. Although, genetic alterations, like methylation in carcinogenesis processes by xenobiotics compounds, are not yet completely understood, epigenetics imparts a certain process by which short-term exposure to an environmental hazard including toxic xenobiotics compounds have relentless lifelong phenotypic impacts. The long-term toxic xenobiotic causes for several diseases, including cancer, have been caused by altering the signaling pathways of several physiological processes which has been challenging to explore the particular factors through which xenobiotics induce carcinogenesis. This review discussed various aspects of toxic xenobiotics in different models to identify the biomarkers for different cancers associated with epigenetic modification and also provides a number of clues for further studies in toxicology research.

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C H A P T E R

9 Carcinogenic effects of nanomaterials with an emphasis on nanoplastics Introduction Nowadays, almost all people have been exposed to nanometer-sized foreign components, whether through inhalation, drinking, or eating. In fact, all organisms on Earth regularly face nanometer-sized particles. Among the highly developed toxic intruders are viruses, consisting of nucleic acid-based structures which permits them to not only interact with biological systems, but also to parasitically seize cellular functions to replicate themselves. Among the highly benign viruses are the ones producing the human symptoms of the prevalent cold or flu that are manifested of biochemical battles occurring between such foreign intruders and immune systems, whose nanometer-sized components like chemicals, and proteins mainly damage and eliminate the viral intruders. Recently, several studies explain that nano- and micro-organisms might play a role in several chronic diseases where pathogens have not been predicted, diseases which had been initially associated with only genetic factors and lifestyle. There are common diseases such as leukemia (developed by Retrovirus and Herpes virus families), cervical cancer (Papilloma virus), liver cancer (Hepatitis virus), gastric ulcer (Helicobacter pylori),

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00006-6

nasopharyngeal cancer (Epstein Barr virus), kidney stones (nanobacteria), severe acquired respiratory syndrome SARS (Corona virus), heart disease (Chlamydia pneumoniae), juvenile diabetes (Coxsackie virus), Alzheimer’s disease (C. pneumoniae), pediatric obsessive compulsive disorder (Streptococcal bacteria), psychotic disorders (Borna virus), and prion diseases for example, mad cow disease (proteins-prions) (Buzea et al., 2007). Now, it has been shown that nanoparticles (NPs) like dust, or ash particles which are similar in size to viruses, will be more benign, as such components hinder the viruses’ capability to replicate. Even though, non-replicating invaders do not directly regulate cellular activities, a few have been revealed to potentially alter cellular activities to affect the fundamental process of cells like proliferation, metabolism, and death. Several diseases are related with malfunctions of such fundamental methods, the highly noticeable being cancer and neurodegenerative diseases. Moreover, various diseases with unexplored causes like autoimmune diseases, Crohn’s, Alzheimer’s, and Parkinson’s diseases, seem to be related to NP exposure. In contrast, the toxic effect of some NPs might be advantageous, as they are thus capable of combatting disease at a cellular extent, and can be

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implicated as a therapeutic agent, for instance, in targeting and killing carcinoma cells (Buzea et al., 2007). Due to their small size, NPs are capable of entering, transferring within, or damaging living systems. Although natural methods have developed NPs for eons, modern science has been presently educated on how to make a bewildering alignment of man-made components with structures that have been engineered at the atomic level. The smallest particles have tens or hundreds of atoms, with dimensions measuring nanometers-thus NPs. The toxicity of nanomaterials highly depends on the specific arrangement of its various atoms. In view of all the possible differences in shape and chemistry of even the smallest nanomaterials, with only tens of atoms, produces a large number of different materials with highly distinct physical, and toxicological characters. Asbestos is a well-known toxic nanomaterial that can develop lung cancer and other several diseases. Asbestos is found in different forms, with slight alterations in shape and chemistry, still appreciably changing toxicity (Buzea et al., 2007). Nanometer-sized particles are generated in uncounted physical methods from erosion to combustion, with health incidence arrays from lethal to benign. At present, industrial NP materials are minuscule but highly pollutive which is, so far, completely buried underneath much greater natural sources and NP pollution risks to other human roles, especially automotive-released soot (Buzea et al., 2007). Recently, the curiosity of general public and scientific community toward the scope and extent of plastic pollution has been highly enhanced. The world-wide manufacture of plastics attained 348 million tons in 2017, from which about half had been manufactured in Asia, whereas Europe produced 64 million tons (Hu & Pali´c, 2020). The growth in manufacturing integrated with chemical cohesion of plastic materials and transfer of consumer inclinations toward “single-use” packaging, expedites production of plastic waste,

causing contamination of different ecosystems and increasing concern about environmental and health issues related with exposure to plastics (Li & Witten, 1995; Lusher, 2015). Exposure of plastic waste to the elements causes its deterioration via mechanical and chemical methods like hydrolysis and UV radiation, to produce microplastic (100 nm 5 mm, MPs) and nanoplastic (,100 nm, NPs) particles (Hu & Pali´c, 2020). In contrast to larger plastic waste, the smaller sizes of MPs and NPs have an opportunity to move several distinct environmental compartments, enhance endeavors needed for their elimination, or clean up and face higher incidences of exposure and transferring food chain. Several studies have explained MP/NPs toxicity, with an emphasis on polyethylene (PE), polystyrene (PS), and polyvinyl chloride (PVC) that have the most manufacturing and usage among various species of plastic components (Hu & Pali´c, 2020). Increasing concern in the examination of MP/NPs is possibly associated with their capability to enter via biological blockade while managing large surface/mass ratio, and their capacity to concentrate in the higher trophic level organisms through the food chain (Hu & Pali´c, 2020; Proki´c et al., 2019). Hence, it is a great interest of research and governing community to assess the possible ecological and human health risks of MPs/NPs. Several methods have been employed in toxicological studies of MP/NPs, such as in vivo (aquatic marine and freshwater, and terrestrial organisms and in vitro models to examine impact effects and nature of MPs/NPs (Avio et al., 2015; Besseling et al., 2014). Results suggest that MP/NPs participate in the stimulation of toxicity, neurotoxicity, cytotoxicity, and oxidative stress (Lei et al., 2018; Lu et al., 2016; Nobre et al., 2015). The detected toxic impacts of MP/NP particles explain that oxidative stress and inflammatory responses are of high significance as the main mechanisms underlying the above-mentioned toxicities. However, risk analysis results from several studies are different

Xenobiotics in Chemical Carcinogenesis

Introduction

and often antithetical, possibly because of the inadequacy of standardized research technology like use of distinct research models due to high diversity of the MP/NPs such as different size, shape, surface charge, and polymer type. For instance, the impacts of high level MPs have shown no adverse effects on crustaceans, which highly contradicts other studies explaining adverse impacts on crustaceans upon exposure to environmentally significant MPs concentrations (Imhof et al., 2017; Weber et al., 2018). Further, discerning toxicity endpoints at distinct biological extents (from molecular to population) can be restricted and ambiguous, due to the intricacy of the determined model system. For instance, maximum in vitro model-based studies explained toxicity endpoints only on the molecular or cellular extent, whereas in vivo studies can determine the negative impacts of MPs/NPs in several organs (Amereh et al., 2019; Schirinzi et al., 2017). Currently, plastic hazards have been a major concern in environmental research. Recently, in addition to MPs pollution (Kokalj et al., 2021; Rezania et al., 2018; Zhang et al., 2020), NPs have also been explored as emerging pollutants (Koelmans, 2019; Lambert & Wagner, 2016). Gigault et al. (2018) and Hartmann et al. (2019) defined the NPs as solid particles of manufactured or largely altered natural polymers with a sizes of 1 1000 nm, while MP particles have a size between 1 and 1000 μm. NPs could either be synthesized intentionally, known as primary, or unintentionally, to produce secondary NPs. Primary NPs could be bottoms-up manufactured or top-down milled; in some conditions, they have pristine non-surface altered components. Milling is a general procedure in the industrial context and is used in polymer particles for size reduction. To investigate primary NPs, they can be purchased or derived from products from which they are intentionally synthesized and added, like coatings, biomedical stuffs, cosmetics, drug delivery, medical diagnostics, electronics, magnetics and

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optoelectronics (Mitrano et al., 2019). In conditions where NPs are synthesized by milling or grinding of bigger plastic materials, for instance for research objectives, these can also be assigned to as primary NPs as they are intentionally made, generally in a particular nano-size range (Hartmann et al., 2019). Such particles, however, can be used as laboratory models to trigger mechanical decrement and production of secondary NPs. Unintentional synthesis occurs during wear and degradation of bigger plastic materials and leads to particles showing colloidal nature (Gigault et al., 2018). Moreover, NPs can also be synthesized unintentionally from MPs within the products, such as in personal care products or from food and beverage packaging (Kokalj et al., 2021). Presently, nanomaterials are highly significant in several areas in the form of nanofibers (NFs), NPs, nanosheets, nanowires, nanofilms, nanoclusters, carbon nanotubes, and quantum dots, which instinctively result in good sensing features (Venkatesan et al., 2020). Consequently, optical sensing associated with NFs is a highly efficient detection approach owing to its different features of flexibility, tailorability, low cost, sensitivity, and reversibility. Polymeric NFs made with fluorescent properties have obtained appreciable research development, such as in centrifugal spinning, melt-blowing, mechanical drawing, self-assembly, and electrospinning (Venkatesan et al., 2020). Particularly, electrospinning has been identified as a potential technique in manufacturing NFs. The significant benefits of this approach is its generation of several structures because of its greater certain surface area, and it could fabricate regularly porous NFs for method flexibility, facile pore development, and high uniformity, where electrospun (ES) NFs have been implicated widely in fields like drug carriers in pharmaceuticals (Kazsoki et al., 2018; Wei et al., 2019), eco-waste purifiers (Yang et al., 2019), energy storage in piezoelectric (Cai et al., 2019; Park et al., 2016), and optical sensors (Camposeo et al., 2015).

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ES NFs have been made by employing a fundamental electrospinning setup made up of a voltage supply, syringe, flow controller, and collector (Aliheidari et al., 2019). However, the present research addressed the impacts of plastic in aquatic systems, whereas only limited data have been obtained regarding the effect of nanosized plastic particles on human health (Revel et al., 2018; Wright & Kelly, 2017), though their production in the environment is increasing and likely to enter humans through the food chain (Lehner et al., 2019). These serious issues based on nanomaterials/NPs considering cancer development have been discussed using cellular uptake and molecular pathways.

Generation of nanoplastic in the environment Over the past decade, the production of MPs has been under scrutiny. The first small plastic particles (,5 mm) were found in open waters in the 1970s (Lehner et al., 2019). The present studies prove the assumption that the degradation method of plastic material does not pause at the micrometer level and that plastic microparticles degrade to produce plastic NPs (Gigault et al., 2016; Lambert & Wagner, 2016). These NPs generally have distinct chemical and physical features in comparison to macroscopic materials based on the same material. Moreover, their interplay with living organisms could also significantly vary (Zhang et al., 2012). Hence, the variations between micro-and NPs are not insignificant, and the interactions of NPs with the environment and organisms are mainly considered (Maurer-Jones et al., 2013). Similar to plastic microparticles, NPs can adsorb and bring hydrophobic compounds which have a greater biological and toxicological effect on the environment like polychlorinated biphenyls (PCBs) derived from objects like electrical instruments, inks, paints, or the pesticide

dichlorodiphenyltrichloroethane (DDT) (Lehner et al., 2019; Velzeboer et al., 2014). Unraveling the interaction of NPs with the environment, mainly with living organisms, is essential in analyzing expected health problems, owing to NP particles that can react in comparison to their micronized counterparts. Currently, the increasing pollution in oceans due to plastics has been a serious environmental issue. However, the long-term effect of micro- and NPs in the aquatic surrounding is very tough to predict, such issues may have a major challenge to society (Villarrubia-Go´mez et al., 2018).

Effect of nanoplastics on human health Exposure to NP may occur through oral inhalation, ingestion, or absorption by the skin in connection with the use of plastic materials or unintentional means (Fig. 9.1). Inhalation can be significant in occupational exposure schemes which participate in NP-having aerosols (Prata, 2018), and skin irritation can happen via the use of personal care products like NPs-containing skin care and sanitizing products, or polluted water or air. Presently, it has been explored that the ingestion of NP materials is possible to represent the major pathway of entry, as NP particles could be consumed by eating seafood or drinking polluted water. Moreover, NP uptake and accumulation, as well as trophic transmission of NP within aquatic organisms has been explained by performing experimental works, hence fortifying the opportunity that NPs may concentrate in the food chain, and hence cause of human exposure (Cedervall et al., 2012; Mattsson et al., 2015). Hitherto, the MP particles have been detected in various seafood species like fish, shrimp, and bivalves, and in other foods like honey, beer, salt, and sugar (Liebezeit & Liebezeit, 2014; Neves et al., 2015; Yang et al., 2015). Present studies employing Fourier transform infrared spectroscopy (FTIR) have also

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Generation of nanoplastic in the environment

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FIGURE 9.1 Three main routes of human exposure to nanoplastics through the skin, GI tract, and lungs. GI, Gastrointestinal.

revealed the presence of MPs in tap water and bottled water, also drinking water from groundwater sources. Of 159 samples of various sourced tap water, 81% contained MP particles, particularly fibers smaller than 5 mm (Kosuth et al., 2018). Out of total 259 bottles of water from 11 distinguished brands and 27 different lots, 93% exhibited indication of MP pollution with an average of 10.4 particles L21 (Mason et al., 2018). Assessment of groundwater of the northwestern part of Germany showed that an all-inclusive mean of 0.7 MPs m23 could be detected (Mintenig et al., 2019). These studies restate that the prevalence of NPs in several food products could not be ruled out. Unfortunately, there have been no studies of NPs in foods, and subsequently, no data has been generated that goes beyond the above-described research works. Human health may also be impacted because of the migration or leaching of chemical additives of the plastic component itself. Within the plastic production method, chemicals like plasticizers, pigments, or stabilizers are applied to produce the desired features of the final product like their flexibility, color, and stability. At present, several different chemicals

are implicated for such concerns, and it has been explored that some of chemicals could percolate out during the product life cycle into the environment, causing endocrine perturbation or acute toxicity after exposure to organisms (Lithner et al., 2011). The same applies for the monomers like chemical building blocks employed to synthesize the polymers in the first place and the products made by the chemical deterioration of polymers. The highly significant instance of a percolating monomer is bisphenol A (BPA) that is employed for the formation of polycarbonate and some epoxy resins. It has been exhibited that BPA produces negative impacts in humans because of its estrogenic potential such as various metabolic diseases and reproductive as well as developmental impacts (Ehrlich et al., 2012; Lang et al., 2008). Mainly, polycarbonate drinking bottles employed for newborns revealed great leaching of BPA. Newborns have a greater incidence in comparison to adults since more internal body concern is anticipated, demonstrated as concentration in blood/plasma, because of enhanced absorption or decreased removal in comparison to the internal body burden of adults (Hengstler et al., 2011).

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Major paths of human exposure to nanomaterials Nanotechnology is an advanced technology with several advantages in fields like food, cosmetics, medicine, and agriculture (Sahu & Hayes, 2017). The US National Nanotechnology Initiative (NNI) explains nanotechnology as “the unraveling and regulating of particles at size between about 1 and 100 nm, thereby different phenomena facilitate novel uses” (Sahu & Hayes, 2017). Despite differences in size, they could also have distinct forms and show exclusive physical, chemical, and biological features which are different from same particles having greater mass and size. The excessively small size and greater surface area of nanomaterials are related with the potential for higher strength, stability, chemical, physical, and biological function. So, they have a broad range of plausible uses in the present world. The predicted enhance in the use of nanomaterials would thus cause to their increased availability in human environment and, so, highly elevating human exposure. As a result, there is high public interest in knowing the negative health impacts of nanomaterials existing in the human environment. Present information of negative impacts of nanomaterial exposure on human health is not sufficient. Owing to their small size and, in some conditions, higher stability they might exist in human environment and in body for prolonged period of time in comparison to their larger counterparts. Specific nanomaterials might be inhaled, ingested, or permeated via the skin more promptly. Hence, interest is increasing to unravel their potential toxicity. Over the last few years, attempts have been accomplished to establish methods for assessing their toxicity and health impacts. Such attempts have caused to the development of a new branch of toxicology known as “nanotoxicology” (Oberdo¨rster, 2010; Oberdo¨rster et al., 2005), an evolving and frequently establishing branch of modern toxicology explaining nanomaterial toxicity.

Ingestion is a main path of human exposure to nanomaterials, both directly via food or indirectly through NP disintegration from food vessels or by secondary ingestion of inhaled particles (Bergin & Witzmann, 2013). Once they come in the body, they might be moved all over the body by blood circulation. It is plausible that their translocation in the body might be a function of their size and surface properties like polarity, hydrophilicity, lipophilicity, and catalytic potential (Wang et al., 2007; Yang et al., 2016). As the particle size reduces, surface area per unit mass enhances and, so, the NPs are speculated to reveal enhanced chemical and biological potential in the body. As a result, it has been proposed that smaller NPs may be higher toxic in comparison to their greater counterparts. It is usually considered that the smaller NPs are engrossed by the cells quicker in comparison to the larger ones. Inhalation and skin absorption are also significant paths of human exposure to airborne nanomaterials (Borm et al., 2006).

Drinking water The availability of MPs in soil and freshwater ecosystems has been estimated, including in regions employed as origin of drinking water exhibiting a path of MPs human exposure, especially whether plastic material could transfer via the filtration systems of wastewater treatment (Carr et al., 2016; Revel et al., 2018). It has been determined that daily emancipation can range from 50,000 to approximately 15 million particles (Mason et al., 2016).

Food chain: marine products Aquatic organisms might be polluted by MPs and NPs, either via loaded water or the feeding from other organisms and might act as an origin of human exposure. Regarding bivalves, humans take the all-soft tissues that might have microscopic plastic waste. Moreover, fish might be

Xenobiotics in Chemical Carcinogenesis

Cellular uptake and intracellular consequences of nanoplastic materials

polluted after fishing while their deposition and transportation in plastic vessels of brittle PS (Revel et al., 2018).

Dermal exposure: water and cosmetics Dermal contact might happen if human interplay with the polluted water containing MPs/NPs while cleaning or via facial/body scrubs also having MPs/NPs. Though, because of the size of MPs and since uptake of particles over skin needs infiltration of striatum corneum that is limited to particles less than 100 nm, absorption via the skin is implausibly to happen. Although, NPs can finally penetrate into/via human skin (Sykes et al., 2014).

Inhalation: air Human exposure to MPs/NPs via inhalation might happen since MPs/NPs become airborne, highly from wave activity in aquatic system or the use of wastewater treatment slime. Further, MPs were identified in atmospheric fallout indicating another potential source of inhalation exposure. MPs (fibers) have been determined on an urban rooftop as a result of atmospheric fallout (Dris et al., 2016). If some MPs are capable of transfer via wastewater treatment plants, again a part of the plastic material would be able to be persisted in the sewage slime. If this polluted slime is employed to land, for agricultural needs, MPs could be observed in terrestrial environments (Horton et al., 2017). Despite the presence of NPs in the atmosphere, no information was easily available (Revel et al., 2018).

Cellular uptake and intracellular consequences of nanoplastic materials After infiltration into the stratum corneum and engrossed into the human body, MPs and NPs are further capable to interplay with several

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target cells. The extent of NPs that are absorbed and eventually interact with cells depends on several factors like their size, surface chemistry, or charge of the biological components they encounter like proteins, phospholipids and carbohydrates. As NPs take proteins from the human body, they generate “protein coronas” on every side of themselves. This suggests that NPs react with organs or skin cells would generally be ringed with protein corona as opposing to an exposed NP. The protein coating would cause modification of the NP properties. Earlier, in vitro studies have explained that protein coronas would surround PS NPs that enable NPs to be transferred at higher rates. Such studies also revealed that the protein coronas will change their shape following to their environment for interaction with cells and thus enhance toxicity. Eventually, it was observed that protein coronas around the PS NPs caused to them to be concentrated in the gut (Yee et al., 2021). MPs and NPs could be consumed by cells through various paths (Krug & Wick, 2011). The primary path is through endocytotic NP uptake thereby adhesive interaction of NPs with channel or transport proteins. Various endocytotic mechanisms have been explored like phagocytosis and macropinocytosis, along with clathrin- and caveolae-regulated endocytosis (Fig. 9.2) (Kaksonen & Roux, 2018; Mani & Pandey, 2019). The initial barricades to NP infiltration into the skin is the external cell membrane. Coarsegrained molecular simulations of PS particles in interplaying with biological membranes showed that PS NPs easily infiltrated the lipid bilayer membranes, leading to alterations in the structure of the cell membrane, finally perturbing the cell activity (Rossi et al., 2014). Uptake inhibition approaches on the absorption rate of 44 nm PS components to human colon fibroblasts and bovine oviductal epithelial cells suggested that PS NPs had been mainly absorbed via a clathrin-independent uptake process (Fiorentino et al., 2015).

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FIGURE 9.2 Major pathways of cellular uptake of plastic particles that is, phagocytosis, macropinocytosis, clathrinand caveolae-mediated endocytosis have been explained. Nanoplastics can be engrossed by cells via various pathways, where endocytotic nanoparticle absorption is the main pathway where adhesive interaction of nanoparticles with channelor transport-proteins occur.

The cellular uptake of carboxylated PS NPs of 40 and 200 nm had been studied employing various cancer cell lines such as human cervical HeLa cells, human glial astrocytoma 1321N1, and adenocarcinomic human alveolar basal epithelial A549 in the presence of transport inhibitors. The outcomes suggested that the NPs had always been absorbed by cells via an active and energy-based approach, explaining that the NP absorption for several cell

types used various mechanisms. Actin depolymerization highly impacted the NP uptake in HeLa and 1321N1 cell lines, whereas clathrinregulated endocytosis of the NPs in 1321N1 had been relevantly decreased the inhibitor chlorpromazine. NP absorption in A549 cell line through caveolae-mediated endocytosis had been markedly decreased because of the perturbation of microtubule synthesis by the inhibitor genistein (Dos Santos et al., 2011).

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Major toxic impact of nanoplastics on human health

The paths of NP uptake in human cells are reliant on the size and surface chemistry of the components, though also differ according to the kind of cell infiltrated. This was observed if 120 nm PS NPs changes with amidine groups had been appeared to infiltrate rat alveolar epithelial monolayers employing non-endocytic mechanisms, whereas MDCKII cells implicate energy-based events to uptake NPs (Fazlollahi et al., 2011; Yee et al., 2021). Macrophages and epithelial cells had been observed to employ several combinations of endocytotic absorption processes to uptake 40 nm carboxylated PS NPs. Employing various endocytotic pathway inhibitors, J774A.1 macrophages had been revealed to absorb NPs through macropinocytosis, phagocytosis, and clathrin-mediated endocytosis routes, whereas uptake in A549 cells based on caveolaeand clathrin-mediated endocytosis mechanisms (Kuhn et al., 2014). If NP components are transferred in the human body through non-vesicular pathways, they might be capable of interplay with intracellular molecules or discharge persistent organic pollutants (POPs) into the cytoplasm. Consequently, this entails that POPs might be accumulated in human cells which can have a adverse toxicological effect (Koelmans et al., 2013). Plastic particles move cells through the intracellular endocytotic mechanism involving with early and late endosomes prior integrating with lysosomes. It has been explored that PS NPs accumulate in the lysosome (Fro¨hlich, 2012), such as the appearance of intracellular localization of 40 50 nm PS NPs in A549 cells. No lysosomal effusion or any breakage of the NPs had been observed since acidic conditions had been implicated (Fro¨hlich et al., 2012). It has been explained that two kinds of NPs constituted of PS and mesoporous silica had variations in cellular uptake events in ovarian cancer cells. The collected data explained that ovarian cancer cells engrossed both kinds of NPs with distinct endocytotic routes (Ekkapongpisit et al., 2012). The mesoporous

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silica particles follow the caveola-mediated endocytosis route to infiltrate the cells depending on the size of the particle, either accumulated in the lysosome (50 nm) or transferred into the cytoplasm (10 nm). In other ways, PS NPs had been absorbed via caveola-independent mechanisms. Localized amine-changed 50 nm PS particles exhibited toxicity to the lysosome after 4 8 hours, while 30 nm carboxyl-modified PS particles had no indication of toxicity and did not move into cells through the standard acidic endocytotic pathways. An earlier study also showed that cytotoxicity is higher with a positive surface charge, and this also causes enhanced uptake of NPs through non-specific attachment, thereby they finish the negatively charged sugar moieties on cell surfaces. Whereas, the repellent interactions of negatively charged components would inhibit endocytosis (Malek et al., 2009). Many studies have explained the various cellular absorption routes and intracellular localization of PS NPs associated with their physicochemical properties. Moreover, there is no sufficient quantitative data regarding absorption of NPs into cells and their eventual consequences. The size of the plastic particles also impact their interplay with human cells (NajahiMissaoui et al., 2021). Because of their greater surface areas, the NP-cell interaction is highly varied in comparison to larger particles. Further, the charge of the particle could also impact its integration with the cell and its structure (Najahi-Missaoui et al., 2021).

Major toxic impact of nanoplastics on human health Many in vitro and in vivo experiments have revealed that micro- and NPs are capable of producing severe effects on the human body such as physical stress and damage, necrosis, inflammation, oxidative stress, and immune responses (Table 9.1) (Yee et al., 2021).

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TABLE 9.1 Some examples of the potential toxic impact of nanoplastics on human health. Toxic impacts

Plastic particles

Size (nm)

Modulating disease causing factors

Inflammation Polystyrene particles Unchanged/ carboxylated polystyrene Carboxylated and amino-alteredpolystyrene particles

202 and 53520, 44, 500, and 1000120

Upregulation of IL-8 expressionStimulated inflammation in human A549 lung cellsUpregulation of IL-6 and IL-8 expressionIncreased inflammation in several human cancersM2 cells stimulated IL-10 formationEnhanced TGFβ1 (M1) and energy metabolism (M2)

Oxidative stress

Amine-altered polystyrene. Cationic polystyreneUnchanged or activated polystyrenepolyvinyl chloride (PVC) and poly (methyl methacrylate) (PMMA)

606020, 40, 50, and 100

Potential integration with mucinIncreased ROS formation and ER stressDecreased cell viability with a declination of ATP and enhance of ROS levels

Metabolic homeostasis

Anionic carboxylated polystyrenePolystyrene nanoparticlesCationic polystyrene nanoparticles

203050 and 200

Stimulated basolateral K1 channelsIncreased Cl2 and HCO32 ion effluxStopped vesicle transport and the contribution of cytokinesisrelated proteinsPerturbed intestinal iron transport and cellular uptakeDecrease in hepatic ATP extents

Inflammation An in vitro study employing several sizes of PS particles observed that bigger particles (202 and 535 nm) created inflammatory impacts on human A549 lung cells. It had more IL-8 expression by the lung cells treated with the bigger particles irrespective to the same cells exposed to 64 nm particles (Brown et al., 2001). Further, unchanged or carboxylated PS NPs carried a consequential up-regulation of IL-6 and IL-8 genes in human gastric adenocarcinoma, leukemia, and histiocytic lymphoma cells, which explains that the enhanced inflammatory responses to PS particles is possible due to the composition of the particle, or the simple particle existence rather than its particle charge (Forte et al., 2016). A study on the effect of carboxylated and amino-modified PS particles (120 nm) on the polarization of human macrophages into M1 or M2 phenotypes showed no alteration in the expression of M1 markers such as CD86, NOS2, TNFα, and IL-1β (Fuchs et al., 2016). However, the explanation of both kinds of NPs negatively

affected the expression of scavenger receptors CD163 and CD200R and liberated the IL-10 by M2 cells. It was a decrease of Escherichia coli phagocytosis by both M1 and M2 macrophages with the use of amino-altered particles. In another way, phagocytosis by M2 had not been impacted by the carboxylated particles. The carboxylated particles also led to the enhancement in the protein mass in M1 and M2, induced the liberation of TGFβ1 by M1, and heightened extents of ATP in M2 (Fuchs et al., 2016). Likewise, an in vitro study also revealed that unaltered PE particles between 0.3 and 10 μm developed murine macrophages to form cytokines like IL-6, IL-1β, and TNFα (Ingram et al., 2004; Yee et al., 2021).

Oxidative stress and apoptosis Several in vitro studies have revealed that distinct PS NPs could stimulate oxidative stress, apoptosis, and autophagic cell death in the cell. For example, amine-changed PS NPs had been revealed to interplay and aggregate with mucin

Xenobiotics in Chemical Carcinogenesis

Carcinogenic impacts of nanomaterials

highly, and trigger apoptosis of mucin- and nonmucin producing intestinal epithelial cells (Chiu et al., 2015). Cationic PS NPs had been exhibited to stimulate ROS formation and endoplasmic reticulum (ER) stress in mouse macrophages and lung epithelial cells through aggregation of misfolded protein, causing autophagic cell death of RAW 264.7 mouse macrophages and BEAS-2B lung epithelial cells (Chiu et al., 2015; Xia et al., 2008). Whereas, unaltered or functionalized PS had been revealed to stimulate apoptosis in different human cell types like primary human alveolar macrophages (MAC), primary human alveolar type 2 (AT2) epithelial cells, human monocytic leukemia cell line (THP-1), human immortalized alveolar epithelial type1 cells (TT1), human colon carcinoma cells (Caco-2), human lung cancer cells (Calu-3), and PS NPs had been shown to control ROS through long non-coding RNAs in Caenorhabditis elegans (Zhao et al., 2021).

Metabolic Homeostasis Instead of stimulated inflammation and apoptosis, present studies have exhibited that MPs and NPs could damage cellular metabolism in both in vitro and in vivo models. PS-based NPs impact signaling pathways in epithelial cells because of NP-cytoplasmic membrane interactions. Upon exposure to negatively charged carboxylated PS NPs determining 20 nm, basolateral K1 ion channels had been observed to be stimulated in human lung cells (McCarthy et al., 2011). NP particles led to the persistent and concentration-dependent enhancements in short-circuit currents by the induction of ion channels and provocation of Cl2 and HCO32 ion efflux (McCarthy et al., 2011). Further, 30 nm PS NPs stimulated greater vesicle-like components in the endocytic path in macrophages and human cancer cell lines A549, HepG-2, and HCT116. As a consequence, vesicle transport and the circulation of proteins

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participated in cytokinesis are inhibited, hence inducing the development of binucleated cells (Xia et al., 2016). Moreover, acute oral exposure to positively charged PS NPs is highly capable of perturbing intestinal iron transport and cellular absorption (Mahler et al., 2012).

Carcinogenic impacts of nanomaterials Due to speedy advancement of nanotechnology, new nanomaterials with multiple properties have emerged, mainly metal nanomaterials. Metal nanomaterials have the properties of metals and nanomaterials, so they are highly utilized in several fields. Though at the same time, whether the utility or discharge of metal nanomaterials into the environment is hazardous to human beings and animals that has recently increased attention at home and abroad. At present, there is irrefutable evidence that cancer is a major cause of death throughout the world. The characteristics of inducing DNA damage and mutations acquired by such metal nanomaterials make them unidentifiable impacts in the body, consequently causing genotoxicity and carcinogenicity (Liu & Kong, 2021). Recently, several studies have revealed that exposure of NPs to the human body could produce DNA damage and mutations, finally increasing the incidence of cancer (Ranjan et al., 2019), and the existence of metal NPs in biological systems causes for cancer development (Wen et al., 2017). With the increasing demand of market share of nanoproducts, synthetic NPs are impacting human life in several ways. So, knowing the environmental health and safety views of NPs has been a major challenge (Kovriˇznych et al., 2013).

Nano-metal elements Carcinogenic impacts of nickel NPs Nickel-associated chemicals have been classified as a group one carcinogen by the

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International Agency for Research on Cancer (IARC), whereas nickel metal is considered as ˚ kerlund et al., 2018). a group 2B carcinogen (A However, the carcinogenic impact of nickel NPs is not widely explored. Earlier studies of rat models have shown that all animals exhibited rhabdomyosarcoma at the implanted region between 4 and 6 months after implanting nickel NPs (Hansen et al., 2006). It had been explained that nickel NPs could trigger antiapoptotic associated elements such as phosphorylated Akt and Bcl-2 proteins that might lead to the carcinogenic impact of nickel NPs (Zhao et al., 2009). Unlike micron-sized nickel, nickel NPs induce a toxicity mechanism of carcinogenic nickel compounds through induction of the fast and long-lasting hypoxiainducible factor-1 pathway that might be closely associated with the potential carcinogenic impact of nickel NPs (Liu & Kong, 2021). Presently, in vitro studies have observed that both fine and NP metallic nickel have carcinogenic impacts in mouse epidermal cell line (JB6 cell), but metallic nickel NPs might have greater astounding carcinogenic impact through upregulation of protooncogenes like phospho-Akt and Bcl-2 (Magaye et al., 2014). In general, despite the DNA damage made by nickel, alterations in gene expression, apoptosis, oxidative stress, and inflammation are the major impacts of nickel-related NPs, and these might lead to the development of cancer. According to several studies, precautionary assessment on the major health impacts of nickel NPs should be performed prior to use in nanomedicine.

protein (Hsp70), and p53 genes enhance, suggesting that silver NPs could produce oxidative DNA damage and cell death, finally stimulating the incident for carcinogenesis (Chae et al., 2009). In another study, it has also been observed that after exposing of Caco-2 cells to silver NPs for long time, extracellular matrix metalloproteinases had been released into the medium, migration potential, and capability of the secretome of exposed cells had been determined to stimulate cancer development tumor, explaining that there is a carcinogenic incidence related with silver NPs exposure under long-time exposure (Vila et al., 2017). Ga´belova´ et al. (2017) have compared the potential of spherical and fibrous silver NPs to activate thymidine kinase mutations in mouse lymphoma cells and to transform B cells and observed that fibrous silver NPs enhanced gene mutations and transformation foci, while spherical silver NPs exhibited neither mutagenic nor carcinogenic potential, explaining that fiber shape might be associated with silver NPs mutagenesis and carcinogenesis (Ga´belova´ et al., 2017). Currently, various studies have observed that, upon exposure to citrate-coated silver NPs (cAgNPs), the structure and activity of liver tissue had been perturbed, as explained by many toxicity investigations and transcriptomic assessment at 7 and 28 days. Moreover, Pathway Studio and Ingenuity Pathway Analysis tools showed that potential molecular networks responding to cAgNPs exposure reveal a positive relation of the genes with inflammation, hepatotoxicity, and cancer (Kim et al., 2019), hence implying higher carcinogenic impact of cAgNPs.

Carcinogenic impacts of silver NPs The growing use of silver NPs in customer commodities and their discharge into the environment have prompted research into carcinogenic impact and its major events. Several studies have explained that silver NPs could activate gene expression alterations in the liver, in which the extent of cytochrome P4501A, heat-shock

Nano-metal oxides Carcinogenic impacts of Titanium dioxide NPs (TiO2NPs) The titanium dioxide had been classified as a possible human carcinogen by IARC (Silva et al., 2013). Several studies have explained the carcinogenic impact of TiO2NPs in vitro and in vivo

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Carcinogenic impacts of nanomaterials

biological models. With prolonged exposure to low doses of TiO2NPs, human bronchial epithelial cells (BEAS-2B) endure a transformation, suggesting that exposure to subtoxic doses of TiO2NPs for a specific time could develop tumors (Vales et al., 2015). In the same way, the prolonged exposure to TiO2NPs could induce mitogen-activated protein kinase/extracellularsignal-regulated kinase transduction mechanism regularly, causing fibroblast cells to come in a mitotic state, accumulating genetic alterations, and subsequently prompting carcinogenic transformation (Huang et al., 2009). Presently, it has been explained that TiO2NPs could stimulate alterations in the expression of genes associated with signal transduction, inflammation, immune system, and cancer development such as colon cancer (Proquin et al., 2019). Moreover, certain studies on Drosophila had explained that TiO2NPs had been identified as carcinogenic by the somatic mutation and recombination test and the epithelial tumor cloning test (Carvalho Naves et al., 2018). Likewise, exposure to TiO2NPs could develop severe gastric damages like gastric mucosa atrophy, erosion, inflammatory cell infiltration, and cell morphologic damages. Notably, these are highly related with the downregulation of IκB, TFF1, and TFF2 expressions and upregulation of NF-κB, TNF-α, IL-lβ, IL-6, IL-8, COX-2, and PGE2 expressions in the stomach (Liu & Kong, 2021). The above explanation revealed that TiO2NPs might have a carcinogenic impact. Carcinogenic impacts of zinc oxide NPs (ZnO NPs) Even though the Food and Drug Administration authorized the anticancer therapy of ZnO NPs (Shen et al., 2013), it is still debatable whether ZnO NPs are useful to cancer therapy due to few studies. Progressive studies have confirmed that both the incidence and advantages associated with the impact of ZnO NPs depend on the dose, procedure of synthesis, and studying object. For instance, the mutagenicity of ZnO NPs in Salmonella

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typhimurium has been assessed, and the mutagenicity had been found at 0.008 μg plate21 in TA98 and TA1537 strains of Salmonella, suggesting that ZnO NPs can cause cancer (Kumar et al., 2011). Currently, it has been explained that ZnO NPs had anticancer potential and again showed plausible molecular events based on their stimulation of apoptosis in chronic myeloid leukemia K562 cells (Alsagaby et al., 2020). In contrast, it has been determined that MTH1, an enzyme upregulated entirely in cancer cells, had relevantly overexpression in cells exposed to ZnO NPs for a prolonged period, elucidating that ZnO NPs could induce cancer development (Barguilla et al., 2020). According to the working group of the German Federal Environment Agency and the German Federal Institute, the various forms of CNTs (carbon nanotubes) and nanoscale TiO2 particles might stimulate cancer in susceptible animal models. It has been expected that the way of action of the inhalation hazards from asbestos-like fibers and inhalable components of bio-persistent course dusts of lower toxicity (nano-TiO2) is associated with chronic inflammatory methods. However, present epidemiological studies on carcinogenic impacts of such synthetic nanomaterials are not enough to achieve conclusion (Becker et al., 2011). In general, the database is not comprehensive enough for analysis of the carcinogenic impact of nanomaterials, but several studies have confirmed a nano-specific ability to develop cancers. This is because of an inadequate identification of the test material, difference in the experimental method, the use of several animal models and species, and/or variations in dosimetry (Becker et al., 2011). Analysis of the carcinogenic impact and its importance in humans are presently fraught with unpredictability. Further, the detected nano-specificity of the carcinogenic impact could not be relevantly assessed. Certain carcinogenic impacts of nanomaterials might be both quantitative and qualitative. In quantitative

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aspects, the carcinogenic impacts of NPs are considered to be easily highly pronounced in comparison to the relative bulk material. In another way, specific nanoproperties like small size, form and reactivity, retention time and transportation in the body after decreasing biological boundaries, as well as subcellular and molecular interactions might be involved in detecting the toxicity in qualitative aspects viz. the carcinogenic impact of the nanomaterial and the non-nanoscale comparison material might be basically distinctive (Becker et al., 2011). All such factors have enough evidence associated the carcinogenic impact of nanomaterials; however, it is highly essential for research in this field to standardize new test methods to have conclusive answers relative to the carcinogenic effect of nanomaterials. Recently, the Global production of nanomaterials with new properties are increasing with greater anticipation of risks for human (Becker et al., 2011). Yet, there is nothing concrete written related to the exposure to NPs and their release from products. First, there is a paucity of knowledge regarding the processing of nanomaterials in products and synthesis. Secondly, there are only limited studies on NP release, and authentic tools for determining and observing nanomaterials in several environmental media are still being advanced that is both complex and expensive (Becker et al., 2011).

Conclusions and outlook Human exposure to nanomaterials from natural and anthropogenic sources has been occurring since ancient periods. However, the invention of ignition engines and the revolution of industries have increased the levels of NP pollution across the world. Toxicity event stimulated by nanomaterials including NPs had been measured with focus on oxidative stress and inflammation. Such adverse impacts had been classified into several extents of biological

complexity from the ecosystem including human health context. Presently, human health is highly affected by the development of nanotechnology for which synthesized nanomaterials cause for NP pollution if not carefully manufactured, managed, and disposed of or recycled. The toxicity of nanomaterials has been studied by considering epidemiological, animal, human, and cell culture studies. Research on humans and animals suggests that some nanomaterials enter the body and immediately move to the organs through the circulatory and lymphatic systems leading to the development of diseases like asthma, diabetes including cancer. Genetic factors might also have essential functions in the reflection of an organism to nanomaterials like NP exposure. The enhanced use of metal NPs in consumer commodities and their liberation into several environments have induced research into their carcinogenic impacts and related mechanisms. NPs are able to interact with human tissues and accumulate to lead to the development of cancer. Both nanomaterials and NPs alter the function of gene expression which also generate adverse health impacts leading to the development of malignant cells. Hence, the use of nanomaterials including NPs should be managed, and any newly manufactured nanomaterial must be assessed for their potential toxicity and carcinogenicity.

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Mattsson, K., Ekvall, M. T., Hansson, L. A., Linse, S., Malmendal, A., & Cedervall, T. (2015). Altered behavior, physiology, and metabolism in fish exposed to polystyrene nanoparticles. Environmental Science and Technology, 49(1), 553 561. Available from https://doi. org/10.1021/es5053655. Maurer-Jones, M. A., Gunsolus, I. L., Murphy, C. J., & Haynes, C. L. (2013). Toxicity of engineered nanoparticles in the environment. Analytical Chemistry, 85(6), 3036 3049. Available from https://doi.org/10.1021/ ac303636s. McCarthy, J., Gong, X., Nahirney, D., Duszyk, M., & Radomski, M. (2011). Polystyrene nanoparticles activate ion transport in human airway epithelial cells. International Journal of Nanomedicine, 6, 1343 1356. Available from https://doi.org/10.2147/ijn.s21145. Mintenig, S. M., Lo¨der, M. G. J., Primpke, S., & Gerdts, G. (2019). Low numbers of microplastics detected in drinking water from ground water sources. Science of the Total Environment, 648, 631 635. Available from https://doi.org/10.1016/j.scitotenv.2018.08.178. Mitrano, D. M., Beltzung, A., Frehland, S., Schmiedgruber, M., Cingolani, A., & Schmidt, F. (2019). Synthesis of metal-doped nanoplastics and their utility to investigate fate and behaviour in complex environmental systems. Nature Nanotechnology, 14(4), 362 368. Available from https://doi.org/10.1038/s41565-018-0360-3. Najahi-Missaoui, W., Arnold, R. D., & Cummings, B. S. (2021). Safe nanoparticles: Are we there yet? International Journal of Molecular Sciences, 22(1), 1 22. Available from https://doi.org/10.3390/ijms22010385. Neves, D., Sobral, P., Ferreira, J. L., & Pereira, T. (2015). Ingestion of microplastics by commercial fish off the Portuguese coast. Marine Pollution Bulletin, 101(1), 119 126. Available from https://doi.org/10.1016/j. marpolbul.2015.11.008. Nobre, C. R., Santana, M. F. M., Maluf, A., Cortez, F. S., Cesar, A., Pereira, C. D. S., & Turra, A. (2015). Assessment of microplastic toxicity to embryonic development of the sea urchin Lytechinus variegatus (Echinodermata: Echinoidea). Marine Pollution Bulletin, 92(1 2), 99 104. Available from https://doi.org/ 10.1016/j.marpolbul.2014.12.050. Oberdo¨rster, G. (2010). Safety assessment for nanotechnology and nanomedicine: Concepts of nanotoxicology. Journal of Internal Medicine, 267(1), 89 105. Available from https://doi.org/10.1111/j.13652796.2009.02187.x. Oberdo¨rster, G., Oberdo¨rster, E., & Oberdo¨rster, J. (2005). Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environmental Health Perspectives, 113(7), 823 839. Available from https:// doi.org/10.1289/ehp.7339.

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Yang, D., Shi, H., Li, L., Li, J., Jabeen, K., & Kolandhasamy, P. (2015). Microplastic pollution in table salts from China. Environmental Science and Technology, 49(22), 13622 13627. Available from https://doi.org/10.1021/ acs.est.5b03163. Yee, M. S. L., Hii, L. W., Looi, C. K., Lim, W. M., Wong, S. F., Kok, Y. Y., Tan, B. K., Wong, C. Y., & Leong, C. O. (2021). Impact of microplastics and nanoplastics on human health. Nanomaterials, 11(2), 1 23. Available from https://doi.org/10.3390/nano11020496. Zhang, X. Q., Xu, X., Bertrand, N., Pridgen, E., Swami, A., & Farokhzad, O. C. (2012). Interactions of nanomaterials and biological systems: Uses to personalized nanomedicine. Advanced Drug Delivery Reviews, 64(13), 1363 1384. Available from https://doi.org/10.1016/j. addr.2012.08.005. Zhang, Y., Kang, S., Allen, S., Allen, D., Gao, T., & Sillanpa¨a¨, M. (2020). Atmospheric microplastics: A review on current status and perspectives. Earth-Science Reviews, 203, 103118. Available from https://doi.org/ 10.1016/j.earscirev.2020.103118. Zhao, J., Bowman, L., Zhang, X., Shi, X., Jiang, B., Castranova, V., & Ding, M. (2009). ‘Metallic nickel nano- and fine particles induce JB6 cell apoptosis through a caspase-8/AIF mediated cytochrome cindependent pathway. Journal of Nanobiotechnology, 7. Available from https://doi.org/10.1186/1477-3155-7-2. Zhao, Y., Xu, R., Chen, X., Wang, J., Rui, Q., & Wang, D. (2021). Induction of protective response to polystyrene nanoparticles associated with dysregulation of intestinal long non-coding RNAs in Caenorhabditis elegans. Ecotoxicology and Environmental Safety, 212. Available from https://doi.org/10.1016/j.ecoenv.2021.111976.

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C H A P T E R

10 Endocrine disruptor activity of xenobiotics in carcinogenesis Introduction Several artificial chemicals such as xenobiotics have been in the environment since World War II to improve the standards of human life without any adverse effects. The hormone-like impacts of such environmental chemicals like pesticides and industrial chemicals have emerged in wildlife and humans. The growing body of evidence on the negative impacts of such chemicals had been investigated at the 1991 wingspread Conference, thereby a new term, endocrine disruption, was introduced. The main objective of this conference was to analyze the negative impacts in wildlife in the Great Lakes in North America and in other parts in the northern hemisphere, and had been coordinated by Dr. Theo Colborn, then at the World Wildlife Fund. The participants had experience in multiple fields like endocrinology, reproductive and developmental biology, toxicology, marine biology, ecology, and psychiatry. After reviewing the published data, they agreed to publish a consensus of discussions which summarized their outcomes about the public and environmental health (Soto & Sonnenschein, 2010). The conference participants designed the developmental changes appearing in wildlife and humans owing to exposure to several

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00004-2

chemicals that disrupt the endocrine system of developing organisms via several pathways. Their center of attention on changes in embryonic and fetal development due to exposure to such hormones had been triggered by the impacts of fetal exposure to the synthetic estrogen diethylstilbestrol was recommended to pregnant women to protect miscarriages over two decades (1940s to the early 1970s). Clinical implications of diethylstilbestrol had been restricted in the US if a report associated with fetal exposure to diethylstilbestrol to the increasing of a rare cancer-clear-cell carcinoma of the vagina. In addition, young women exposed to diethylstilbestrol in utero exhibited genital tract malformations resemble to those observed in wildlife exposed to pesticides (Colborn et al., 1993). The Wingspread Conference proceedings developed a hypothesis that designed the fetal exposure to hormonally active components that might describe epidemiological trends found in the last half of the 20th century in European and North American populations. Such epidemiological observations suggested the reduced sperm quality and enhanced risk of congenital malformations of the male genital tract like undescended testis and hypospadias, and an increased risk of cancer for example, uterine leiomyoma, testicular cancer and breast cancer (BC)

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(Markey et al., 2002). Since this conference, both laboratory works and epidemiological outcomes have supported the above hypothesis and exhibited that exposure to environmental endocrine disrupting chemicals (EDCs) while developing generate more other impacts like changes in male and female reproduction, and changes in neuroendocrinology, behavior, metabolism and obesity, prostate cancer, and thyroid and cardiovascular endocrinology (Vom Saal et al., 2007). Currently, environmental pollution has been the first risk factor linked with the generation of lung cancer, stroke, and heart disease. The occupational xenobiotics compounds which are introduced into the environment have increased the risk for development of different types of cancer (Table 10.1). The complex mix of pollutants within the universe which form the environment, the significance of EDCs like bisphenols, phthalates, polycyclic aromatic hydrocarbons (PAHs), and pesticides, has been emphasized in current years due to chronic and ubiquitous exposition, especially by ingestion of food and water, and their interactions in hormone and immune activities. It has been explored that the EDCs mainly cause BC and are still now well known in other malignancies like colorectal cancer (CRC) (Rodriguez-Santiago et al., 2021). Hence, environmental endocrine disrupters are sorted into four groups (1) direct-acting agonists, (2) direct-acting antagonists, (3) indirect-acting agonists, and (4) indirect-acting antagonists. Competitive binding is an essential step for direct-acting compounds, and their affinity is determined by employing ligand-binding assessment. Some chemicals act indirectly, exhibiting endocrine disrupting potential only after inducing metabolic events, viz. after transformation into an associated derivative but more native, structurally analog to hormones (Roszko et al., 2018). Endocrine disruptors (EDs) are also xenobiotic chemicals which interact with any aspect of hormone activity; so, they disturb the normal mammary and female genitalia development, function and carcinogenesis, particularly if exposure

TABLE 10.1 Instances of occupational xenobiotics exposure to endocrine disruptors. Xenobiotics as EDCs

Risk of cancer

Dioxin

NonHodgkin’s Lymphoma

Occupational exposure Combustion sources

Chemical manufacturing sources metalsHerbicides Smelting

Benzene

Leukemia

Paint Rubber

Acrylonitrile

Lung

Emission Fumigant Auto exhaust

Arsenic

Lung

Smelting product

Skin

Herbicides Fungicides Drinking water

Vinyl chloride

Liver

Plastics and vinyl products Refrigerant in furniture automobile wall Coverings

Trichloroethylene Prostrate Kidney and liver

Dry cleaning solvents Coffee decaffeination Chemical industries, dyes Polyvinyl chloride Perfumes

EDCs, Endocrine disrupting chemicals.

happens during early life (Pup et al., 2016). Growing exposure to different chemicals has led to the various abnormalities in the reproductive

Xenobiotics in Chemical Carcinogenesis

Introduction

system of human beings and several animal species. According to the World Health Organization (WHO), an EDC is defined as an exogenous substance which changes the activity of the endocrine system and subsequently develops negative impacts in an intact organism, its progeny, or their populations (Requena-Mullor et al., 2021; WHO/IPCS, 2002). The large number of such chemicals are found on the global market. EDCs are a heterogeneous group of compounds like polychlorinated biphenyls (PCBs), polybrominated diethyl ethers (PBDEs), dioxins, plasticizers (bisphenol A: BPA) and phthalates, pesticides (methoxychlor), dichlorodiphenyltrichloroethane (DDT), fungicides (vinclozolin), and herbicides (Fig. 10.1). Exposure to such EDCs is highly toxic and dangerous to the reproductive system (Piazza & Urbanetz, 2019). They interfere with the hypothalamo
hypophyseal
gonadal axis by altering hormones which lead to modulation of development and gonadal growth leading to ovarian or testicular disorders (Senthilkumaran, 2015). EDs are classified into six groups of chemicals such as pesticides (DDT and methoxychlor), fungicides (vinclozolin), herbicides (atrazine), industrial chemicals (PCBs, dioxins), plastics (phthalates, bisphenol A, alkylphenols),

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and plant hormones (phytoestrogens) (Fig. 10.2) (Karoutsou et al., 2017). The most significant impact of EDs is genomic instability, stated as an enhanced capacity of the genome to generate mutations (Kulis & Esteller, 2010). It develops if several events participate in balancing the genome are dysfunctional or if exposure to carcinogenic xenobiotics happens (Desaulniers et al., 2015). The process by which EDs modify the incidence of hormone-sensitive female malignant like breast or endometrial cancers, are diverse, interactive, and complex. They work at very low concentration, with non-linear dose response curves (Maqbool et al., 2016). They also influence on the formation of natural hormones, their secretion and/or transport. EDs could decrease or increase the impact of natural hormones on their receptors and signaling cascades in the targeted tissues. Carcinogenic xenobiotics stimulate cancer or trigger tumor growth by several processes like enhanced expression of oncogenes, reduced expression of tumor suppressors, and alterations in expression of cell cycle or apoptosis mediated genes. Except diethylstilboestrol (DES), EDs are usually not considered carcinogens per se, although they can indirectly interact with the endocrine and immune

FIGURE 10.1 EDCs have different groups of chemicals: industrial solvents, pesticides, plasticizers, and pharmaceutical compounds. EDCs, Endocrine disrupting chemicals.

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10. Endocrine disruptor activity of xenobiotics in carcinogenesis

FIGURE 10.2

Sources of exposure to xenobiotics compounds as endocrine disruptors. Several natural or synthetic compounds which enter in contact with humans via different activities can alter hormonal signaling pathways.

systems supporting true carcinogenic impacts (Soto & Sonnenschein, 2010). Xenoestrogens are a kind of EDC that imitate the activity of estradiol and influence estrogen signaling by binding to its receptors, altering its biosynthesis or degradation, or stimulating its transcriptional activity (Eve et al., 2020). Xenoestrogens are either synthetic or natural, such as phytoestrogens found particularly in soybeans (Ziaei & Halaby, 2017). The effect of xenoestrogens on the incidence of BC has been explored due to the carcinogenic impacts of estrogens on breast epithelial cells. The certain modes of EDCs activities get them problem to study in vitro and in vivo, however, impacts have been determined for some. Moreover, epidemiological approaches are tedious to carry out due to EDCs and are present everywhere in the environment at low doses, forming the constitution of a control cohort apparently impossible. For some EDCs, although, specific pathways have explored a population to EDCs, forming it possible to

have a high exposure cohort in comparison to a low exposure cohort (Rodgers et al., 2018). In the present scenario, the environment has been a dumping place of natural and synthetic chemicals and this occurs because of inadequate wastewater treatment and poor solid waste management (Kasonga et al., 2021; Vieira et al., 2020). Due to this, wastewater treatment plants have been known as the hot-spots of chemicals like EDCs, pharmaceuticals and personal care products, and active pharmaceutical ingredients or pharmaceutically active chemicals into aquatic systems (Kibambe et al., 2020). The failing of the typical wastewater treatment approaches to eliminate such chemicals at broad spectrum pose as human, animal and environmental health matters as their quantities are capable to enhance from a few nanograms per liter (ng L21) to 15 μg L21, levels that are high enough to develop acute and chronic toxicity (Verlicchi et al., 2015). Due to their prevalence as trace elements, synthetic compounds of which contaminants of emerging concern (CECs) are more bioactive

Xenobiotics in Chemical Carcinogenesis

Introduction

with the efficacy to influence the endocrine system and interact with the balanced hormonal systems. Of the several CECs, EDCs are comprised as chemicals that develop negative impacts on animal and human health, influencing directly their endocrine system, and are capable to stop or mimic the natural hormones causing for the activities in certain organs of their body (Vieira et al., 2020), hence, all compounds revealing estrogenic activity could be known as EDC. The circadian clock is a type of transcriptional oscillator causing for entering 24-hour rhythms of physiology, behavior and metabolism. The highly bidirectional cross talk develops between circadian and endocrine systems and circadian rhythmicity is found at all stages of endocrine control, from synthesis and secrete of hormones, to sensitivity of target tissues to hormone function. In mammals, areas of hormones directly change clock gene expression and circadian physiology through nuclear receptor (NR) binding along with genomic function, regulating physiological mechanism like nutrient and energy metabolism, stress response, reproductive physiology and circadian behavioral rhythms. The efficiency for EDCs to disturb circadian clocks or circadian-driven physiology has not been explored widely yet. Circadian consequences happened in parallel to endocrine and metabolic changes like depraved fertility and dysregulated metabolic and energetic homeostasis (Bottalico & Weljie, 2021). Globally, chemical substances are presently screened for endocrine activity in modulatory risk analysis such as in the European Union’s Biocides regulation, using standard test protocols which introduce to chemical substances as endocrine active if interacting with sex hormone receptors, steroidogenesis, or thyroid hormone signaling. It has been identified that the endocrine system is a very complex and intricated mechanism, however, often evolutionary highly conserved. It has all hormone signaling mechanisms, interlinking and regulating a vast set of

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functions like development, growth, reproduction and metabolism, and this is being highly investigated at inter-governmental stages. The endocrine system is very sensitive and circulating hormone levels are in the pM
μM range, forming it highly susceptible to interacting chemicals (Kubickova et al., 2021). Based on the above explanation, the different aspects of the endocrine-disruptive chemicals that is, xenobiotics will be discussed in regarding of cancer developments.

Endocrine disruption of xenobiotic exposure Xenobiotics as an EDC are capable of perturbing hormonal and homeostatic systems. It acts through NRs, nonnuclear steroid hormone receptors (membrane ERs), nonsteroid receptors (neurotransmitter receptors like serotonin receptor, dopamine receptor, norepinephrine receptor), orphan receptors (aryl hydrocarbon receptor AhR), enzymatic mechanism participated in steroid biosynthesis and/or metabolism, and several other pathways that concentrate upon endocrine and reproductive systems. The endocrine disruption is mainly associated with xenoestrogens, antiestrogens, antiandrogens, disruption of thyroid activity, and perturbation of corticoid activity, and other metabolic impacts. The several xenobiotics characterized as EDs is highly heterogeneous and includes synthetic compounds employed as industrial solvents/ lubricants and their by-products, plastic chemicals, plasticizers, pesticides, pharmaceutical chemicals, and heavy metals for example, cadmium and lead (De Coster & Van Larebeke, 2012). Xenoestrogens, xenoandrogens, antiestrogens, and antiandrogens Several chemicals have estrogenic, androgenic, antiestrogenic, or antiandrogenic properties and also same compounds containing more than one of such properties.

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Xenoestrogens Several chemicals have estrogenic properties which comprise phytoestrogen isoflavonoids, flavonoids and terpenoids and the mycotoxin zearalenone and its metabolites, and also various industrial substances (Cohn et al., 2007). The man-made xenoestrogens have PCBs, PBDEs, some endocrine disrupting derivatives of which present naturally; phthalates; alkylphenols; bisphenol A, employed in the formation of polycarbonate plastic and epoxy resins; UV filters; the fragrance galaxolide; preservatives and pesticides. Among 200 pesticides screened for two human estrogen receptor (ER) (hER) subtypes, hER-α and hER-ß by highly sensitive transactivation assessment employing Chinese hamster ovary cells, 47 and 33 exhibited hER-α and hERß-mediated estrogenic functions, respectively. Various PAHs, mainly pollutants generated by incomplete combustion, have also been exhibited as estrogenic activity (Santodonato, 1997), for example, 3-methylcholanthrene had been explored to be estrogenic in MCF-7 human BC cells. Also, number of metals had been explored to have estrogenic effects (Fechner et al., 2011; Maqbool et al., 2016), and specific cadmiumcontaining nanocrystals may even be potential estrogens (Jain et al., 2012).

Xenoandrogens Xenoandrogenic activity is not frequently reported in comparison to xenoestrogenic activity. Although, many authors have described about xenoandrogenic activity of xenobiotics for example, Delor 103, a commercial mixture of PCB congeners in a bioluminescent yeast strain. Employing a yeast androgen assessment expressing the human androgen receptor (AR), Kunz and Fent screened 18 UV filters for androgenic activity and observed that benzophenone-2 and homosalate generated complete dose-response curves, whereas octyl methoxycinnamate,

octyl salicylate, octocrylene, and isopentyl-4methoxycinnamate exhibited a partially agonistic behavior suggested by submaximal dose-response curves (Maqbool et al., 2016).

Antiestrogens Several compounds attaching on ERs produce antiestrogenic impact rather than estrogenic effects. Antiestrogenic impact had been detected for methoxylated brominated diphenyl ethers (mainly of natural emerging in the marine environment) (in reporter gene assessment); 20S protopanaxadiol, a main gastrointestinal metabolic product of ginsenosides (on MCF7 human BC cells); genistein, a phytoestrogen, mainly huge in soybeans which could attach ERs and sex hormone binding proteins, developing both estrogenic and antiestrogenic activity; the polybrominated diphenyl ethers heptaBDE and 6-OH-BDE-47; the UV-absorber benzophenone-4 (in the liver of zebra fish); of 18 UV filters, 13 (4Methylbenzylidene camphor, 3-Benzylidene camphor, Benzophenone-3, Benzophenone-4, Isopentyl-4-methoxycinnamate, Octyl methoxycinnamate, Homosalate, Octocrylene, Benzyl salicylate, Phenyl salicylate, Octyl salicylate, Para amino-benzoic acid and Octyl dimethyl para amino benzoate) totally suppressed the function of estradiol at the highest concentrations tested and developed complete dose response curves (in yeast having a activity); polycyclic musks (on human U2OS cells with an ER associated with reporter gene); the di-ortho PCB congeners 38, 153, and 180 and the monoortho PCB 118 (on MCF-7-BUS cells in vitro); PCB 126 and phenanthrene (in the liver of fish); the pyrethroid insecticide metabolite 3-(2,2dichlorovinyl)-2,2-dimethylcyclopropne carboxylic acid (DCCA), the pyrethroid insecticides cycloprothrin, etofenprox, the pyrethroid insecticide metabolite 3 phenoxybenzoic acid, the pyrethroid insecticides cyuflthrin and permethrin; the pyrethroid insecticide tetramethrin (on

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Endocrine regulators in the food chain

female rats in vivo); some nonylphenol isomers (on MVLN cells, MCF -7 human breast carcinoma cells with an ER regulated luciferase reporter gene); dichlorostyrene (in the E screen assay on MCF-7 cells); benzotriazole, an anticorrosive agent well characterized for its implication in aircraft de-icing and antifreeze fluids and also employed in dishwasher detergents (Maqbool et al., 2016).

Endocrine regulators in the food chain Presently, the main attention has been emphasized on specific environmental contaminantsEDs- of industrial sources which might imitate the activity of sex hormones. Natural substances and their impacts on other kind of hormonal action such as on adrenal or thyroid activity have for some cause not triggered similar attention. For instances, the availability of tributyltin and particular bioaccumulating chlorinated substances suggests that “endocrine disruption” produced by xenobiotics is major ecotoxicological issues. Some phenylmethyl-substituted siloxanes have been identified in mammals as a potential endocrine disrupter among several synthetic xenobiotics. In other case, it has not been easy to prove scientifically either particular alarming reports of potential synergistic impacts between chlorinated pesticides or the supposed adverse impacts on the male reproductive tract in rodents. While there is engrossing evidence that estrogens in some foods and herbal medicines could stimulate hormonal alterations in women and toxicity in men, available data are not sufficient to assist a causal relationship between exposure of the common human population to nonpharmaceutical industrial substances and negative impact generating through the endocrine system. In addition, in terms of magnitude and level, all these exposures to EDs are underestimated by the highly implication of oral contraceptives and estrogens for medication of menopausal and postmenopausal problems.

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Additionally, the exposure to hormonally active xenobiotics is not significantly effective in comparison to the intake of the phytoestrogens which are found in food and beverages, and comparatively it is also highly insignificant to specific herbal mixture employed in “alternative medicine.” Further, it has been highly focused on negligible exposure to xenobiotics with weak hormone-like action, the potential ED licorice is freely given to children. Long-term exposure to such chemical stimulates serious toxic problems of mineral corticoid hormone imbalance. However, exposure to xenobiotics and several natural substances brings about by similar paths of administration and might generate the same toxicological end point, they are, deliberately, judged by totally different standards. In case of other chemicals, rational risk analysis and risk management of man-made and natural endocrine regulators is relied on the way of action and dose-response relationships. Such end points as the stimulation of reproductive developmental impacts, cancer, etc., associated with real exposure must also be considered (Nilsson, 2000). Despite pharmaceuticals specifically designed to imitate or antagonize the function of hormones, a plethora of synthetic and natural substances have been identified to stimulate such impacts at certain extent of exposure in mammals, birds, and/or aquatic organisms. Of the xenobiotics, 2 phenyl-substituted cyclic tetrasiloxanes are highly potential endocrine disrupters in mammals. According to ecotoxicological view, the potential of tributyltin (TBT) seems to be quite excellent, while among the natural endocrine regulators, the isoflavone coumestrol and the mycotoxin zearalenone as well as some Chinese herbal components have higher efficiency in comparison to most xenobiotics. Xenobiotic endocrine regulators have very less structural similarity with the natural hormones, several phytoestrogens and, to a lower level, the potential synthetic estrogen diethylhexylstilbes-trol and the mycotoxin zearalenone have molecular structure which are similar to mammalian sex hormones.

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Endocrine disruptors action on mechanism of estrogen and androgen Rising pollution of the environment by toxic substances including EDCs is one of the main reasons of reproductive problems in both sexes. Estrogen/androgen mechanisms are very important in gonadal development, analyzing of secondary sex properties and gametogenesis (Amir et al., 2021). Almost all groups of EDCs are capable of binding with either ARs and/or ERs. Estrogens are a steroid hormone synthesized by distinct parts of the body like gonads, placenta, breasts, bones, adipose, vascular tissues and some parts of the brain. Though estrogens are found in both males and females, their mode of expression is different. Their major functions are to develop the secondary sex characteristics in females like breast development. These also play a vital role in the thickening of the endometrium and the controlling of menstrual cycle. In men, these hormones are found in lower extent and regulate the spermatogenesis mechanisms. Estradiol is main estrogen hormone whereas others have estriol and estrone. Estradiol plays a significant role in the male reproductive system by inducing spermatogenesis (Amir et al., 2021; Kula et al., 2001). There is available in the brain and male sex organs and its formation is enhanced at the time of sexual provocation; however, overproduction of the hormone could cause erectile problems (Amir et al., 2021; Schulster et al., 2016). In females, estradiol has a major function in the development of the reproductive organs, mainly secondary sex characteristics (Bakker & Baum, 2008). The steroidal activity of estrogens on target tissues is mainly regulated by two cellular mechanisms (1) via the nucleus and (2) via the plasma membrane. In first mechanism the estrogen hormone, especially estradiol, attaches to both the ER-alpha (ERα) and ERbeta (ERβ). Both ERα and ERβ contain an

amino-terminal group causing for ligand independent activation of transcription, a DNA binding domain (DBD) in the center and a ligand binding domain (LBD) at the carboxyl end (Marino et al., 2006). After attaching to the ligand, the receptors transfer into the nucleus and integrated to certain transcription components referred as estrogen response elements (ERE), eventually beginning the transcription of target genes (Revankar et al., 2005). The second mechanism is not direct and is known as the membrane-mediated mechanism, in which the ligand works via membrane-bound ER or G-Protein-coupled E2 receptors. Such interaction stimulates downstream signaling through second messengers induced via the epidermal growth factor receptor (EGFR), insulin-like growth factor receptor (IGFR) and G proteincoupled receptors (GPCRs) (Likhite et al., 2006). In this condition, the dependent proteins like nuclear factor-kB (NF-kB) or Activator Protein 1 (AP-1) produce their activity either by selecting coactivators or by manifesting protein-DNA complexes. In a ligandindependent mechanism, the second messengers phosphorylate ER, which induces the transcription of target genes. These kinases in estrogen mechanisms are MAPK, PKA, Akt, Erk, and PAK. Androgens are also group of the steroid superfamily and are usually participated in gonadal development. Testosterone is main hormone, known as the male sex hormone, whereas others have dihydrotestosterone (DHT) and androstenedione. Androgens are found in both males and females, but they vary in levels. Like ER, AR contain an N terminal domain with phosphorylation sites for the stimulation of receptors, a C terminal having a ligand binding domain and a major DNA binding domain. At resting condition, the receptors are attached to heat shock proteins (HSP) to prevent degradation. The binding of the ligand phosphorylates the receptor leading a conformational alteration and thus the release of HSP. The receptor ligand

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Endocrine disruptors action on mechanism of estrogen and androgen

complex is transferred to the nucleus where it attaches to androgen response components to induce transcription of target genes (Roy et al., 2001).

Impacts of EDCs on AR and/or ER Chromosomal abnormalities Chromosomal aneuploidy that is, alteration in structure or number of chromosomes, in gamete cells is a major reason for developing sterility and abnormality in the progeny. The syndromes contain sex chromosomes such as Klinefelter’s syndrome (47, XXY or in some cases 48, XXXY; 49, XXXXY) and Turner Syndrome (a defected or lacking X chromosome in women). Estrogen mechanism regulate mainly chromosomal separation and integration of microtubule at the time of meiosis targeting to EDCs (Metzler et al., 1996). Exposure to EDCs causing to aneuploidy in germ cells also develops defects and infertility in progeny and also leads to miscarriages and infertility of sperm cells (Amir et al., 2021; Hodes-Wertz et al., 2012). BPA has been revealed to produce defects in the meiosis occurring in mice and Caenorhabditis elegans. The treated rat seminiferous tubule culture with BPA and various genes participated in meiosis had revealed the defects in chromosome synapsis, that is a main reason of chromosomal aneuploidy (Ali et al., 2014). Another study on C. elegans exhibited that BPA could enhance sterility by leading defects in chromosome synapsis while meiosis and it also perturb the normal pathways of double-stranded break repair while the process of cell division, that finally produced impaired gametes with chromosomal aneuploidy. MCF7 cell lines showed the cytogenetic impacts of BPA in both ER-dependent and independent pathways at very low level (0.4 μg mL21) (Aghajanpour-Mir et al., 2016). Several studies have explained that BPA is a highly clastogenic agent, in many cases via disruption of the

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estrogen mechanism. Exposure to PCBs and DDTs also lead to chromosomal defects as explained by a study in which serum level of PCBs and DDTs in infertile men exhibited a positive relation with chromosomal disomy (McAuliffe et al., 2012). The perfluorinated compounds (PFCs) in blood and seminal plasma in infertile men had been identified as directly associated with chromosomal disomy and DNA dimer segmentation (Governini et al., 2015). DNA damage Besides potential DNA repair mechanisms, several cells are susceptible to DNA damage such as nicks or DNA strand breaks, mainly sperm cells. In spermatozoids, DNA damage caused in deformity of the normal activity and it is predominantly produced by mainly oxidative stress (Aitken & D Iuliis, 2007) and by also influencing DNA methylation (Tunc & Tremellen, 2009). Reactive oxygen species (ROS) not only produce defects in the fertilizing capability of sperm and also stimulate developmental deformity in children conceived by defective sperms. Egg cells have potential to repair DNA damage in the sperm DNA after fertilization on limited parameter. Estrogenic and androgenic disruptors like DDTs, PCBs and BPA also produce DNA damage due to ROS leading developmental deformity in the male reproductive axis, resulting to infertility (Sikka & Wang, 2008). BPA produces DNA damage by enhancing the intracellular ROS contents and thus forming DNA breaks and inducing DNA migration from the nucleus to tails (Xin et al., 2014). BPA has the ability to enhance DNA damage in sperm cells and deformity in spermiogenesis, although it is not well studied in human. Epidemiological studies explain a relationship between DNA damage and BPA level in urine samples of human (Xin et al., 2014). Similarly, several studied have shown that DDTs also causes DNA damage (Xin et al., 2014). Estrogens are participated

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in the prevention of cells against DNA damage by suppressing the generation of ROS (Ayres et al., 1998). Estrogen’s major role for protecting DNA can be suppressed by estrogenic chemicals, thus making cells high susceptible to DNA damage. Micro RNAs Micro RNAs (miRNAs) mainly belong to the non-coding RNAs family consisting of 18
25 nucleotides that have regulatory function on gene transcription (Gottardo et al., 2007). Recently, several studies have elucidated that miRNAs play significant roles throughout the developmental process, as modified miRNA profile may cause developmental deformities in both the male and female reproductive system (Amir et al., 2021; Nothnick, 2012). EDCs have also been revealed to influence the expression of miRNAs. Chronic exposure to EDCs mixture in human males might highly cause to spermatogenic failure by changing in miRNA expression that can post transcriptionally dysregulate mRNA targets encoding proteins involving in cell death in testicular cells (Bun˜ay et al., 2019). Different miRNA expression modes during oocyte/embryo development elucidates the significant regulatory functions of miRNAs, whereas EDCs like BPA are capable of disrupting their expression/ activity modifying gene expression (Amir et al., 2021; Sabry et al., 2019). Estrogen signaling regulates the biogenesis of miRNAs like miR-21, -155 and -124 (Klinge, 2009). If BPA has similar functionality to estrogen, it can interfere with the expression of several miRNAs (Klinge, 2009). An in vivo study explored that BPA, functioning at the transcriptional level before to processing, caused in decreasing the expression of 45 distinct miRNAs in the fetal ovary and the changed expression related with target genes (VeigaLopez et al., 2013). Another in vivo study suggested that BPA dysregulates miR-224 in rat granulosa cells that is essential for cumulus

cell expansion/oocyte maturation through regulation of aromatase (Lite et al., 2019). In human BC cells, BPA induces ERα signaling causing decreased miR-21, Let-7, and miR-15b expression while increasing miR-638, miR-663, and miR-1915 expression. The treated human placental cells with BPA enhance miR-146a with slow proliferation and more prone to toxic impacts of hazardous substances. BPA employing human endometrial cells significantly inhibited miR-149 and enhanced miR107 (Chou et al., 2017). The events by which EDCs influence gene expression in oocytes and embryos are possibly not restricted to microRNAs that directly target crucial genes although might also participate in microRNAs playing a role in epigenetic regulation (Jacobs et al., 2017). Similar to all estrogen-dependent mechanism, BPA treatment might disrupt this axis perturbing downstream gene alterations which regulate oocyte competence (Sabry et al., 2019).

Data associated with exposure to endocrine disruptors in carcinogenesis The World Health Organization predicts that about 20% of all cancers will be due to environmental components. However, until now, various components are well identified carcinogens, whereas others are still unexplored (Hardonnie`re et al., 2017). Exposure to EDs while main stages of development hinder normal hormonal signaling and causes in modified gene expression. Iatrogenic gestational exposure to DES stimulated changes in the genital tract and sensitive individuals to form clear cell carcinoma of the vagina (Verloop et al., 2017). Gestational exposure of rodents to a similar chemical, the xenoestrogen bisphenol A (BPA) enhances the possibility to form mammary carcinoma during adulthood, long after cessation of exposure, increasing the assumption of

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Data associated with exposure to endocrine disruptors in carcinogenesis

estrogens being in the wrong place at the wrong time (Paulose et al., 2015). Low-dose exposure to BPA influences mammary gland development in male and female rats; however, higher concentrations reveal a multiple mode of effects. The resultant intraductal hyperplasia in female rats can be related with an induced risk for forming hyperplastic lesions that are similar to initial signs of BC in women (Mandrup et al., 2016). Long-term exposure to BPA or benzo[a] pyrene changes the consequences of human mammary epithelial stem cells by prestimulating bone morphogenetics proteins signaling. Treatment with BPA and methoxychlor causes in the formation of human BC cells and changes in of cell cycle-linked genes, cyclin D1 and p21, through an ER underlying signaling pathway (Lee et al., 2012). Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase which has been associated with BC incidence and epigenetic regulation of carcinogenesis. Mice exposed in utero to DES or BPA exhibited the enhanced EZH2 expression in the mammary gland (Doherty et al., 2010). Of different EDs, mainly xenoestrogens like BPA, dioxins, and di (2-ethylhexyl) phthalate induce ERs and regulate cellular activity stimulated by ERs. Further, they seem to be highly linked with carcinogenicity in estrogen-dependent cancers such as breast, ovary, and prostate cancers (Johnson, 2011). Several scientists focused to analyze the relationship of dietary PCB exposure with breast, endometrial, and ovarian cancer incidences in middle-aged and elderly women, understanding that dietary exposure to PCBs has no major role in forming of such cancer units (Ruder et al., 2017). Moreover, over 4.5 years of follow-up, it has been identified in 67 cases of carcinoma in skin. After multivariable reconciliation, exposure to dietary PCBs had been related to fourfold enhancement in incidence of malignant melanoma (Donat-Vargas et al., 2017). The impact of PBDE-209 in controlling growth and apoptosis of breast,

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ovarian, and cervical cancer cells has been revealed to modify cell cycle by stimulating the S phase or G2/M phase. Further, PBDE-209 partly inhibited tamoxifen-stimulated cell apoptosis in BC (Li et al., 2012). Organotin molecules like tributylin stimulate the G2/M cell cycle in human embryonic cancer cells, whereas proliferation of BG-1 ovarian cancer cells had been induced by 4-tert-octylphenol and 4-nonylphenol through downregulation of TGF-β receptor 2 and upregulation of cmyc (Park et al., 2011). A dose-response relationship between lung cancer and rising arsenic level in drinking water and cumulative arsenic exposure amidst the residents with less methylation ability has been analyzed. The association of arsenic exposure and lung cancer among high methylaters was not showing relevant outcomes (Hsu et al., 2017). In another study, 205 patients with urothelial cancer and 406 control subjects for a 2 year-case control study were selected; patients with urothelial cancer exhibited increasing urinary levels of arsenic, cadmium, chromium, nickel, and lead in comparison to the controls (Chang et al., 2016). Data for genotoxicity in humans has revealed chromosomal abnormalities, sister chromatids exchanges in lymphocytes and micronucleus development in lymphocytes, buccal mucosal cells, and exfoliated urothelial cells in the urine. Cohen faced critical problems in the interpretation of results like inadequate analysis of exposure to arsenic, estimation of micronuclei, and potential confounding components for instances like tobacco exposure, folate deficiency, and inorganic arsenic is a nongenotoxic carcinogen (Cohen et al., 2016). Exposure to benzene, used as a solvent, is associated with acute myelogenous leukemia. It is questionable that if children present a subpopulation in which a more incidence of leukemia is related with much lower levels exposure to environmental benzene (Infante, 2017; Karoutsou et al., 2017).

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Incidence of breast cancer due to endocrine disrupting chemicals BC is ranked second among common cancers and the fifth deadliest in the worldwide. Several researchers have examined the impacts of highly employed environmental agents with endocrine disrupting qualities on BC formation in in vitro and in vivo and epidemiological studies. The complicated impacts of EDCs on hormonal mechanism participate in oncogenic impacts and enhanced mammary gland sensitivity to carcinogenesis-along with certain properties of the mammary gland emerging over the periods of life and the multifactorial etiology of BC-make the assessment of such chemicals a complicated problem. Several suspicious EDCs inducing the risk of BC development, where major evidence has only been suggested for some EDCs such as diethylstilbestrol, dichlorodiphenyltrichloroethane, dioxins and bisphenol A. However, provided the ubiquitous nature and high use of EDCs, it must be continued to analyze their long-term health impacts, especially on carcinogenesis, to eliminate the worst of them and sensitize the population to reduce their implication (Eve et al., 2020).

Multiple combinations of risk components BC is a multiple of diseases, hence its main reason has not been known yet. Several risk components are suspected to enhance its prevalence, though the short-term effect of each of them is not identified. BC risk factors are sorted into several groups such as reproductive factors, exogenous hormones, anthropometric factors, sex and age, breast density and personal history of BC, familial history of BC, lifestyle, occupation, and exposure to radiation. Besides the significance of the above established risk components, they are associated with only about 36.8% of BCs, indicating the

support of more studies on the crucial role of environmental pollutants in BC incidence (Rogel, 2018). Moreover, some risk components are related with certain histological and molecular subtypes. Indeed, a meta-analysis of 38 studies disclosed that the maximum established risk components were particular for the luminal A subtype (Barnard et al., 2015).

Identification of problems associated with the mode of action of EDCs Presently, there is no agreement on the correct description of EDCs between the several health institutions. Both the Food and Drug Administration (FDA) and WHO have defined EDCs on the basis of their mode of action instead of their origin or structure. However, these two agencies vary on their explanation of the impacts of EDCs. The WHO explains the intrinsic harmful impact of EDCs (WHO/IPCS, 2002) while the FDA describes the endocrine system without harmful impacts (Zoeller et al., 2019). Such variations in explanation are critical because if EDCs stimulate intrinsic harmful impacts, hence the ordinance related to their implications must be stricter. In 1991, the biologist Ana Soto provided evidence for the first time that EDCs, like nonylphenols, could have harmful impacts if available in materials employed daily by the population (Soto et al., 1991). Such compound is known toxic to aquatic life by the USA Environmental Protection Agency (EPA). However, nonylphenols are still employed in various products such as industrial and domestic cleaning products, cosmetics and personal hygiene products (United States Environmental Protection Agency, 2017). The nonylphenol has been identified as an EDC by other countries like France and is no longer implication in the composition of such products (Vincent, 2014). The IARC (a WHO agency) studies agents and sorts them on the basis their carcinogenicity

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Incidence of breast cancer due to endocrine disrupting chemicals

impacts: carcinogenic, probably carcinogenic, possibly carcinogenic, and not classifiable as to its carcinogenicity on humans. For this, the IARC analyzes the epidemiological, in vitro and in vivo studies published on such components. The assessment of such studies as to the plausibility of a causal relation underlies on Bradford Hill’s principle since their publication in 1965 (Fedak et al., 2015). Hill’s criteria such as: potential of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy, lead to developing an impact to a component. The potential insights into carcinogenesis, important for characterization of carcinogen agents, have explored the IARC monographs to combine a novel method for a comprehensive application of the mechanistic evidence of carcinogenic agents (Guyton et al., 2018). Many challenges are shown in applying the Hill criteria for the analysis of EDCs, especially with respect to their multiple modes of action, the presence of non-monotonic dose-response relationships, constant exposures to EDC mixtures, impact of exposure while crucial time critical, and differing impacts underlying the hormonal condition of the targeted organ. Currently, a consensus explanation on the major properties of EDCs had been published (La Merrill et al., 2020). This gives a basis for the search, organization, and assessment of mechanistic information for the exploration of carcinogenic components.

Case studies of endocrine Disrupting chemicals associated with breast cancer More than 1000 chemical components have been assessed by the IARC, and out of them, 121 have been identified as Group 1 “carcinogenic to humans” (WHO, 2020). In vitro, in vivo, clinical and epidemiological studies required to link an impact with a component are either difficult to work or to illustrate for EDCs. For epidemiological studies, it is generally case-control studies

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determining the serum level of an EDC during diagnosis of a disease. Though, such studies are not perfect due to addition to synergistic and cocktail impacts, EDCs and their metabolites usually have several ways of mechanisms. Owing to probable long latency between exposure to EDCs and diagnosis, such case-control studies are usually not reproducible. Some proposed studies which determined exposure to EDCs have achieved more consistent outcome. As explained above, exposure to radiation during childhood or adolescence enhances the incidence of generating BC (Kawaguchi et al., 2009). The IARC has kept ionizing radiation as Group 1 “carcinogenic to humans” for certain cancer like BC in women. In utero exposure to DES also enhances the incidence of producing BC (Troisi et al., 2007), and the IARC classified it as Group 1 “carcinogenic to humans” (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2012).

Endocrine disrupting chemicals: Diethylstilbesterol in pregnant women In 1938, a group of Oxford researchers published an article explaining various stilbene derivatives with estrogenic potential, as part of a project to make possible synthesizable estradiol-like chemicals. Of several derivatives explained, DES had highly estrogenic activity (Chatten & Huston, 1950). In fact, DES is 5 times more efficient than estradiol (the high potential natural estrogen in mammals) (Korach et al., 1978). Several clinical trials performed to analysis the effect of DES in pregnant women revealed a reduce in abortion, untimely births and cases of pre-eclampsia (Watkins Smith & Smith, 1949). As a final conclusion of such studies, DES had been marketed in the USA and other countries to prevent the abortion, and also for the decreasing the prematurity and pregnancy-associated hemorrhages. The galenic form is the most

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familiar tablet, although it is marketed as an injectable solution, suppository, and cream (Mullard, 2021). In the 1960s, seven subjects of vaginal cancer had been prognosed in female (age 15
22 years) at the Vincent Memorial Hospital in Boston. After all, no diagnosis had ever been done in this age group and the seven subjects had been diagnosed within 3 years, a reflective study of the patients and their relatives was performed. This study emphasized the implication of DES in the mothers of such women while pregnancy. However, DES had been recommended to 675 other patients in the hospital for same time and only seven subjects of vaginal cancer had been diagnosed (Herbst et al., 1971). After some years, a larger study revealed an enhanced incidence of vaginal cancer with in utero hazard to DES (Herbst et al., 1977). The prognosis of vaginal cancer in various women showed in utero the follow-up of all subjects exposed to DES in several countries. Five main

cohorts such as the National Cooperative Diethylstilbesterol Adenosis Project (DESAD) cohort, the Women’s Health Study cohort, the Mayo Clinic cohort, Deckman’s clinical study performed at the University of Chicago (1951
1952), and Horne’s study done in a private clinic in Massachusetts had been assessed.

Impact of endocrine disruptors on the development of cancer in women The proposed oncogenic pathways of identified EDs: pesticides, DDT, dioxins, phthalates, bisphenol A, diethylstilbesterol, heavy metals, has been explained in Fig. 10.3.

Dioxins Until now, dioxins are the most highly related with BC in exposed humans. Dioxins

FIGURE 10.3 Flow chart of the action of some EDCs: dioxins, plastics, DDT, and DES on the stimulation of breast and endometrial cell proliferation. DDT, Dichlorodiphenyltrichloroethane; DES, diethylstilbestrol; EDCs, endocrine disrupting chemicals.

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Impact of endocrine disruptors on the development of cancer in women

are a group of environmental compounds identified by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). Dioxins and dioxin-related chemicals interplay with certain polymorphisms to increase the incidence of BC (Pup et al., 2016). Dioxins function via the AhR, a ligandstimulated nuclear transcription factor, intracellular moderator of xenobiotic signaling mechanisms. Such ligand dependent transcription factor regulates a certain area of biological and toxicological impacts, all pivoting around the cell responses to endogenous: hormone and exogenous: xenobiotic challenges. Owing to the general pathways and prevalence in the same matrices, the intake and body concern of dioxins have been assessed in a cumulative way, all chemicals causing to the toxic equivalent (TEQ) of a provided mixture in biological samples, its content and potential (expressed as AhR induction); the dioxin TEQ is an unlikely instance of a straightforward implication of in vitro cell biology data viz AhR stimulation potential into risk analysis. Dioxins in women perform as antiestrogenic EDs as AhR stimulation results to a decrease in ER transcriptional activity, that is highly identified on ERβ than on ERα. In fact, a number of studies have disclosed an enhanced incidence of BC related with more body concern of dioxin-like PCB in interaction with specific genetic polymorphisms participated in carcinogen stimulation and steroid hormone metabolism (Pup et al., 2016).

Dichlorodiphenyltrichloroethane DDT is a main agent of persistent, bioaccumulating pollutant of the food chain. In spite of the various implication rule since the 1970 and the banning in Europe as a pesticide in 1986, residues are still detected in feeds, foods and in the fat of several organisms, including humans. In fact, DDT is made up from mixture of DDT and DDE isomers, all capable to bioaccumulate and enhance the body concern of

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DDT and associated compounds. The isomers p,p0 -DDT and o,p0 -DDE exhibit estrogenic potential both in vitro and in vivo, while other isomers, like highly persistent p,p0 -DDE are only antiandrogenic. Long-term exposure to DDT via food can be imagined to enhance the incidence of generating estrogen underlying carcinoma like BC. It has determined that a higher incidence of BC was found among women with increasing serum levels of DDE, the main metabolite of DDT, in comparison to women with low contents (Wolff et al., 1993). Since then, several epidemiologic studies have examined such hypothesis. In humans, DDT/DD has been related with BC and endometrial cancer (Hardell et al., 2004). The antiandrogenic p,p0 DDE might increase the onset of cancer in mice and there is positive relationship of BC with DDE, though irrelevant because of low statistical power (Pavuk et al., 2003).

Methoxychlor Methoxychlor (MXC) had been subjected as a less persistent alternative to DDT although, sadly, several studies have explained that MXC is also an estrogenic ED (Tiemann, 2008). Gestational exposure to MXC perturbs the female reproductive system for long-term impacts on neuroendocrine gene expression and DNA methylation, as well as rapid reproductive senescence. Animal and present epidemiological studies exhibited that reproductive aging had been increased by ED developmental exposures: instead of MXC, also bisphenol A, dioxins and perfluorocarbons were explored highlighted. By rapid senescence and/or enhancing cancer incidence, EDs might remove the chances of biological children for women who might extend childbirth for personal or professional causes. Considering the significant functions of estrogens on targets in the body and brain, early reproductive senescence might also enhance

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several disease-associated conditions with menopause and influence the nature of life in the aging population of women (Gore et al., 2011).

Atrazine and triazine herbicides Atrazine is the main herbicide of this group and works as EDs in female rats by changing the release of luteinizing hormone (LH) and prolactin at the hypothalmic-pituitary level. Triazine herbicides do not have a significant bioaccumulation potential, however they could be major pollutants of water bodies. Atrazine is an instance of species and strain-specific promotion of mammary cancer. Adult female Sprague-Dawley rats had been administered with diet-supplemented atrazine generated BC earlier and with high risk in comparison to controls, whereas such outcomes was not determined in other rats (Wetzel et al., 1994). In Sprague-Dawley rats, atrazine led a persistent estruses with a longer and sustained estrogen secretion from ovarian follicles, that was unsuccess to ovulate because of the herbicidal activities on gonadotropin balance. This process of ovulation failure is usually different from menopause in women. Several studies have explained an enhanced incidence of ovarian carcinoma among women exposed to triazine herbicides. Importantly, triazine herbicides are among the very few EDs for which an epidemiological relation with epithelial ovarian carcinoma may be hypothesized (Young et al., 2005).

Chlorpyrifos and other pesticides 2,4,5-Trichlorophenoxypropionic acid and the fungicide captan has been observed to significantly enhance the incidence of postmenopausal BC of women whose husbands had ingested these pesticides. The incidence was quite higher if the residence was closer to the pesticide-applied region. Some indications,

not statistically relevant, of an enhanced incidence for breast carcinoma had been observed in premenopausal women taking certain organophosphorus insecticides, mainly chlorpyrifos, dichlorvos, and terbufos (Ventura et al., 2016). A significantly enhanced incidence of BC was also related with self-reported residential pesticide implication; although, owing to the proposed study, no dose response pattern was determined and in fact it was not easy to detect (Teitelbaum, 2000). The above explanation of all studies has no rigorous evidence on non-occupational insecticide exposure and breast carcinoma. Such chemicals might regulate various pathways for cancer development, especially in the breast, although the cell type-specific reflections are at nanomolar range concentrations. Whereas some cancer cell lines, like MCF-7, reveal a relevant enhancement in all the cancer events, other cell lines, like MDA-MB-231, show a relevantly declined invasion impact following exposure to pesticides (Pestana et al., 2015). Hence it is quite difficult to detect the allcarcinogenic impacts, without targeting the ED, dose, exposure period, and certain kinds of cancer cells.

Health issues The available research articles are insufficient in clearly investigating the health impacts of chronic exposure to the compound isolated and detected in the study. Scientific communities have not achieved unanimity on the major health impact of low-dose exposure to weak EDCs (European Food Safety Authority, 2013) and subsequently on the safe/tolerable exposure/intake concentration. The Swedish Chemical Agency explored various hurdles to this, such as the complexity of the human endocrine system, different susceptibility at several human development stages, and longer time periods between exposure and generation of

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Conclusions and future prospective

any detectable negative impacts. Both the Swedish Chemical Agency and Hass et al. (Roszko et al., 2018) explained that it was impossible to detect a threshold for a working system which was usually active under normal conditions. In this aspect, even the moderate alteration in hormone levels will cause to physiological impacts. The assessment of ED activity is concerned with high ambiguity, mainly if experimental data are extrapolated to several species. It has been suggested that some scale of interaction with or occupation of receptor functional portions with EDs could be reached to generate toxic impact in respect of the several pathways of cyto- and homeostasis prevention and the plethora of cellular and molecular components capable to interact with hormonal signaling. Body homeostasis pathways are capable of responding to any disrupting action developed by xenobiotics at levels lower that the main thresholds. Although, when such pathways are ineffective at particular stages of organismal development, susceptibility to xenobiotics observed at that stage may be increased (Roszko et al., 2018). Instead of the above explanation, the data of estrogen equivalents determined for the investigated samples might be correlated with the sufficient daily intake (ADI) values described in the research articles for standard chemicals. Earlier, this method was approved by Caldwell et al. (2010). The WHO designed an ADI of 0.05 μg E2 kg21 b.w. day21 associated with no observed effect level (NOEL). For comparing the fish oil associated exposure to the toxicity underlying benchmark, a conservative view had been accepted by considering several hypotheses (Green, 2009). A standard adult body weight of 60 kg, a high concentration (0.073 pg g21) had been employed for estimations, and 80 g dietary fat intake mainly from fish oil. On the basis of this hypotheses, the average estimated E2 equivalent will amount to 5.84 pg E2 equivalent person21 day21. Such number is much lesser in comparison to 3 μg E2 equivalent person21 day21ADI value.

191

Following the same hypotheses, the consumption of flutamide equivalent had been calculated at 17.28 μg person21 day21. The ADI value for flutamide not leading anti-androgenic impact was fixed at 2.5 μg kg21 b.w. day21 that results in 150 μg kg21 person21 day21 (Schneider et al., 2017). The calculated values in the worst-case condition are only 10 times less than the ADI. Instead of reality, the accepted worst-case condition is unlikely, the estimated consumption value may indicate that high implication of polluted fish oil in certain population cohort may be a health burden when anti-androgenic impacts are assessed. Moreover, it has also been noted a balance between androgens and estrogens might be essential in balancing normal spermatogenesis (De Falco et al., 2015). If the investigated oil samples exhibited both estrogenic and antiandrogenic potential, its biological function may be essentially stronger because its complex pathways of action. Exposure to xenoestrogens and antiandrogens while fetal and neonatal generation has already been related with a arrays of male reproductive protuberance, like cryptorchidism, hypospadias, impaired fertility, and enhanced risk of testicular cancer (De Falco et al., 2015). Earlier, it was observed that flaws of the model and tests employed in this study are highly accepted. Moreover, the way of action of the compound assessed is only one element in its toxicological profile that has carcinogenicity, genotoxicity or interactions with other NRs. This suggests that such polluted fish oils may generate unwanted health impacts such as sex hormone system disruption, rather than giving important nutrients if employed as a food.

Conclusions and future prospective Xenobiotics as EDC compounds have widely enticed attention worldwide among the scientific community. Even at low concentrations of xenobiotics, they are able to exhibit endocrinedisrupting properties: acute and chronic

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toxicity. It has been reported that xenobiotics develop cancer by altering the metabolic function of endocrine. The xenobiotics can disrupt the hormone signaling and cell function via several molecular, cellular and biochemical events. However, the chronic exposure to xenobiotics as EDs can completely change physiological hormone signaling and induce epigenetic and genetic alterations in tissue stem cells leading to cancer development. However, the clinical consequences of various xenobiotics in the carcinogenesis mechanism are not yet well understood. Therefore, more research on this aspect is required to explore the possible precautionary methods to prevent the cancer development via basic alterations in lifestyle and also their outcomes will assist the desperate need for health and environmental guidelines focused at preventing the population as well as the developing fetus and women of reproductive age.

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1156. Ziaei, S., & Halaby, R. (2017). Dietary isoflavones and breast cancer risk. Medicines, 4, 18. Zoeller, R. T., Doan, L., Demeneix, B., Gore, A. C., Nadal, A., & Tan, S. (2019). Update on activities in endocrine disruptor research and policy. Endocrinology, 160(7), 1681
1683.

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11 Environmental exposures as xenoestrogens (bisphenol A and phthalates) enhance risk for breast cancer Introduction Human milk is without any contaminants and a great source of nourishment for infants with various immunologic, developmental, and practical benefits expending over childhood into adulthood. Identification of the several advantages of breast milk (BM) has resulted to the acceptance of breastfeeding regulations by various health and professional organizations (Massart et al., 2005). Presently, the World Health Organization (WHO) suggested its member states to enhance activities “to secure, encourage, and uphold exclusive breastfeeding for 6 months as a world public health recommendation, and to give safe and balanced complementary foods, with endured breastfeeding for up to 2 years of age or beyond” (Weise, 2012). Such focus on breastfeeding is proven by the proof that BM contributes the most complete form of nutrition for infants, grants enhanced protection from chronic diseases like asthma and diabetes, and boots-up

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00001-7

maternal health over the physiological reflections related with lactation. Sadly, human BM has been contaminated due to the decades of partially regulated pollution of the environment by toxic materials. Polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT) and its metabolites, dioxins, polychlorinated dibenzofurans (PCDFs), polybrominated biphenyls (PBBs), polybrominated diphenylethers (PBDEs), and heavy metals are the most prevalent toxic chemicals usually observed in BM. These chemicals are experienced to different levels among women in industrially established and developing nations. Some of the higher concentrations of pollutants have been observed among women in agricultural fields of developing countries that have been highly treated with pesticides (Solomon & Weiss, 2002). Intriguingly, women in remote areas, like the Canadian Inuit, who consume nutrients rich in seal, whale, and other species high on the marine food chain also acquire more concerns of relentless organic contaminants. For instance,

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methylmercury and PCBs are environmental pollutants that accumulate in fish and human BM. In populations where fish is a maximum part of the nutrition, maternal consumption could assess the infant’s exposure extent to such toxins. However, BM contamination and its health impacts on next generations are a worldwide concern (Pronczuk et al., 2002). Breast cancer is a highly prevalent cancer in women throughout the world. The US risk rate is balanced however among the world’s highest, and risk is increasing globally. The National Cancer Institute calculate that the expenses of breast cancer treatment would reach $20.5 billion in the US in 2020 (Rodgers et al., 2018). Inherited genes contribute to 5% 10% of breast cancers (Campeau et al., 2008; Rodgers et al., 2018) and also develop preventive efficiency in a several part of all cases. The changeable incidence factors have pharmaceutical hormones, paucity of exercise, intake of alcohol, weight gain after menopause, nulliparity, late pregnancy, and not lactating. Moreover, mechanistic and rodent, as well as epidemiology, explain that environmental factors possibly play a vital role in the development of breast cancer (Richter, 2019). Xenoestrogens are a kind of compound of synthetic and natural agents identified as endocrine disruptors due to their ability to disturb normal hormonal functions. It has been explained that some endocrine disrupters might lead to the generation of hormonedependent cancers like breast and endometrial cancers (Fernandez & Russo, 2010). Over the last seven decades, the industrialization of the world has produced an enormous number of chemicals, many of which are employed in the plastics industry (Martı´nez-Ibarra et al., 2021). The enormous production and implication of plastics has been a serious environmental issue, although mainly an issue of burden for human health because of the regular and undesirable intake of plastic particles usually

produced from plastic packaging by association with food, beverages, and air (Delfosse et al., 2012; Martı´nez-Ibarra et al., 2021). Such particles are synthesized from polymers and additives like bisphenol A (BPA) and phthalates. BPA and phthalates are found almost everywhere in the environment, wildlife, and the human body (Flint et al., 2012; Warner & Flaws, 2018). They have been classified as endocrine disrupting chemicals (EDCs) because of their capacity to perturb hormonal systems by altering the formation, secretion, transport, binding and/or removal of natural hormones from the body. The exposure to such chemicals are related to several negative impacts on human health like flawed reproduction and development, cancer, changed metabolism, and neurological and behavioral ailments (Benjamin et al., 2017; Goldstone et al., 2015). During the development of such ailments, multifactorial activities can contribute to the communication between genetic and environmental components; the latter is observed to have a vital role in disease development and progression (Becker et al., 2011; Martı´nez-Ibarra et al., 2021). Providing concurrent regular exposure to a cocktail of toxic chemicals, it is problematic to explore a direct causality related to the impact of EDC exposure on human health. Until now, about 1400 EDCs have been identified (Street et al., 2018). BPA and phthalates are employed in the synthesis of plastics and plasticizers, which is why exposure to such components has been considered chronic, unavoidable, and undesirable (Martı´nez-Ibarra et al., 2021). In addition, evidence collected via in vivo and in vitro assessment supports the relationship between such EDC exposures and their impacts on humans (Gore et al., 2015). Over the last fifty years, substances like phthalates, BPA, parabens, and triclosan (TCS) have been employed in different consumer products, personal care products, and medical commodities (Kim et al., 2020). Although present, they have been banned or restricted in several products due to their suspected harmful effects and

Xenobiotics in Chemical Carcinogenesis

Introduction

acts as endocrine disruptors (US Food and Drug Administration, 2019). The harmful effects of phthalates are identified in reproductive developmental damage, neurodevelopmental issues, growth deceleration, asthma, and allergies (Kim et al., 2020). BPA is a group of synthesized chemicals with structural semblance to the hormone 17-ß-estradiol (Zimmers et al., 2014) that might lead to damage to the pituitary thyroid axis, immune system issues, adverse reproductive and developmental impacts, alterations in thyroid hormone extents, and enhanced incidence of type II diabetes, infertility, retarded neuropsychological development, low birth weights, and adverse birth results (Kim et al., 2020). In addition, strong endocrine functions of BPA substitutes, like bisphenol S, bisphenol F, and bisphenol B, have been reported in research articles (Rochester & Bolden, 2015; Serra & Willot, 2019). Various studies on animal and human have explained that parabens and triclosan are related to endocrine disruption, mainly alterations in thyroid hormones and intervention with ion channels (Kim et al., 2020; Weatherly & Gosse, 2017; Yueh & Tukey, 2016). Such chemicals enter the human body via the consumption of foods, dermal absorption from the skin, and air inhalation. Chemicals which go inside the body are secreted to the urine within a few hours; however, some accumulate in the body and are identified in serum, saliva, BM, and the placenta, whereby directly or indirectly influencing health (Kim et al., 2020; Lee et al., 2018). The above studies aid public health agencies, especially in developed countries, to develop and direct functions which monitor human exposure to BPA and phthalates. As an outcome, information is created and employed in models to calculate the social and economic costs contributable to exposure to such chemicals. Subsequently, exposure to BPA and phthalates and their several contributions to the main child and adult morbidity has been determined. This has a higher economic burden, all of which focuses on the need to

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regulate the exposure to EDC (Legler et al., 2015; Trasande, 2014). The present calculated extent of human exposure to BPA and phthalates has been confirmed safe by US and EU food safety agencies (Martı´nez-Ibarra et al., 2021). However, there is an argument regarding their safety because of the political, economic, and scientific stakes (Nielsen et al., 2020). An enormous number of evidence suggests that EDCs can produce negative impacts at very low doses (Vandenberg et al., 2012). In addition, the exposure to EDC during the early stages of development affects the sensitivity of individuals to several diseases later in life. Indeed, exposure to EDC is mainly important if it happens in utero due to it can predispose the fetus to produce metabolic diseases later in life (Haugen et al., 2015). Over the last decade, environmental health and oncology have shown estrogen as an evolutionary conserved component. Due to endocrine, paracrine, and neurotransmitting action, estrogen is only restricted to the development and regulation of the reproductive system. The circulation of estrogen receptors (ERs) in mammalian tissues explains that estrogen has an important function in orchestrating several mechanisms in living organisms during development and adulthood. In addition, new results assure potential effects of this component on carcinogenesis (Fucic et al., 2012). A few studies have been done on alterations in estrogen extent and the tissue ratio between alpha and beta ERs in progress (Fucic et al., 2012). In the second trimester of human fetal progression, the highest level of ER beta mRNA has been observed in the testis and ovary and of ER alpha mRNA in the uterus. Comparatively more concentrations of either receptor is also found in the spleen, during which low levels are determined in the kidney, thymus, skin, and lung. The prepubertal ratio between ERs alpha and beta in human tissues in males and females has not been determined. In addition, ER alpha and

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beta are polymorphically circulated and as such they play several activities in cancer development (Fucic et al., 2012). At higher concentrations, estrogen is carcinogenic (Cavalieri et al., 1997); similar to ionizing radiation it might generate reactive oxygen species and leads to hypomethylation and microsatellite instability (Kaup et al., 2006; Roy et al., 2007). Its metabolites, quinones, lead to the production of DNA adducts, depurination, lipid-deficient aldehyde-DNA adducts, and aneuploidy (Cavalieri et al., 1997; Fucic et al., 2012). By decreasing glutathione-S-transferases, estrogen might enhance cellular oxidative DNA impairment in estrogen-responsive tissues, if the organism is together exposed to genotoxicants. It is an initial step in the process of cancer development (Ansell et al., 2004). Gender variations in the risk of cancers like the lung, kidney, or pancreas cancer explain that hormones might play a vital role in their etiology. The present outcome elucidates that all neoplastic mammalian tissues are recognized by alterations in ER extent. As gender-associated estrogen extent in fetal and prepubertal tissues, the tissue-based ER circulation and estrogen bimodal functions regulate the development of the biological mechanism, and organogenesis in some cancers might have origins in its prenatal and postnatal alteration produced by exposure to xenoestrogens (Fucic et al., 2012). This chapter emphasizes the potential role of environmental xenoestrogens like BPA and phthalates in the development of breast cancer.

Risk factors as models for environmental chemicals and breast cancer The results of both laboratory and human experiments support the functionality for chemicals in (1) genotoxic action, (2) changes of mammary gland development or hormone responsiveness, and (3) hormonal cancer progression.

Genotoxic components impair genetic material in a cell that might lead to cancer-inducing mutations (Rodgers et al., 2018). The development from damaged DNA to cancer has other methods like genomic instability, inflammation, and immune suppression (Hanahan & Weinberg, 2011). Ionizing radiation enhances the incidence of breast cancer in both males and females (Little & McElvenny, 2017; Rodgers et al., 2018) and is a model for the genotoxic function expected from typical cancer-inducing agents. Exposure to ionizing radiation highly enhances breast cancer incidence if it happens at initial life, such as before the age of 20 for atomic bomb survivors and medical radiation (Henderson et al., 2010). Mammary cells are considered to be highly sensitive to impairment from carcinogenic agents in adolescence and prior to pregnancy, if the cells are speedily proliferating and not yet completely differentiated (‘Molecular basis of breast cancer. Prevention & treatment’, 2004). Second, exposure to EDCs in initial stages of life might change breast development and enhance adult sensitivity to breast cancer. For instance, the synthetic estrogen diethylstilbestrol (DES) alters the structure of mammary gland and gene expression in rodents and has been related with breast cancer after age 40 in a US cohort of women. Animal studies have suggested that perinatal exposure to DES could enhance terminal end bud (TEB) and ductal formation during puberty (Rodgers et al., 2018; Rudel et al., 2011), explaining a pathway for stimulated breast cancer incidence. Prenatal exposure to hormones and some compounds, which change mammary development, also induce mammary cancer if animals are challenged with a carcinogenic agent while puberty. The prenatal time, puberty, and pregnancy, if cells divide and differentiate, are major apertures for exposure which modify mammary gland development; however, the association of mammary morphological alteration with breast cancer incidence has not been widely explained (Rudel et al., 2011).

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Introduction

Third, some EDCs might play nearer to the moment of prognosis by stimulating cancer growth via estrogen-or progesterone-mediated mechanism or other hormonal actions (Lee et al., 2014; Rudel et al., 2014). The induced breast cancer in women having hormone replacement therapy (HRT) is a model for this mechanism. The enhanced incidence remains for five years after inhibiting therapy and then reduces (Roth et al., 2014). The increasing levels of estradiol are also an incidence factor for postmenopausal breast cancer through a genomic reflection which stimulates cell division or suppress apoptosis, causing to tumor development (Yager & Davidson, 2006). Next, chemicals induce enzymes participating in estradiol metabolism or formation, like cytochrome p450 enzymes (CYPs), which might contribute to breast cancer via downstream impacts on endogenous estrogen, and progesterone is also essential in regulating the cell growth in the adult breast (Brisken et al., 2015).

Chemical properties and main sources of exposure to bisphenol A and phthalates BPA is an organic synthetic chemical which had been first manufactured as an estrogenic chemical. The structure of BPA is composed of two phenol functional groups attached by a single carbon having two methyl components. It is an essential monomer employed for synthetic plastic products, food packaging, toys, and epoxy resin layer for preserved food (National Center for Biotechnology Information, 2020) because of its capability to polymerize and synthesize flexible polycarbonate plastics. In addition, BPA is highly employed as a color developer in thermal paper and can be adsorbed on contact via skin. There is an annual BPA synthesis of over 3 million tons, upgraded primarily by potential industries from the electrical, production, and automobile areas and the food industry, all of

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which have immediately increased the demand for polycarbonate (Delfosse et al., 2012). BPA can disperse to food and water under specific circumstances like elevated temperatures, high contents in packaging, acidity, frequent utilization of containers and bottles, conventional and microwave heating, solar radiation, and storage (Bhunia et al., 2013). Phthalates are chemical esters made from phthalic acid and classified into two groups based on molecular weight. Therefore, low molecular weight (LMW) phthalates have dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP) diisobutyl phthalate (DIBP), and butyl benzyl phthalate (BBP), and high molecular weight (HMW) phthalates have di-2-ethylhexyl phthalate (DEHP), din-octyl phthalate (DOP), and diisononyl phthalate (DINP). Phthalates are particularly employed to soften and enhance the pliablility of plastic and vinyl (US Food Drug Administration) and as a fragrance ingredient used as a transporter to allow the perfume to endure. The most regularly implicated phthalates are BBP, DBP, and DEHP, which are found in a wide range of products such as coatings, vinyl flooring and wall covering, toys, shoes, kitchen accessories, rain gear, medical devices, blood storage bags, cosmetics, shampoos, hairspray, nail polish, perfumes, and other fragrance. Phthalates are also semi-volatile components not chemically attached to polymers. So, migration or emission of phthalates into water, air, or other media takes place in production through to product disposal (Martı´nez-Ibarra et al., 2021). Humans are exposed to BPA and phthalates via drinking and eating food viz. concentration of such components are mainly high in animal fat, highly processed or preserved food within plastic utensils or plastic film, and microwavable packaging. Further, exposure is attributed to personal care products, cleaning products and children’s toys. Exposure to phthalates may occur by breathing air having phthalate vapors or dust polluted with phthalate molecules. Young children might be at a higher

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incidence of exposure to phthalate molecules in dust than adults due to hand-to-mouth behavior (Martı´nez-Ibarra et al., 2021). People having blood transfusions or in intensive care units are exposed to certain levels of phthalates due to medical devices manufactured of polyvinyl chloride (PVC).

Bisphenol A and breast cancer Women are mainly exposed to xenobiotics via environmental factors and foods that can produce exogenous endocrine impacts on the body. Such endocrine disruptors produce estrogen (E2)-like impacts that may lead to breast cancer incidence; examples include PCBs, pesticides, and plastic additives. One such plastic additive is BPA that has chemical resemblances with other bisphenols like bisphenol AF (BPAF), bisphenol F (BPF), and bisphenol-S (BPS). BPA is an industrial chemical particularly implicated in the synthesis of polycarbonate plastics and epoxy resins. It has been classified as an EDCs because of their structural resemblance to E2. Bisphenols can interact with usual endocrine activities based on dose and period of exposure over its lifetime. Studies have investigated the biological impacts of exposure to bisphenols during several stages of life like gestation, lactation, and puberty, and as causative components in the generation of endocrine cancer, particularly of the breast. Breast cancer is the most prevalent cancer in women. Breast cancer has three main clinical subtypes: 70% of breast cancers are associated with hormone receptors for example, estrogen and progesterone, 15% 20% are human epidermal growth factor (ERBB2) positive (earlier HER2), and 15% are “triple negative” or do not have receptors for hormones or ERBB2. Such clinical subtypes explain treatment and diagnosis in most cases of breast cancer. BPA, as an EDC, has been explored as a main component in these cancer subtypes with different impacts based on the dose (Stillwater et al., 2020).

Government policy for bisphenol A In 2012, the FDA prohibited BPA in plastic baby bottles, sippy cups, and baby formula packaging. However, according to scientific review, the FDA, as of 2018, has “not received any instruction to prompt a revision of FDA’s security analysis of BPA in food packaging.” So, it is still used in non-infant applications like food packaging (Wang et al., 2017). BPA has been categorized by the US Environmental Protection Agency (USEPA) as an EDC. The USEPA has fixed an oral Reference Dose (RfD) for BPA at 50 μg kg21 bw day21 (Kang et al., 2006). The RfD is explained as an amount of daily oral exposure that is possible without experiencing lifetime impacts. However, such recommendation only considers daily oral consumption and does not investigate higher exposure in utero or as an infant, exposure from environmental pollutants, or accumulated stores in adipose tissue which are steadily released at all times (Vom Saal et al., 1998). The USEPA makes strategies to collect data in reference to environmental impacts of BPA to further investigate whether “BPA either does or does not present an undesirable incidence of injury to the environment (Latchoumycandane et al., 2003).” In 2016, the European Chemicals agency recognized BPA as a chemical of very high burden regarding its use in thermal paper and hence BPA had been added to the REACH Annex XVII Restricted Substances List. Such recent entries prohibit BPA’s use in thermal paper with a level equal to or above 0.02% by weight (Zsarnovszky et al., 2005).

Mechanism of bisphenol A-induced breast cancer The outcome of epidemiological and clinical testing shows that ER has a vital function in breast cancer progression. Above 65% of all breast cancers are ER-positive (Sonnenblick et al.,

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Government policy for bisphenol A

2014). BPA has been recommended as a synthetic estrogen and has the capacity to stimulate cell growth by triggering ERs, the primary event of BPA-induced carcinogenesis (Ma et al., 2019). BPA acts via both estrogen-dependent and -independent mechanisms. The main events by which BPA produces its carcinogenic impacts are epigenetic modification, DNA damage, and changes in breast microenvironment. Estrogenic potential of bisphenol A Estrogen is the main hormone that stimulates cell proliferation in the female genital portion. The main indication of estrogen action is its proliferative impacts (Soto et al., 1995). Estrogens perform their activity binding to nuclear ERs and the transmembrane receptor (G protein-coupled receptor 30: GPR30). Based on the E-SCREEN method for screening of estrogenic activity, BPA has explained estrogenic activity and could stimulate proliferation of MCF7 breast cells (Soto et al., 1995; Wang et al., 2017). The estrogenicity of BPA has also been elucidated in in vivo studies. Estrogenic

reflection, like increased uterine wet weight, enhanced luminal epithelial cell height within the uterus, and stimulated lactoferrin expression, have been determined in immature female mice treated with BPA (Markey et al., 2001). The proliferation of mammary epithelial cell had been increased in animals exposed to low concentrations of BPA, suggesting an estrogenic response of the mammary glands to BPA. Several studies have explained that BPA could attach to classical nuclear ERs, classical and non-classical membrane-bound ERs (mERs), and receptor GPR30 (Fig. 11.1) (Wang et al., 2017). In vitro binding assessment have revealed that BPA integrates both subunits of the ER, ER α and ER β, and has a 10-fold higher efficiency for ER β than ER α (Kuiper et al., 1998). The potential of BPA for such ERs is about 10,000-fold less than that of estradiol; hence, BPA is known as a weak environmental estrogen (Kuiper et al., 1998). Although, studies of molecular pathways have shown that, relative to estradiol, BPA integrates with the ligand-binding domain of ERs and then select FIGURE 11.1 Xenoestrogen BPA interplays with nuclear ERs, cytoplasmic ERs, membrane-bound Ers, and GPR30 receptors, stimulating mammary epithelial cell proliferation via genomic and non-genomic signaling mechanisms showing estrogenic potential of BPA. BPA, Bisphenol A; ERs, estrogen receptors.

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distinctive transcriptional co-regulators in target cells. In another way, the attachment of BPA to the ER changes its potential to select co-factors or co-repressors, by which BPA induces cellular responses. Owing to the recruitment of co-regulators by BPA ER complex being unequal to the capacity of BPA for ER, (Routledge et al., 2000) the type and the expression degree of ER-regulated targets, not the binding capacity, are essential determinants of cell and tissue specificity countering to BPA. Several pieces of evidence suggest that BPA stimulates genomic reflections in various cells at concentrations lower than the levels where BPA is investigated to attach nuclear ERs. BPA also binds to orphan estrogen-related receptor gamma (ERR γ). The induction of ERK1/2/ERR γ triggers cell proliferation in breast cancer cells upon exposure to low concentration of BPA. Similar to estradiol, BPA has also been exhibited to integrate membrane ERs and GPR30, inducing rapid cellular reactions via non-genomic signaling mechanism (Wetherill et al., 2007). For example, exposure to BPA produces calcium flux and leads in the secretion of prolactin in pituitary cells via mER mechanism (Watson et al., 2014). Employing breast cancer cells without classic ERs, it has been shown that BPA stimulates cell proliferation and invasion via the GPER/EGFR/ERK mechanism (Pupo et al., 2012). BPA works via several signaling mechanism in various cell types. In general, BPA has estrogenic impact by integrating to several ERs, which has a large impact on BPA-related breast cancer development. Epigenetic impacts of bisphenol A Epigenetic impacts are identified as heritable changes in gene expression or cellular phenotype without disturbing in real DNA sequence. Intriguingly, some studies have explained that BPA-stimulated epigenetic alteration moderately accounts for enhanced breast cancer incidence in women and pre-neoplastic and neoplastic gland lesions in animals (Singh &

Li, 2012). BPA epigenetic regulation has DNA methylation, histone alteration, and expression of non-coding RNAs. Treatment with low concentrations of BPA caused in relevantly increased overall histone H3 trimethylation at lysine 27 and enhanced contents of histone methyltransferase: enhancer of Zeste Homolog 2 (EZH2) in human breast cancer cells (Doherty et al., 2010). The enhancement in DNA methylation in the promoter site of lysosomal-associated membrane protein 3 (LAMP3) had been detected both in human primary epithelial cells and breast cancer cells upon exposure to low-dose BPA, suggesting that epigenetic activities are critical pathways of BPA’s carcinogenic impacts (Liu et al., 2014b). In addition, it had been explained that BPA-stimulated alterations in expression levels of microRNAs (a type of epigenetic regulation) in placental cells may have aberrant mammary gland structures following fetal exposure to BPA (Montes-Grajales & Olivero-Verbel, 2013). The enhanced expression of epigenetic regulatory components in hypothalmic cells regulating the extent of transporting ovarian hormones and mammotropic hormones might also be responsible for BPA’s harmful impacts on growth of mammary gland (Warita et al., 2013). Recently, some studies have further elucidated that BPA can lead to a high number of methylation alterations in genomic DNA fragments (7412 out of 58,207 segments) and high contents of histone H3 trimethylation at lysine 4 (H3K4me3) in the promoter region of alphalactalbumin in neonatal rat mammary glands. A wide-scale epigenetic alteration from fetal BPA exposure might cause a change in the mode of gene expression, intraductal hyperplasia, and ductal cancer in situ in adults. DNA damage Impaired DNA and genetic mutations have critical pathways for the induction of cancer (Hanahan & Weinberg, 2011). Various in vitro and in vivo results have elucidated that BPA in

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Phthalates

high concentration can integrate with DNA and produce DNA adducts in human cell lines and in mammary cells from mice. BPA has also been observed to elicit aneugenic impacts by interacting with microtubule congregation, spindle machinery activities, and chromosome separation during mitosis in human umbilical vascular endothelial cells and human fibroblasts (Wang et al., 2017; Xin et al., 2015). Such outcomes suggest that BPA exposure can highly stimulate carcinogenic impacts via DNA stability interference. In addition, present studies have explained that low concentrations of BPA can induce DNA instability by perturbing DNA damage signaling mechanisms (Wang et al., 2017). For instance, treatment of human breast cells with different concentrations of BPA (10 100 nM) triggered the generation of reactive oxygen species (ROS) and DNA double-strand breaks via upregulation of cMyc protein (Ibrahim et al., 2016). Changes of breast microenvironment The mammary gland has several kinds of cells that develop epithelial structures: ducts and acini and the vicinity of microenvironment (Polyak & Kalluri, 2010). The breast microenvironment has an extracellular matrix (ECM), several stromal cells with endothelial cells, fibroblasts, adipocytes, and immune cells, and different cytokines (Fig. 11.2). However, breast cancer usually grows within the ductal part,

FIGURE 11.2

where the microenvironment plays a major function in mammary gland development and epithelial malignant invasion (Polyak & Kalluri, 2010). Some studies have elucidated that BPA can affect the mammary gland microenvironment via impacts on ECM factors and density, as well as on stromal cells and immune cells. The decreased expression of ECM factors and decreased density of collagen fibers in the stromal regions were determined in the fetal mammary glands of BPA-induced mice (Liu et al., 2014a). Adipocytes are highly present in stromal cells; they generate adipokines that stimulate mammary branching. The impacts of BPA on adipocyte differentiation and maturation have been explained in animals and multipotent stromal stem cells (Chamorro-Garcı´a et al., 2012). The alterations in ECM and progressive development of fat cells perturbed the unified interactions among epithelial cells and stromal cells, causing changes in mammary epithelial phenotypes and neoplastic lesions.

Phthalates The regular exposure to several kinds of chemicals available in the environment and to which humans are exposed during their daily works might negatively impact human health, and hence, develop into a global issue. Phthalates

Diagrammatic presentation of BPA mechanism inducing mammary carcinogenesis. BPA, Bisphenol A.

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(PAEs) are esters of phthalic acid highly dispersed in several industrial implications as major plasticizers employed in the polymer industry since the 1930s. They are mainly supplemented to plastic materials like PVC, polyethylene (PE) terephthalate (PET), polyvinyl acetate (PVA), and PE, at percentages of 10% up to 60% of PAEs by weight, to enhance the elongation, modulus, and hardness of the polymers (Giuliani et al., 2020). PAEs have great economic and commercial importance in plastic-associated consumer products like building materials, baby toys, clothing, printing inks, packaging materials, pesticides, personal care and cosmetics, pharmaceuticals, as well as medical appliances (Giuliani et al., 2020). Phthalates are chemicals formed from the esterification of phthalic acid with several types of alcohol. Phthalates are generally less soluble in water, whereas they are highly soluble in oils, fats, and alcohol. In the industrial field, phthalates are highly implicated as plasticizers added to enhance the plasticity, the flexibility, and malleability of materials (Zuccarello et al., 2018). Phthalates are fascinating EDCs because of the regular and long-term exposure for which the world has been exposed (Romero-Franco et al., 2011). Some phthalates show high lipophilicity, such as DEHP, and invade the body via the skin (Pan et al., 2014), are assimilated by inhalation, or orally ingested (Mittermeier et al., 2016). They are immediately transformed into important metabolites such as those summarized in Fig. 11.3.

Exposure via diet The major source of exposure to phthalates is diet, especially via the intake of food and beverages wrapped in several plastic packaging (Fierens et al., 2012). Several studies elucidated daily consumption and cumulative incidence analysis of phthalates (Dewalque et al., 2014; Zuccarello

et al., 2018). The dramatic enhancement in the implication of plastic things in the last decades has caused the spread of phthalates in water reservoirs, mainly surface waters (Kong et al., 2017). DBP, DEHP, and DOP have been observed in relevant amounts in agricultural soils and, subsequently, in cultivable vegetable. Seafood is also a source of exposure, thereby the contaminations of phthalates are not caused by packaging (Zuccarello et al., 2018). After several years of widespread uses of such materials, their safety has been questioned in current years by analyzing the health incidence related to exposure to such compounds (Frederiksen et al., 2014; Zuccarello et al., 2018). An unsolved problem is linked with breast cancer and phthalates exposure as well as the process that will stimulate the cancer processes. Breast cancer is the most prevalent cancer in women, and one of the major reasons of cancer-associated mortality among women (Alamolhodaei et al., 2017; Roszak et al., 2017). Several studies explained that various phthalates are capable of attachment and simulating ERs. ERs have been investigated in vitro to compare with natural ligands and observe a higher capacity of mono-phthalates, which produce more hydrogen bonds with receptors. Also, phthalates suppress tamoxifen-stimulated apoptosis in MCF-7 human breast cancer cells to induce growth of ER-positive mammary malignant cells (In et al., 2004). It has also been revealed that 9 of 22 tested phthalates have an estrogenic potential on ERα higher than the maximum function stimulated by β-estradiol, the natural ligand of ERα, mainly phthalates containing lateral alkyl chains of certain size and carbon abundance between C3 and C6. Also, other modes of action will be employed by phthalates. Some studies have reported whether the expression of vascular endothelium growth factor (VEGF) had been controlled by various phthalates (including BBP and DEHP), since it plays a major role in angiogenesis and cancer

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Phthalates

FIGURE 11.3 Metabolic mechanisms of phthalate esters in humans.

development events. Indeed, such chemicals stimulated a dose-dependent rising of VEGF secretion in MELN’s cells with regular expression of ERα receptor (Zuccarello et al., 2018). In some studies, it has been assumed that phthalates will impact the genomic and nongenomic function of the female reproductive parts both directly via integration with ER and, also, indirectly as regulators or co-activators of transcription components. Indeed, they could be transferred in cells through MDR1. The development of breast cancer might occur by induction of the PI3K/AKT mechanism or through the estrogenindependent AhR/HDAC6/c-myc mechanism,

regulated by the cAMP-PKA-CREB1 signaling cascade: MDA MB-231 Breast adenocarcinoma cells (Benjamin et al., 2017). Toxicological aspects and human health effects Extensive exposure to PAEs has been shown problematic regarding their effects on human health. Results of the last two decades explain that such chemicals, after transformation into primary and secondary metabolites, will work as suspected EDCs, by integrating with several endocrine molecular signaling mechanisms. Various processes of human biomonitoring

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offer the investigation of biomarkers for parent molecules and their metabolites in biological process for highlighting the suspected function of PAEs in a wide range of pathophysiological human condition (Giuliani et al., 2020). Still, exposure to PAEs has been associated with various types of health problems such as endocrine and reproductive dysfunction (Liu et al., 2018), quick puberty, endometriosis, sex abnormalities, infertility, modified fetal development, breast and skin cancer, obesity, type II diabetes (Casals-Casas & Desvergne, 2011), attention deficit hyperactivity disorder, autism spectrum disorders, cardiotoxicity, hepatotoxicity, nephrotoxicity, asthma, and allergy (Giuliani et al., 2020). Once absorbed, PAEs are transferred into their respective monoesters or PA through hydrolyzation by esterase or lipase, and in a second step, through sulfonidation or glucuronidation prior to being excreted (Genuis et al., 2012). In an experiment to analyze the incidence of phthalate exposure, US EPA and other scientific organizations entrenched a standard dose i.e., tolerable daily intake; TDI represented in microgram (μg)/kilogram (kg) body weight (bw)/day (d) of phthalate such as: 3500 for mono-methyl phthalate (MMP), 800 for DEP, 100 for DBP, 200 for BBP, 80 for ΣDEHP metabolites, 120 for DINP, and 3500 for DnOP. Phthalate esters (DEHP, BBP, DNBP, and DIBP) are available in the Registration, Evaluation, Authorization and restriction of CHemicals (REACH) Candidate List within the section “Substances of Very High Concern” (SVHC). That is, a concentration of exposure to DEHP metabolites [mono(2-ethyl-5oxohexyl) phthalate (MEOHP), MEHP, and mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP)] must be within 20 μg kg21 bw day21 (Wang et al., 2019). It has been calculated that, in normal conditions, humans are exposed to $ 1.0 g day21 of phthalates. As PAEs are immediately metabolized and excreted, the analysis of such chemicals in urine are relevant. It is noticeable that children and adults encounter distinct ways to PAEs exposure, as a result of the children’s hand-to-mouth

habit which will easily get them to consume DEHP (Weiss et al., 2018).

Phthalates and breast cancer Phthalates have been highly related to various human cancers, such as skin, liver, prostate, including breast cancer (Fiore et al., 2019; Zhu et al., 2018). Importantly, PAEs like BBP and DEHP will enhance the expression of VEGF and, further, angiogenesis and tumor progression in breast cancer cells (ButeauLozano et al., 2008). In a Mexican study (N 5 233), it has been determined that higher MEP doses were observed (169.58 g g21 creatinine) in females with breast cancer in comparison to healthy females (106.78 g g21). One likely pathway may underlie the capability of PAEs to stimulate DNA damage in mammary epithelial cells (Rodgers et al., 2018), and on the stimulation of PPARs signaling related to BARC gene activation (Rusyn & Corton, 2012). In both hepatic and breast carcinoma, PAEs possibly stimulate phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) or cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)- cAMP response element binding protein (CREB) signaling cascades, the latter responsible for the induction of the AhR provoked proliferation of mammary cancer cells (Giuliani et al., 2020; Vacher et al., 2018). In general, the enhanced Histone Deacetylase 6 (HDAC6) expression triggers the stimulation of the nuclear β-cateninlymphoid enhancer binding factor 1 (LEF1)/T-cell factor-4 (TCF4) transcriptional complex and, consequently, that of the oncogene c-Myc (Hsieh et al., 2012). Intriguingly, in a study performed by Ito et al. (2007), they determined a PPARα-independent impact of phthalates which will elicit hepatic cancer through c-jun/cfos/Activator protein-1 (AP1) signaling (Ito et al., 2007). Moreover, it has been assumed that phthalates deregulate various miRNAs participating in breast cancer

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development such as miR-34b-5p, miR7686 5p, and miR-1291 (Zhang et al., 2018). Studies based on the pathways of phthalateinduced breast cancer emphasize its estrogenic function that leads to abnormal endocrine activity of steroid receptors. Interestingly, several in vivo and in vitro studies have revealed that phthalates like BBP show only delicate estrogenic activity in breast cancer cells, explaining that phthalates might be attributed to cancer development via ER-independent events (Hsieh et al., 2012). Women have more incidences compared to men for potential adverse health impacts of phthalates from cosmetics. Although, potential impacts of phthalate exposure have been observed mainly in males. Health impacts in women have not been well recognized, and also no more studies have been performed on endometriosis and thyroid hormone alterations (Lo´pez-Carrillo et al., 2010). For the first time, such studies have elucidated which urinary level of certain phthalate metabolites might be associated with BC independent of other identified risk components such as MEP, the major DEP metabolite, is relevantly correlated with incident BC in premenopausal women, and the metabolites of BBzP (MBzP) and of DOP and other phthalates (MCPP) have opposite relation with BC (Lo´pez-Carrillo et al., 2010). Recently, two epidemiologic results based on men attending an infertility clinic exhibited that sperm DNA damage had been related with urinary level of MEP but not of MBP or MBzP (Hauser et al., 2007). Other phthalates and/or their metabolites have been explored to impair DNA, as analyzed by the alkaline comet assay. DNA damage had been identified in human lymphocytes exposed to DEHP and MEHP (Anderson et al., 1999). Additionally, DBP and DiBP had been revealed to be genotoxic in human epithelial cells of the upper aerodigestive part, mucosal cells, and lymphocytes (Kleinsasser et al., 2000). The above studies explain that MEP and other

phthalates have capacities to stimulate DNA damage and enhance cancer incidence, although further research is required to completely identify the genotoxic impacts of phthalates on human breast cancer. The epigenetic impacts of phthalates like DNA methylation, may describe the adverse correlations of MBP and MBzP with BC determined in the above study. BBzP and DBP, parent chemicals of MBzP and MBP, respectively (MBP is also a minor metabolite of BBzP), caused demethylation of ER α promoter-associated CpG islands, developing a growth suppressive impact on human MCF-7 BC cells, hence decreasing BC incidence. In addition, other potential pathways explore the described negative impacts associated with phthalates on peroxisome proliferator-activated receptors (PPARs) and the major role of such ligand-induced transcription components have in the growth and differentiation of BC cell lines and in breast development. PPARγ is related with differentiation, enhanced lipid accumulation, and suppression of BC cell proliferation, and present evidence reveals that DBP/MBP and BBzP/MBzP have modest but continuous associations with PPARγ stimulation. In this aspect, further knowledge is required to describe the negative relationship observed in the above study on MCPP, a nonspecific metabolite of various phthalates like DOP and DBP, as well as BC (Lo´pez-Carrillo et al., 2010).

Conclusion It is increasing burden that environmental xenoestrogen chemicals acting as EDCs have adverse impacts on hormone-sensitive organs mainly in the breast. The common population is naturally exposed to BPA and phthalates and is especially vulnerable during the perinatal stages. The intricacies of xenoestrogen (BPA and phthalates) pathways of action and the function of the endocrine system itself makes it

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difficult to envisage the impact of such compounds on the human body. However, the experimental, epidemiologic, and clinical studies reveal relationships between increasing urinary levels of BPA and phthalates and various deleterious impacts to human health. Moreover, the results of in vivo and in vitro assessment exhibit that exposure to BPA and phthalates lead to the progression and/or severity of various diseases including breast cancer. The greater concentrations of BPA and BBP have estrogenic potential in the development of breast cancer. Further, more studies of the BPA and BBP impacts in human breast epithelial cells are needed to provide essential information on whether such chemicals have the potential to proliferate cancer cells as well as generate ideas for the prevention and treatment of breast cancer.

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C H A P T E R

12 Biotransformation of toxic xenobiotics by human gut microbiota Introduction Microbes of the gastrointestinal (GI) tract like bacteria, yeast, and viruses, are likely the first to interact with consumed xenobiotic compounds. From the stomach to the small and large intestines, bacterial communities dividing the intestinal tract substantially increase from about 108 bacteria mL21 of ileal concentration to 1010
1011 bacteria g21 of stool. The number and multiplicity of the gut microbiome is huge if considering that their aggregative 3.3 million different genes overburden human genes by approximately 150 times. This catalog of bacteria is usually presented by the taxa Bacteroidetes, Firmicutes, Proteobacteria, and Verrucomicrobia, although the proportions of these vary relevantly between individuals and over time. However, the metabolic mechanism associated with the genomes of such community are highly conserved. Such functional conservation has a potential adaptation that is generated via the coevolution of microbes and host, where certain functions, instead of bacteria, had been conserved underlying the conditions in the gut. In humans, a symbiotic association has developed within the commensal gut microbiome. The nutrient-rich, anoxic environment of the colon encourages anaerobes which employ human-

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00013-3

indigestible components, whereas the products formed by such organisms have several advantages to the host like decreasing inflammation and enhancing digestion (Collins & Patterson, 2020). Alterations in composition and function of the gut microbes cause several human diseases. An indicator of microbiome health is community diversity, as superabundance in functional events encourages the conservation of major functions upon disturbances. These imbalances are attributed to different conditions all over the body like inflammation, muscle mass, depression, and blood pressure (Claesson et al., 2012), inhibited infant weight gain (Obermajer et al., 2017), disturbed immune (Collins & Patterson, 2020; Gensollen et al., 2016) and endocrine (Sudo et al., 2004) system generation, enhanced allergic reactions (Trompette et al., 2014), and behavioral and neurochemical modifications (Collins & Patterson, 2020; Hsiao et al., 2013). The most noticeable and well-known instances are in association with the metabolism. Interfaces in normal regular metabolic activity of the microbes may be attributed to obesity and metabolic disease via the dysregulation of lipid and carbohydrate metabolism (Claesson et al., 2012; Collins & Patterson, 2020; Rastelli et al., 2018).

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© 2022 Elsevier Inc. All rights reserved.

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It had been previously identified that gut microbes impact host metabolism of not only endogenous and dietary components, but also xenobiotic compounds. Pioneering researchers have explained that prontosil, an older antibiotic, had been transformed into its active components by gut bacteria (Colebrook et al., 1936), which is the basis to describe interindividual differentiation in the metabolism of different kinds of drugs (Williams, 1971). The notion that host xenobiotic metabolism is associated with microbe activity had been explained by Selye in 1971, who determined that hormones prime the body to metabolize extra components and protect against pathogens (Collins & Patterson, 2020). The studies at the time were unable to profile the complete microbiome or their metabolites, manipulations employing antibiotics were implicated to depict that microbes can affect xenobiotic metabolism. However, with advanced high-throughput, lowcost sequencing and metabolomics approaches, entire profiles of the microbiome and its metabolic activity can be observed and connect to the metabolism of consumed drugs. These methods recognized the bacterial genes involved in metabolizing 271 drugs in 76 gut microbes in vitro prior to extending to the entire microbiome ex vivo and in vivo (Zimmermann et al., 2019). These potent techniques permit thorough investigation of xenobiotic metabolism pathways within the gut microbiome. Moreover, advancement in the manipulation of wide scale data from such “omics” techniques have been necessary to start to dissect the links between bacterial metabolism and disease (Nicholson & Wilson, 2003). Hence, there is high interest in knowing the molecular pathways following the connection between gut microbes and host that impact the pharmacokinetics of xenobiotics compounds. The concept of xenobiotic metabolism is explicated as the metabolism of ingested exogenous compounds, accentuate the function of the liver as the chief part of biotransformation

upon ingestion by the host. Therefore the liver is known anatomically, morphologically, and physiologically exclusive as a metabolic organ and unrivaled in metabolic potential in comparison to extrahepatic host regions of xenobiotic chemicals transformation. This aspect discounts the fact that prior orally administered components move the liver, an enhancing number are first disclosed to the gut microbiota and their related collection of metabolic enzymes. Indirectly, metabolites formed by gut microbes can also tune the expression and activity of main liver enzymes like those in the pivotal cytochrome P450 (CYP) superfamily. Hence, the metabolism of several clinically employed drugs can possibly be affected by either direct or indirect impacts of the gut microbes (Clarke et al., 2019). Humans take several small molecules that are foreign to the body that is, xenobiotics, like dietary compounds, environmental chemicals, and pharmaceuticals (Fig. 12.1). The trillions of microbes residing in the human GI tract could directly modify the chemical structures of these xenobiotic compounds, hence altering their lifetimes, bioavailabilities, and biological impacts. The familiarity of how gut microbial transformations of xenobiotics impact human health is in its infancy, but the initial results are startling (Koppel et al., 2017). The gut microbiota’s newly unraveled functions in human biology are the capability to alter chemical structures of xenobiotics compounds. Increasing evidence has now disclosed knowledge of the activity of the gut microbiota on xenobiotic metabolism that will have a major effect on therapy for several diseases in the future. Gut microbial xenobiotic metabolites have modified bioavailability, bioactivity, and toxicity and can interfere with the functions of human xenobiotic-metabolizing enzymes to impact the destiny of other ingested components. Such alterations are diverse and can cause to physiologically essential significance (Nakov & Velikova, 2020).

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Introduction

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FIGURE 12.1 The microbes which reside in the human gut change the chemical structures of consumed compounds such as dietary substances, industrial chemicals, and pharmaceutical molecules. Such modifications impact xenobiotic toxicity, biological function, and bioavailability (Koppel et al., 2017).

The GI region is occupied by a dense microbial community referred to as the “microbiota,” which is constituted of viruses and members of three territories of life: bacteria, archaea, and eukarya (Ba¨ckhed et al., 2005; Nogacka et al., 2019). Metagenomic research shows that the number of bacteria in the body increases about 10 times the number of nucleated eukaryotic cells (Sender et al., 2016), having a genetic efficiency 100-fold larger than (O’Hara & Shanahan, 2006) that of the complete human genome (Qin et al., 2010). The intestinal bacterial population usually consists of members belonging to mainly two phyla, Bacteroidetes and Firmicutes, both containing about 80%
90% of the microorganisms in this environment. Additional subdominant microorganisms, in declining order of abundance that is, less than 10% of all intestinal bacteria, are members of the phyla Actinobacteria, Proteobacteria and Verrucomicrobia, respectively (Arumugam et al., 2011). The intestinal microbes perform critical roles that are useful to the host and can be usually classified as the metabolic degradation of

nondigestible carbon compounds and formation of several metabolites like vitamins and short chain fatty acids (SCFAs), protectiveinhibition of pathogen attachment to intestinal areas and trophic-maintenance of the intestinal epithelium integrity and activity (O’Hara & Shanahan, 2006). Intestinal microbiota have the potential to alter the harmful effects of food xenobiotics by direct microbial interactions with such chemicals and/or by regulating host-microbial interactions. Initially, some lactic acid bacteria (LAB) and other microbes of the human gut can directly attach or metabolize diet-derived HCAs or other xenobiotics components (Nogacka et al., 2019; Zhang et al., 2017), attributing either to the sequestration and release of such compounds in feces or to their conversion into less toxic components that highly aids in protecting from DNA damage and formation and development of preneoplastic lesions. The gut microbiota also metabolizes xenobiotics transforming them into chemically obtained components with increased mutagenic action

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TABLE 12.1 Name of some gut bacteria involve in cancer development (Chattopadhyay et al., 2021). Name of bacteria

Mode of action in carcinogenesis

Bacteroides fragilis

Stimulate the disintegration of cancer suppressor protein E-cadherin Induction of protooncogene MYC and upregulation of Wnt/β-catenin in the nucleus Trigger inflammation via the induction of NF-kB and MAPK signaling mechanism

Enterococcus faecalis Generate reactive oxygen species and superoxide anions which lead DNA damage and genomic instability Fusobacterium nucleatum

Stimulate inflammation via triggering the NF-kB mechanism and overexpression of inflammatory cytokines like IL-6, IL-8, and IL-18 The Fly Away Pack 2 (Fap-2) protein of F.nucleatum prevent malignant cells from host immune attack via integrating with TIGIT on NK and T cells

Escherichia coli

Stimulate the expression of the Colibactin gene that causes for DNA damage, chromosomal aberrations, and gene mutations in host cells Increase the survival of cancer cell via the stimulation of macrophage inhibitory cytokine 1, transforming growth factor β-activated kinase 1, RhoA GTPase, and overexpression of COX-2

Streptococcus gallolyticus

Trigger the growth and inflammation via the induction of COX-2 in the microenvironment of cancer cells. COX-2 stimulates angiogenesis and suppress apoptosis

Helicobacter pylori

Stimulate perturb the epithelial cells and inflammatory reaction via IL-8 formation Gastrin is released due to infection of H. pylori increases proliferation of the mucosal cells The virulent factor CagA of H. pylori stimulates for carcinogenesis via inflammatory responses

Streptococcus bovis

Trigger cellular proliferation and angiogenesis via formation of pro-inflammatory cytokines NF-κB, IL-1 and IL-8, and COX-2 overexpression

MAPK, Mitogen-activated protein kinase.

for cancer development (Table 12.1). Hence, more studies are required to demonstrate the dimension of bacteria enabling the performance of each such conversion of several xenobiotics formed while food processing, the metabolic impacts of these biotransformation on the microbiota and host, and the significance of such transformations to intestinal ailment and cancer development. The human diet impacts the incidence of developing cancer. Amongst the participating components are consistent exposure to genotoxic materials available in food and gut microbial dysbiosis driven by diet. For instance, eating well-cooked meat is related with

enhanced risk for colorectal cancer in humans (Sinha et al., 2001; Zhang et al., 2017), and red and processed meat are likely identified as human carcinogens, respectively (Bouvard et al., 2015). High-temperature or extensive cooking of meat leads in the production of mutagenic and carcinogenic heterocyclic amines (HCAs) like 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), 2-amino-3,8dimethylimidazo [4,5-f] quinoxaline (MelQx), and 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) (Zhang et al., 2017). PhIP, MelQx, and IQ are the main mutagens for bacterial and mammalian cells and are carcinogens in several organs in rodent models (Chen et al., 2017). This

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Habitat of microbes in human body

data explains that HCA exposure from the intake of meat might cause enhanced colorectal cancer incidence. The fundamental of HCA mutagenicity is well identified. Cytochrome P450 enzymes transform HCAs to hydroxylamines that are transformed to respective esters by N acetyltransferases or sulfotransferases (Kim & Guengerich, 2005; Zhang et al., 2017). Such esters are unstable and hydrolyze immediately, producing reactive aryl nitrenium ions which covalently integrate to DNA (Kim & Guengerich, 2005), hence forming HCADNA adducts, that are prone to stimulate frameshift or point mutations (Zhang et al., 2017). Subsequently, HCA-stimulated mutagenesis is highly regulated by its metabolism. Gut microbiota change HCAs in the human colon, for example by hydrolyzing their glucuronide conjugates and catalyzing their oxidation. Presently, a potential transformation participating in the conjugation of PhIP to a glycerol obtained by complex human fecal microbiota in vitro and by Enterococcus spp., Lactobacillus reuteri, Lactobacillus rossiae, and Eubacterium hallii, has received attention. Such transformation needs the changes of glycerol to 3-hydroxypropionaldehyde (3-HPA), and is modulated by bacterial glycerol/ diol dehydratases encoded by the pduCDE gene that is found in E. hallii, L. reuteri, and L. rossiae. Eventually, 3-HPA is released, chemically decomposes to form acrolein, which further reacts with PhIP producing PhIP-M1 (Zhang et al., 2017). This chapter will provide an overview of xenobiotics transformation through human gut microbes and prognosis and identification of their toxicants by several approaches.

Habitat of microbes in human body The word “microbiome” usually includes the collective genomes of all of the microbes that reside the human body, whereas “microbiota” and “microflora” mainly refer to the real community of microbes in a certain niche on or

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in the human body. The view of the microbiota and microflora impacted human health stages at least to the early 1900s, and it was studied based on its impact on nutrition and periodontal health. Although, the word microbiome only referred to typical uses, the “omics” era, with the advent of enhanced DNA sequencing technologies, has supported a more thorough assessment of the constituents of the microbiota (Koontz et al., 2019). Inside the human gut microbiota, 10 and 100 trillion microbial cells have been counted, highly exceeding the calculated 10 trillion cells in the human body (Koontz et al., 2019; Qin et al., 2010; Sender et al., 2016). In the human gut, there are approximately 1000 to 1150 exclusive bacterial species, which, in totality, have 3.3 million nonredundant microbial genes, about 150 times larger than the all genes encoded in the human genome. Such microbial genes directly impact the extent of several metabolites in the human body like amino acids, vitamins, antioxidants, isoflavanoids, and SCFAs (Wikoff et al., 2009). They also metabolize xenobiotic chemicals that influence the bioavailability or toxicity of such compounds. Further, humans are reliant on bacterial enzymatic methods to digest chemicals present in the diet like plant polysaccharides, emphasizing the essential and antique symbiotic relationship (Kau et al., 2011). In the wake of the Human Genome Project, it had been realized that efforts were insufficient until our microbial coinhabitants had also been identified (Proctor et al., 2019; Statistics et al., 2017). The strength of scientific concern in the microbiome have exhibited more than a 400-fold enhance in the full yearly publication of microbiome-associated publications of 2007
18. Over the endeavors of the Human Microbiome Project, 4788 total samples from 242 patients had been implicated to compare the structure, role, and variation of the healthy human microbiome over 5 areas of the body like oral cavity, nasal cavity, skin, GI tract, and urogenital tract, with 18 sampling sublocations (Human Microbiome

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Project Consortium, 2012). The main body parts explained dominant patterns of diversity. Commonly, oral and stool flora had many variations, while the bacterial population in the vagina had less variation. In spite of this diversity, the occurrence of main metabolic components was regular over most of the subsites, suggesting conserved community roles like ribosome and adenosine triphosphate formation. Such main metabolic components are conserved over several bacterial species and provide similar activities between groups. Such core modules could be performed by several enzyme families at distinguished body regions, although the core activity is conserved (Abubucker et al., 2012). The relevant diversity has appeared among several individuals microbiomes (Flores et al., 2014; Huttenhower et al., 2012). Several components like diet (Turnbaugh et al., 2009), geographical region (Yatsunenko et al., 2012), and host-genetic composition (Koontz et al., 2019; Lu et al., 2014; Stewart et al., 2005), attribute to such variability. Further, the changeable variation within the microbiome is highly related with the diversity of one’s microbiota constituents (Flores et al., 2014). Interpersonal variation has been revealed to be more than intrapersonal variation across time (Costello et al., 2009). A positive relation has been shown between diversity and stability of the microbiome, with enhanced stability with higher diversity and enhanced instability with lower diversity (Costello et al., 2009; Koontz et al., 2019). The particular microbiota habitats have different ways of diversity, with the skin exhibiting maximum variations (Flores et al., 2014). In GI microbiota, temporal variability is related with alterations in the abundance of species in the gut (Flores et al., 2014). In general, the view of a “personalized” microbiome is encouraged by the highly interindividual variability and the variable frequencies of alteration in one’s microbial communities (Costello et al., 2009).

Role of microbes in health and disease Dysbiosis of the microbiome can highly affect human health and disease. Previously, it has been described that alterations in the microbiome accomplish were due to a several factors such as diet (Johnson & Versalovic, 2012; Turnbaugh et al., 2009), antibiotic implication (Johnson & Versalovic, 2012; Koontz et al., 2019; Noverr et al., 2004), and other environmental factors like stress (Moloney et al., 2014). Disturbance of one’s microbiome is based on enormous human disorders like obesity, diabetes, nonalcoholic steatohepatitis, and coronary heart disease (Koontz et al., 2019). The gut microbes could have a relevant functions in immunological and neurological ailments, such as allergic reactions, asthma, atopic dermatitis, and inflammatory bowel disease (Koontz et al., 2019). Several studies have exhibited the microbiome’s usage as a predictor of health and disease. The constituent of gut microbiota is a novel indicator of BMI, blood glucose extent, cholesterol amount, and cardiac health than genetic components (Rothschild et al., 2018). The contents of the microbiota of amniotic fluid is an indicator of preterm birth and chorioamnionitis (Urushiyama et al., 2017). The gut microbiota constituents are predictive of hospitalization incidence and disease seriousness in patients with cirrhosis (Bajaj et al., 2018). These studies explain that our microbiota play a vital role as the first line of defense against disease and also as a predictor of health condition and disease sensitivity.

Microbiome regulation of toxicity Microbes naturally have the capability to interact with and metabolize components, and hence it is not surprising that they are playing such roles in the human body. Five major groups of bacterial

Xenobiotics in Chemical Carcinogenesis

Microbiome regulation of toxicity

metabolizing chemicals have been explored: azoreductases, nitroreductases, b-glucuronidases, sulfatases, and ß-lyases; however, other activities exist (Claus et al., 2016). Evidence indicates that the metabolism of environmental factors by enzymes of the host’s microbes influence the toxicity of components to the host (Claus et al., 2016). The first process by which toxicity can be altered is by enzymatic alteration of chemicals to a form that is more or less toxic. Several reports explain that intestinal microbes metabolizes xenobiotics compounds more potentially in comparison to other organ (Koontz et al., 2019; Scheline, 1973; Sousa et al., 2008). Bioavailability modification of chemicals is a second process through which the microbes might influence the toxicity, synthesizing the toxin more or less available to the human body. A third method through which the microbes might alter toxicity is intervening with the host’s detoxification processes. The interactions of the gut microbes with the host’s endogenous detoxification enzymes have not yet been widely explored; hence, further studies are required to explain the effect of the gut microbes and endogenous xenobiotic metabolism (Claus et al., 2016). The potentiality of microbial life to decrease the toxicity of chemicals has been concomitantly exhibited via several bioremediation approaches. There are about 1200 compounds, 800 enzymes, approx. 1300 reactions, and almost 500 microbes entries have been enlisted in the University of Minnesota Biocatalysis/Biodegradation Database which explain such concept (Gao et al., 2009). However, these instances do not have direct results that such reactions are happening inside the human body. Human gut microbes interact with around 40 distinct drug substrates, by metabolizing, sequestering, or modifying the substrate, explaining that they might have an effect on the metabolism of the host (Wilson & Nicholson, 2017). The most studied work having attention at microbiome regulation of xenobiotics inside

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the human body is the circumstances of the metabolism of xenobiotics chemicals in the gut (Sousa et al., 2008; Tralau et al., 2015). The data on MMT (microbiome modulation of toxicity) outside of pharmaceutical components are scattered, however they suggest that human microbiota is modulating the toxicity of xenobiotics compounds by modifying the parent chemicals. A study on polyaromatic hydrocarbons such naphthalene, phenanthrene, pyrene, and benzo(a) pyrene, revealed that colon bacteria produced estrogenic metabolites from such chemicals (Van De Wiele et al., 2005). Other groups characterized bacteria from skin that completely degraded benzo(a)pyrene (Sowada et al., 2014), but certain intermediate metabolites might have more toxicity impacts (Tralau et al., 2015). Impacts of the gut microbes on the host detoxification compartment have also been explored that might result in MMT. Two direct pathways have been elucidated: (1) microbial metabolites leading controlling the phase I and phase II enzymes and (2) interruption of host excretion pathways by elimination of phase II conjugates in the intestines (Koontz et al., 2019). An instance of microbe-isolated metabolites impacting host-associated detoxification mechanism had been revealed, thereby dietary polyphenols distinctively affected expression of many phase I and phase II enzymes in germfree rats in comparison to rats with flora of a human donor (Lhoste et al., 2003). Chemicals which are conjugated in the liver by phase II enzymes are released in the bile to the intestines. Now, it is understood that bacterial enzymes cause deconjugation of chemicals, supporting them to be reabsorbed. Such a mechanism is known as enterohepatic circulation and is thought of as a normal process (Clemente et al., 2012; Ridlon et al., 2006). Alterations in the frequencies of such deconjugation owing to differentiations in the microbiome, might highly influence the biological half-life of a chemicals and, subsequently, its toxicity.

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12. Biotransformation of toxic xenobiotics by human gut microbiota

The metabolome of microbes The metabolome of an individual is also affected by the symbiotic gut microflora or microbes. The metabolome of an organism has metabolites which are synthesized via the activity of the gut microbes, and metabolism by such microbes might directly impact the metabolome of the host. For instance, the hippurate and phenylacetyl glycine have been observed in the urinary metabolome and are produced from the microbial degradation of bigger dietary phenols and phenylalanine, respectively. They usually respond to small perturbances to the host’s environmental circumstances. The gut microflora is related with diseases like inflammatory bowel disease, obesity, and diabetes. The gut microflora impact immunity and anaerobic metabolism of peptides and proteins, are a protective shield against pathogens, and affect the formation of intestinal microvilli of the individual (Johnson et al., 2012). Most significantly, in regard to metabolomics, gut microflora plays a vital role in the metabolism of xenobiotics compounds. The major reactions like: dehydroxylation, decarboxylation, dealkylation, dehalogenation, and deamination have been explored as gut microflora-regulated reactions (Wilson & Nicholson, 2009). They impact the xenobiotic metabolite pool in organisms, and such impact might have critical outcomes for toxicity. The stability of gut microflora could be altered by xenobiotics compounds, mainly digoxin (Lindenbaum et al., 1981) that enhances sensitivity to enteric infections (Sekirov et al., 2008). The certain antibiotic remedy perturbs the gut microflora equilibrium and influences several metabolic events like those participated in bile acid formation and steroid metabolism (Antunes et al., 2011; Johnson et al., 2012). Other xenobiotics, such as those in dark chocolate, pomegranate by-products, and probiotics, have been shown to regulate the gut microflora aura (Johnson et al., 2012). The view of a metabotype covers all the genetic, environmental, and gut microflora

alterations that are not significantly observable and provides each organism a metabolomic fingerprint. The concept of metabotype had been first accepted and described as “a probabilistic multiparametric explanation of an individual in a provided physiological condition associated with assessment of its cell types, biofluids or tissues” (Gavaghan et al., 2000). The genetic and environmental components may impact each other and provide interindividual differentiation and hence a unique metabotype. Therefore, the metabotype is an essential aspect relative to the impact of xenobiotic compounds in organisms.

Function of gut microbes in cellular physiology The human body contains 1014 bacterial cells that are 10 times more than the number of cells in the body. In humans, the colon has a maximum microbial density and species populations (1011 cells g21 of feces) (Chattopadhyay et al., 2021). Facultative anaerobes are present in the colonic mucosa while obligate anaerobes are found in the lumen because distinctive oxygen stress in the colonic part (Albenberg et al., 2014). The decreased oxygen stress in the colon supports the growth of specially Bacteroidetes and Firmicutes that is followed by Actinobacteria and Verrucomicrobia (Tomazetto et al., 2018). The colon is known to be a supportive niche for the growth of bacteria owing to its increasing pH, nutrients, and low amount of bile salts and pancreatic secretions (Kahouli et al., 2013). Lipopolysaccharide (LPS) of gram-negative bacteria stimulate the activity of innate immunity that protects inflammation (Liang et al., 2018). Anaerobes like Bacteroides, Eubacterium, Bifidobacterium, Fusobacterium, Peptostreptococcus, and Atopobium are highly ample in the gut while facultative anaerobes like Lactobacilli, Enterococci, Streptococci, and Enterobacteriaceae present a small part of the gut microbiota (Peterson et al., 2008).

Xenobiotics in Chemical Carcinogenesis

Gut microbial interactions with xenobiotics

The gut microbiota had a relevant function in mucosal homeostasis of the host and modulation in activity of the epithelial hurdle in the gut (Shreiner et al., 2015). The constituents of host microbiome in the gut is controlled by diet, medications, as well as lifestyle components like smoking, drinking, and physical activities (Saus et al., 2019). It has been observed that the ratio of Firmicutes to Bacteroides was greater in human following a western-style diet (Microbial Interactions and Interventions in Colorectal Cancer, 2017). Commensal microbiota of the gut is participated in the breakdown of nutrients, elimination of xenobiotics, colonization inhibition of pathogenic microbes, differentiation of epithelial cells, and formation of immune cells in the gut (Goubet et al., 2018). In the gut, Gramnegative Bacteroidetes and Gram-positive Firmicutes are usually found in maximum number. The ratio of Bacteroidetes and Firmicutes is changed because of food habit and alterations of intestinal microenvironment like the extent of pH and oxygen (Bevins & Salzman, 2011). People adopting a habit of intake of maximum protein and fat revealed a maximum communities of Bacteroides, while people following a habit of carbohydrate-rich diet had higher intake of Prevotella (Wu et al., 2011). SCFAs like acetate, propionate, and butyrate are formed by Bacteroides, Bifidobacterium, Clostridium, Lactobacillus, Prevotella, and Propionibacterium. Butyrate stimulates the anti-inflammatory potential of macrophages and dendritic cells. It also induces production of anti-inflammatory cytokine IL-10 from the Tregs and T cells. Probiotic- and prebiotic-rich food increases the extent of Bifidobacterium and butyrate-forming bacteria which play a crucial role in intestinal homeostasis. IL-33 and TGF-β stimulate production of IgA from B cells. Intestinal IgA aids against enteric microbes and toxins. IL-33 stops IL1αdependent CAC formation via the stimulation of the IgA-microbiota axis. Siderophore-binding antimicrobial protein Lipocalin 2 (LCN2) in the gut suppresses the development of colitogenic

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microbiota (Yang & Jobin, 2017). Gut microbes contain NAD(P)H dehydrogenase (azoreductase), nitroreductase, β-glucuronidase, β-glucosidase, and 7-α-dehydroxylase which trigger for cancer development (Plotnikoff, 2014).

Gut microbial interactions with xenobiotics The interaction of maximum human microbiota-xenobiotic is accomplished inside the GI tract. Several parts of this organ system differ in epithelial cell physiology, pH, oxygen extent, and nutrient amount; hence, providing different habitats for microbes and impacting several metabolic events which happen. Hundreds of different microbial species make colony in the human gut. However, the obligate anaerobes like Firmicutes and Bacteroidetes phyla usually dominate, large differentiation in community architecture has been seen among individuals (Koppel et al., 2017). Microbial transformation of xenobiotics is known with respect to the constant and often competing metabolic events happening in the human host. Orally consumed chemicals move via the upper GI tract to the small intestine; thereby, it could be altered by digestive enzymes and engrossed by host tissues. Immediately absorbed xenobiotics compounds move between or via intestinal epithelial cells, where it might be metabolized by host enzymes prior to transport to the liver through the portal vein. Excessive exposure to the liver’s rich assemblage of metabolic enzymes, xenobiotics, and their metabolites move into systemic circulation, affecting tissues and highly impacting different organs. Opposite of this, intravenously injected chemicals circumvent this “first-pass” metabolism and are frequently entered directly into systemic circulation. Chemicals in the circulatory system are finally then transformed and/or excreted that usually happens either through the biliary duct back into the gut lumen (biliary excretion)

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or via the kidneys into the urine. Metabolites moving back to the gut lumen could either progress on to the large intestine, where it would finally be excreted in the feces, or it could highly be reabsorbed by host cells in the small intestine via a mechanism referred as enterohepatic circulation (Koppel et al., 2017). Therefore, xenobiotics chemicals encounter gut microorganisms through several pathways. In contrast to chemicals that are absorbed in the small intestine, less absorbed xenobiotics continue via the small intestine into the large intestine and might be metabolized by gut microbes. The frequently absorbed components and compounds injected through other pathways that is, intravenous injection could also move to gut microbes via biliary excretion. The output of gut microbial metabolism could be engrossed by the host and transported systemically or interact nearby with the epithelial cells of GI tract. Finally, such microbial metabolites are secreted in feces or permeated by the kidneys and removed in the urine. Conclusively, human and microbial interactions produce a complex intertwined metabolic network which impacts both the host and the difference species of the microbiota (Koppel et al., 2017).

The complementary chemistry of microbial xenobiotic metabolism Within the different and complicated ecology of the human gut, microbes convert consumed compounds through a wide range of enzymatic reactions. Gut microorganisms usually employ the hydrolytic and reductive reactions to metabolize xenobiotics chemicals (Sousa et al., 2008), most of which are different to such organisms. This is entirely different to host enzymes that usually employ the oxidative and conjugative chemistry. Such slight differences are due to physiological aspects, although they also response different evolutionary pressures. Moreover, it is possibly that

particular gut microbial enzymes had not evolutionarily recruited to process the particular xenobiotics, instead of that metabolism generated from relaxed substrate specificity. Hence, the integrated metabolisms of host and microbiota produces metabolites that will not be formed by the host alone and could substantially modify the bioactivities and lifetimes of xenobiotics compounds inside the human body. Several enzyme groups related with xenobiotic metabolism that is, hydrolases, lyases, oxidoreductases, and transferases and emphasized here are largely attributed among sequenced gut microbes (Koppel et al., 2017; Martı´nez-del Campo et al., 2015). Metagenomic assessment have also shown them to be among the highly common protein families in such environment (Ellrott et al., 2010; Kurokawa et al., 2007). Hence, it is readily assumed that several essential transformations of xenobiotics might be achieved by multiple distinct phylogenetic classes of gut microorganism. However, it is crucial to consider that wide annotations are unpredictive of substrate specificity, as enzymes with large sequence similarity could catalyze different chemical reactions. Metabolic action could also be randomly attributed to closely associated strains and collected through horizontal gene transfer, where synthesis is problematic to interacting with gut microorganism metabolic capacities from phylogenetic assessments alone. Such issues focus the importance of culture-based experiments and meticulous biochemical identification of gut microbial enzymes in unraveling the xenobiotic metabolism.

Metabolization of environmental chemicals by GI microbiota GI microbes have been known for decades to play a major role in the biotransformation of xenobiotics chemicals. It has been explained that the efficiency of the GI microbes to metabolize the foreign chemicals was at least similar

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Metabolization of environmental chemicals by GI microbiota

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TABLE 12.2 Interplaying of pollutants with human gut microbiota. Chemicals

Source

Metabolism by microbes

PAHs

Air and food contaminants from insufficient ignition of fossil fuels, tobacco

Hydroxylation, deconjugation of liver metabolites, participated in the synthesis of CH3S-metabolites

Nitro-PAHs

Air and food pollutants, derivatives of PAHs

Reduction to amine metabolites

Nitrotoluene Dyes, chemicals, explosives

Reduction to amine metabolite and hydrolysis of glucuronide conjugates

Pesticides

Dechlorination of organochlorides.

Contaminants in air and food

Deconjugation of propachlor PCBs

Industrial chemicals and soils

Bacterial C-S-lyase involve in generation of methyl sulfone (MeSO2)-metabolites

Metals

Environmental pollutants

Participate in demethylation of mercury, methylation of arsenic and bismuth

Azo dyes

Food colorants

Azoreduction of the azo group to form aromatic amines

Melamine

Highly implicated in plastics, illegitimate food pollutants

Metabolized to cyanuric acid

Artificial sweeteners

Food additives

Cyclamate metabolized to cyclohexamine

PAHs, Polycyclic aromatic hydrocarbons; PCBs, polychlorobiphenyls.

to the liver (Scheline, 1973). About 40 drug chemicals have since been explored for the GI microbes (Claus et al., 2016; Haiser & Turnbaugh, 2013), emphasizing the capability of gut microbiota to work different chemical transformations on xenobiotic molecules like reduction, hydrolysis, the elimination of a succinate group, dehydroxylation, acetylation, deacetylation, the breakage of a N-oxide bounds, proteolysis, denitration, deconjugation, thiazole ring opening, deglycosylation and demethylation (Table 12.2). Currently the significance of the bioremediation literature has been noted; especially with respect to the metabolism of environmental factors (Haiser & Turnbaugh, 2013): an archive of biocatalytic reactions of microbes on environmental hazards presently lists about 1500 reactions performed by 529 microbes impacting some 1369 compounds (Gao et al., 2009). Microbes in the human gut are less diverse in

comparison to soil environments (Gans et al., 2006), although these outcomes still explain that the GI bacteria might have a significant, yet underrated, potential to metabolize environmental compounds. The GI tract is the major path through which xenobiotics enter the human body. The frequency and level of bacterial metabolism is affected by the quantities of xenobiotics arriving the distal gut, thereby number of bacteria is maximal. Environmental chemicals might be poorly absorbed after consumption, consequently being cleared to the distal small intestine and cecum by peristalsis. In another way, they or their metabolites might force their way from the blood and through the intestinal wall. Therefore, several chemicals are directly metabolized by the GI microbes (Fig. 12.2). Environmental compound/or their metabolites might also be released in the bile. Maximum xenobiotics compounds are

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12. Biotransformation of toxic xenobiotics by human gut microbiota

FIGURE 12.2

Xenobiotics compounds and the GI microbes’ interplay through several events. (A) Xenobiotics compounds which are less absorbed upon ingestion are transported to the small intestine and cecum by peristalsis, where it is directly metabolized by the GI microbes. (B) Maximum xenobiotics are nonpolar and hence highly absorbed from the GI parts, next circulated by the blood to the liver for detoxification. The liver contributes to oxidize xenobiotics, synthesizing conjugates with glucuronic acid, sulfate, or glutathione which are released in the bile and transfer to the intestine where microbe’s metabolism occur. The GI microbes usually deconjugates and reduces the hepatic xenobiotic metabolites leading to the generation of nonpolar molecules of lower molecular weight that are highly reabsorbed. Microbe-regulated deconjugation of metabolites initially conjugated by the liver resynthesize the parent xenobiotic or produce new toxic metabolites. (C) Xenobiotic compounds also interact with the composition of the GI microbes that cause to harmful impacts for the host. (D) Pollutants also modify the metabolic function of the GI microbes that impact the function of endogenous metabolites or the toxicity of other xenobiotics which is based on gut microbes for their metabolism (Claus et al., 2016). GI, Gastrointestinal.

nonpolar and hence absorbed in the GI tract and carried by the portal blood to the liver for detoxification. The liver usually oxidizes xenobiotics and forms glucuronic acid, sulfate, or glutathione conjugates. In other cases, conjugation reactions entice excretion and conjugates are removed in urine. Although conjugates may also be in the bile. The components which elucidate whether a chemical is released into bile are not completely

explored, a common rule is that low molecular weight chemicals (325 kDa) are abysmally released into bile, while chemicals with higher molecular weight (4325 kDa) could be easily excreted (Rafii et al., 1990). Conjugates released into bile move toward the small intestine a place where their absorption from the GI tract highly differ. Those are not absorbed further go toward the large intestine where they might be

Xenobiotics in Chemical Carcinogenesis

Metabolization of environmental chemicals by GI microbiota

metabolized by the microbes. The GI microbes contribute to deconjugate and decrease hepatic xenobiotic metabolites, causing in the generating of nonpolar compounds of lower molecular weight that are easily reabsorbed. The reabsorption of such nonpolar chemicals into the liver are known as “enterohepatic circulation.” Enterohepatic circulation regulates the storage and reimplication of endogenous compounds in the body like the bile acids and steroids. However, it also suspends the removal of environmental components from the body.

Metabolism of environmental chemicals by the GI microbes Polycyclic aromatic hydrocarbons Polycyclic aromatic hydrocarbons (PAHs) are one of the most widespread organic contaminants produced by the partial combustion of carboncontaining fuels and are present in tobacco smoke, urban-air material, diesel exhaust, and certain food products like grilled and smoked meat. The toxicity effect of PAHs is structural-based; some have estrogenic potential and some have been characterized as human carcinogens. Adult exposure to PAHs is related with more incidences of lung and bladder cancer (Bosetti et al., 2007). The estrogenicity of four PAHs that is, naphthalene, phenanthrene, pyrene and benzo(a)pyrene has been assessed prior to and after digestion by common human microbes (Van De Wiele et al., 2005). However, parent PAH molecules were not estrogenic, and the colonic digests exhibited a potential estrogenic activity. Hydroxy-PAHs, especially 1OH pyrene and 7-OH benzo(a)pyrene had been recognized as estrogenic metabolites. This explains that the microbes found in the human colon could bioactivate PAHs by transforming them to estrogenic components. Moreover, rat and human gut microbes can also reproduce benzo(a)pyrene from its hepatic conjugate, reversing the endogenous detoxification event of highly toxicological significance (Renwick & Drasar, 1976).

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Nitrated PAHs or nitro-PAHs Nitro-PAHs are synthesized by the nitration of PAHs. Humans are usually exposed via inhalation of nitro-PAHs from urban-air matter and diesel fuel exhalation. Nitro-PAHs exhibit a wide array of mutagenic, genotoxic, and carcinogenic effects. They are usually metabolized by the human organism by GI microbes (Moller, 1994). 2-Nitrofluorene (NF) is one of the major components of nitro-PAHs in the environment and it has been elucidated as a model compound for nitro-PAHs. In vitro, incubation of human feces with NF eliminated the directinvolving mutagenicity of NF (Hirayama et al., 2000). In vivo, NF administered by conventional rats was converted to 2-aminofluorene through the intestinal bacteria, acetylated, and finally hydroxylated in the liver. Such metabolic pathways are quantitatively significant and lead to the generation of hydroxylated 2-acetylaminofluorene (Mo¨ller et al., 1988). Other metabolic pathways lead in the production of hydroxylated nitrofluorenes that are involved in direct mutagenic effects (Mo¨ller et al., 1988). Comparative studies of NF metabolism in GF and conventional rats explained that, after consumption, the mutagenic effect of urine from GF animals was six times greater than the one derived from conventional animals. It has been revealed that such impacts are usually because of the presence of hydroxylated-NF and the absence of hydroxylated acetylaminofluorene (Mo¨ller et al., 1988). So, GI bacteria plays a vital role in preventing the host from the production of mutagenic metabolites of NF. Although, if comparing the efficiency of NF to produce DNA adducts in mice with or without microbes, none had been detected in GF mice, while DNA adducts had been observed in the liver, colonic epithelium, and kidney of all types of mice hosting a microbes (Hirayama et al., 2000). The synthesis of DNA adduct is known as a crucial step in the progression of

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cancer and might be employed as an in vivo biomarker of cancer incidence. Such GI microbiota underlying enhance in DNA adduct synthesis may be associated with the nitroreduction of NF through the bacteria, since 2-acetylaminofluorene is identified as a potential carcinogen to stimulate DNA adducts. Nitrotoluenes Nitrotoluenes are essential intermediate components in the synthesis of dyes and plastics. It has been explained that 2-nitrotoluene has genotoxic potential and 2,6-dinitrotoluene has hepatocarcinogenic potential in rats (Claus et al., 2016; Rickert et al., 1984). After administration of a single oral dose of 2,4-dinitrotoluene, conventional rats released four main metabolites like 2,4-dinitrobenzoic acid and 2,4-dinitrobenzyl glucuronide, produced from oxidation then glucuronidation of the parent components, respectively, and 4-N-acetyl-2nitrobenzoic acid and 2-amino-4-nitrobenzoic acid, as outcomes of nitroreduction and oxidation, respectively. These final products of two metabolites were hardly observed in GF rats, explaining that the GI microbes is highly accountable for the nitroreduction of 2,4 dinitrotoluene (Guest et al., 1982). Human fecal samples also reduce 2,4-dinitrotoluene. However, the genotoxicity potential of 2-nitrotoluene and 2,6-dinitrotoluene is because of a product of (di) nitrobenzyl alcohol reduction despite of reduced metabolites and the gut bacteria has an essential function in this toxicity: both 2-nitrotoluene and 2,6-dinitrotoluene are engrossed in the small intestine and converted by the liver to 2-nitrobenzyl alcohol and 2,6-dinitrobenzyl alcohol. Such components are conjugated with glucuronic acid prior release in the bile. Further, the bound glucuronide is hydrolyzed by the GI microbes which further reduces one or both of the nitro compounds. The amino derivatives are finally reabsorbed and oxidized in the liver thereby covalently attaching to DNA (Claus et al., 2016).

Pesticides Pesticide is a common term that includes herbicides, fungicides, insecticides, and antimicrobials. Thousands of compounds are employed as pesticides, and human exposure to such pesticides is highly prevalent. The most commonly used chemical groups are organochlorines, organophosphates, carbamates, triazines, and pyrethroids. Even though the function of gut microbes on their metabolism is not known, various chemicals have been connected with microbial metabolism. The use of dichlorodiphenyltrichloroethane (DDT), an organochlorine insecticide, is presently prohibited in many developed countries. However, DDT is highly persistent and its harmful effect is yet widespread. DDT exhibits estrogenic and antiandrogenic potential in several tissues (Kim et al., 2014). DDT exposure has been related with enhanced incidence of breast, liver and testicular cancers and metabolic disorders (Claus et al., 2016). Rat and human GI feces metabolize DDT to dichlorobiphenyl dichlorophenylethane (DDD) (Mendel & Walton, 1966). In vivo, DDD had been observed in rats taking DDT by stomach tube (Mendel & Walton, 1966), explaining the likely participation of GI microbes in DDT metabolism. However, it is still not clear whether such biotransformation is involved in bioactivation or detoxification, as both DDT and DDD are known as endocrine disruptors in humans. Propachlor is an acetamide herbicide whose manufacturing was banned 1998. The continuous treatment of propachlor-stimulated cancer at single sites in rats has been studied (Dearfield et al., 1999). Propachlor is metabolized by the rat GI microbes following the biliary release of glutathione and cysteine bindings of the parent chemicals (Gustatsson et al., 1981). Glutathione conjugation prevent propachlor-stimulated cytotoxicity in hepatocytes (Dierickx, 1999); hence, the deconjugation of conjugates by GI microbes is anticipated to enhance propachlor toxicity.

Xenobiotics in Chemical Carcinogenesis

Effect of environmental chemicals on the activity of GI microbes

Polychlorobiphenyls Polychlorobiphenyls (PCBs) produce 209 highly existent compounds. Since its first commercial implication in the late 1920s, about more than one million tons of conventional PCB mixtures have been synthesized throughout world. Environmental exposure to PCBs causes for an incidence of breast cancer, negative reproductive results, slow neurodevelopment, disability of the immune system and metabolic perturbance (Claus et al., 2016). The synthesis, transforming and distribution of PCBs have been banned in many industrialized countries since the late 1980s, however they are still being discharged into the environment, via insufficient disposal approaches or leaks in electrical instrument and hydraulic apparatus. Human exposure to PCBs happens mainly through consumption of contaminated food, but also through inhalation and dermal absorption. The first event in the metabolism of PCBs is stimulation by oxidation catalyzed by hepatic cytochromes P450, causing to the synthesis of an arene oxide intermediate. Two more metabolic mechanisms have been explored in mammals: hydroxylation to form biphenylols and metabolism via mercapturic acid pathways that synthesize methyl sulfone (MeSO2) metabolites (Claus et al., 2016). The main metabolic pathway is hydroxylation mainly followed by excretion. However, relevant levels of MeSO2 metabolites of PCBs concentrates in tissues: the arene oxide intermediate is integrated to glutathione, the glutathione conjugate is broken down to produce a PCB-cysteine conjugate that could be then cleaved by a bacterial C-S-lyase enzyme, causing the production of a PCB thiol. Such thiol could be methylated to a PCB methyl sulfide (MeS-PCB) in the GI tract, absorbed and oxidized to the MeSO2-PCB in the liver. Hence, the gut microbes have an essential function in the production of MeSO2-PCB. If injected with 2,40 ,5-trichlorobiphenyl, the extent of

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radioactivity was 15 times greater in the adipose tissue, lung, kidney and liver of animal models because of the accumulation of MeSO2triCB. Bacteria-regulated metabolism of PCBs to MeSO2-PCBs is toxicologically significant as they integrate to certain proteins and concentrate in lipophilic tissues. In humans, they accumulate in the liver, lungs, and adipose tissue and might cause the chronic lung disorder symptoms seen as a mass food-poisoning risk (Claus et al., 2016).

Effect of environmental chemicals on the activity of GI microbes The constituents, variations and enzymatic potential of the gut microbes are highly influenced by several environmental components like the host’s lifestyle, diet and implication of antibiotics. Various environmental chemicals have also been shown to suppress GI bacterial growth or stimulate dysbiosis in vitro and in vivo conditions, as the above explanations stated that dysbiosis of the gut microbes has been associated with an array of intestinal and systemic diseases (Ba¨ckhed et al., 2012). Interestingly, several disorders have also been related to exposure to environmental components. For instance, there has been an extensively enhance in the prevalence of allergic issues like asthma and food allergies in the last few years. Present result describes that both changes of microbial colonization while the perinatal time and early-life exposure to environmental component might stimulate dysregulated immune reactions (Claus et al., 2016; Menard et al., 2014). Hence, it is appreciable that exposure to chemicals might influence the normal colonization of the gut microbes, with impacts on host physiology later in life. Hence, chemical-stimulated alterations of the composition of the GI microbes might develop an underestimated pathway through which they interact with human health.

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Pesticides Glyphosate is the effective chemical of Roundup (Montsanto, St Louis, MO, United States), the most widely used herbicide over world. It has been revealed that the growth of Enterococcus faecalis bacteria derived from cattle and horse feces is suppressed by the lowest amounts of glyphosate and the herbicide conceptualization investigated (Kru¨ger et al., 2013). Several studies explained that sensitivity to glyphosate is based on the bacterial strain. Mainly, in poultry, pathogenic bacteria like Salmonella enteritidis, S. gallinarum, S. typhimurium, Clostridium perfringens and C. botulinum have more resistant toward glyphosate, while advantageous bacteria like E. faecalis, E. faecium, Bacillus badius, Bifidobacterium adolescentis and Lactobacillus sp. are slightly to highly susceptible (Shehata et al., 2013). It had been described that glyphosate stimulated same dysbiosis in mammals, further this will be of toxicological significance owing to it will cause to an inhibition of effective beneficial bacteria in the GI tract. Chlorpyrifos, an organophosphate insecticide, is generally employed to treat fruit and vegetable crops and vineyards. The impact of chronic exposure to chlorpyrifos has been examined in an in vitro inducer of the human GI tract inoculated with feces of healthy humans, and in vivo in rats exposed from in utero up to 60 days old (Joly et al., 2013). Exposure to chlorpyrifos stimulated dysbiosis of the microbial community, which had been related with growth of Bacteroides sp., and reduced levels of Lactobacillus sp. and Bifidobacterium sp.

Other organic pollutants The continuous use of organic pollutants is largely resistant to environmental and biological deterioration and hence exist in the environment and concentrate in the food chain. The persistent organic pollutants are ligands of the aryl

hydrocarbon receptor (AhR) that regulates the harmful impacts of such components. Currently, it has been understood that the major function of AhR activation in stimulating the toxic impact of 2,3,7,8-tetrachlorodibenzofuran (TCDF) on gut microbes employing AhR-/- mice administered a diet enriched with TCDF (0.6 μg kg21 day21) for 5 days (Zhang et al., 2015). TCDF regulated the balances of gut microbes by largely reducing segmented filamentous bacteria in the ileum of AhR 1 / 1 but not in AhR 2 / 2 mice. TCDF also reduced the Firmicutes/Bacteroidetes ratio in an AhR-dependent way. Such alterations had been done by highly metabolic variations in the feces, cecal level, liver and gut tissues between TCDF-treated and control AhR 1 / 1 mice, while TCDF had no impact on the metabolic profiles of AhR 2 / 2 mice. Mainly, TCDF reduced glucose and oligosaccharide level and enhanced the contents of SCFAs (butyrate and propionate) in feces and cecal level, consistent with a stimulation of bacterial fermentation. Such results describe that exposure to persistent organic pollutants has largely affected on the host-microbes metabolic axis, via the stimulation of AhR signaling. In addition, this study implicated the increased doses of TCDF, so it has to be explained whether identical alterations are determined at environmental levels of exposure.

Factors affecting the rate and level of gut microbes in xenobiotic metabolism Xenobiotics are considered as candidate substrates for processing when they are not absorbed perfectly, accordingly formulated, or indirectly arrive the colonic lumen following biliary excretion that is also a pathway via which intravenously administered drugs could be a subject to chemical conversion by gut microbiota. Regarding the rate and level to which drugs would be exposed to direct microbes metabolism, there are innumerably

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more components that must be considered (Hall et al., 1999). Maximum orally administered drugs usually accumulate in the upper small intestine, the main absorptive site of the intestine, considering that the drug is largely soluble and more permeable in this part. However, several drugs exhibit poor solubility that cause to moderate and inadequate absorption with the drug being accumulated from distal sites of the small intestine and colon. Drugs with less permeability via the intestinal membrane, or drugs which are subject to efflux by typically integrated efflux proteins like p-glycoprotein, could increase period of drug residence inside the intestine, with higher quantities of those drugs moving distal part of the intestine (Hall et al., 1999). Eventually, it should also be explored that however microbial community is lesser in the small intestine, this should not cause to the implicit presumption which would have some effect on the drugs predominantly accumulated in this site. On the other hand, intestinal CYP enzymes are found in the intestine, although expressed in highly lower extent than the liver, intestinally regulated CYP metabolism could be the main region of drug metabolism (Hall et al., 1999). For instance, cyclosporine is metabolized up to half by intestinal CYP enzymes (Benet & Cummins, 2001), explaining that relatively low concentrations of enzymes in the small intestine can still show effects of orally taken drugs. This is essential in the condition that is based on fecal microbes analysis, where comparatively little has been explored about the microbes of the less detectable small intestine (Aidy et al., 2015). Oral administration of modern drug formulations proposed for extended secretion, like sustained release tablets, is on the rise, bypass absorption profiles which will mainly limit exposure of several drugs to the colonic gut microbes. Such a methodology has become more familiar, especially for the more potential treatment of neuropsychiatric ailments, though, instead of the

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increasing the economic life cycle of drugs, such altered release formulations also enhance the horizon for drug-microbiome interactions (Enright et al., 2016), and this has been rarely evaluated for its involvement in bioavailability. In contrast to the fundamental objective of host metabolism, biochemical alteration of exogenous chemicals by gut microbiota is not constantly regulated toward removal of such foreign components. Once a component undergoes for microbial metabolism, there are a several aspects which assess its fate and the level to which it goes through biotransformation. Similar to the host, these are appraised in regard of interindividual and intraindividual differentiation (Kra¨mer & Testa, 2009). Individual-specific genetic makeup of the host genome describes certain variations in drug metabolism, and host-genetic impacts on gut microbes constituents (Rothschild et al., 2018) are also possibly to play a role in impacting the rate and level of microbial xenobiotic metabolism. Microbial enzymes like b-glucuronidases, vary in substrate selectivity and functionality underlying on the bacteria from which they emerge (Pollet et al., 2017). Praiseworthy, interindividual variations in the myriad of a cytochrome-encoding operon, leading for the inactivation of the cardiac drug digoxin, have currently been elucidated, and such operon was peculiar to drug-metabolizing strains of Eggerthella lenta and was induced by the drug (Haiser et al., 2014). Other instances of inducible bacterial enzymes have the lac operon of Escherichia coli that has genes participated in lactose metabolism (Wilson et al., 2007), which is expressed only in glucose free condition where lactose is available. Presently, it is the limit is not clear as to which of these properties of inducibility, or in fact repression, is most significant for xenobiotic metabolism or if constitutive expression is the most common leading rule in the GI part. The components which have been explored to impact the distribution of the gut microbes

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like age and geography, also overlap with different drug pharmacokinetics and effect on the corresponding several genes coding for xenobiotic-metabolizing enzymes (Das et al., 2016; Quigley, 2017). However, studies indicate a stable array of main activities instead of such variable gut microbes profiles, real metabolic functionality of the gut microbes might divert from its functional capacity (Tanca et al., 2017). Owing to the functionality of gut microbes, it shows resilience in spite of the oscillating community and structure (Song et al., 2015), it is still unclear how much of the differentiation related with changes in the constituents and cohesivity of the gut microbes such as diet (Shanahan et al., 2017), leave their sign on the capability for xenobiotic metabolism. Although, it is noticeable that there are several instances of disease-related gut microbes like depression which changes in behavioral phenotypes and host physiologic properties if transferred into animal models (Kelly et al., 2016). The microbiomerelated metabolite phenylacetic acid has also been revealed to impact disease phenotype in nonalcoholic fatty liver ailments, causing to hepatic lipid accumulation (Hoyles et al., 2018). Host xenobiotic metabolism is affected by circadian rhythms (Ozturk et al., 2017), and this might also be fact of microbial enzymatic functionality due to gut microbes community structure and metabolic potentiality also peculiar biologic rhythms, controlled by diet and time of feeding instead of environmental 24-hour lightdark cycles (Johnson et al., 2017). Jet lag could perturb this diurnal microbial biology, a characteristic developed by changes in feeding patterns. Diurnal microbial behavior in turn is considered to impact the system of the colonic and hepatic circadian transcriptome through oscillating microbial metabolites with implications, for instance, for the hepatic detoxification of acetaminophen which was based on the timing of administration (Thaiss et al., 2016). This was related to differentiation in the number of mucosa-associated microbes in the mouse gut over the circadian

period that was 10 times greater while the dark phase than during the light condition. Circadian rhythm disturbance and appetite variation like carbohydrate hankering, are dominant in stresslinked psychiatric problems like major depression, that is also related with changes in gut microbes (Dinan & Cryan, 2017).

Advanced technologies for the identification of xenobiotic-degrading microbes The environmental pollution with a complex combinations of xenobiotics compounds has been a major environmental problem over world. Several xenobiotics chemicals highly affect the environment because of their potential toxicity, prolonged endurance, and less biodegradability. Microbial-induced degradation of xenobiotic chemical is known to be the highly effective and useful approach. Microbes have miraculous catabolic capacity, with genes, enzymes, and degradation mechanisms employed in the method of biodegradation. A large number of microorganisms like Alcaligenes, Cellulosimicrobium, Microbacterium, Micrococcus, Methanospirillum, Aeromonas, Sphingobium, Flavobacterium, Rhodococcus, Aspergillus, Penecillium, Trichoderma, Streptomyces, Rhodotorula, Candida, and Aureobasidium, have been derived and identified, and have exhibited tremendous biodegradation capacity for a different of xenobiotic pollutants from soil/water environments. Microbes highly use xenobiotic pollutants as carbon or nitrogen sources to retain their growth and metabolic functionality. The multiple microbial populations endure in stressful polluted environments, revealing a relevant biodegradation activity to degrade and convert contaminants. However, studies these microbial populations need a more modern and multiple methods. Presently, several advanced approaches like metagenomics, proteomics, transcriptomics, and metabolomics, were successfully implicated for the identification of contaminants-degrading

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Methods

microbes, their metabolic apparatus, novel proteins, and catabolic genes participated in the degradation mechanisms. Such technologies are largely complicated, and capable for acquiring knowledge about the genetic diversity and community constituents of microbes. The modern molecular technologies employed for the reorganization of intricated microbial communities provide an in-depth knowledge of their structural and functional concepts, and aid to solve problem associated to the biodegradation capacity of microbes (Mishra et al., 2021).

Computational method for the prognosis of species-specific biotransformation of xenobiotic compounds by gut microbiota The experimental approaches of metabolic profiling like nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) are used to detect the respective metabolic enzymes and microbes involving for the biotransformation of xenobiotic compounds. Although, the complicated and dynamic metabolic interactions between hostmicrobes and bacteria-bacteria have highly inhibited the experimental assessment of the species-specific role of gut microorganisms in the metabolism of xenobiotic chemicals. It has been again contradicted by the time-taking and exhausting nature of experimental approaches that have depth metabolic profiling of host gut microbes for every xenobiotic molecule. Hence, maximum orally taken drugs face to gut microbes prior to their absorption, the gut microbes’ species and the respective enzymes enable of their metabolism are not widely understood. In this aspect, a potential computational approach is needed to predict the microbial species and enzymes which can be employed in metabolization of toxic xenobiotics in the human gut (Sharma et al., 2017). Currently, some tools that are applicable for determining drug metabolism are associated with human phase-I: hydrolysis, oxidation and

reduction reactions, and phase-II (conjugation reactions) metabolic methods, namely MetaSite (Cruciani et al., 2005), Metaprint2D (Boyer et al., 2007), ADMET predictor, Metabolism Module simulations Plus (http://www.simulations-plus.com/), RS WebPredictor (Zaretzki et al., 2013) and FAME (Kirchmair et al., 2013). But there is no tool or computational method applicable to determine the biotransformation of xenobiotic compounds in human gut by the metabolic enzymes of gut microbes. An enzyme is able of functioning on chemicals that have structurally resemblance to their substrate, and this characteristic has been explored as promiscuity. So, the molecular characteristics of substrates of all identified metabolic enzymes of the gut microbes could be implicated to determine the metabolic enzymes and gut microbes that could highly perform the biotransformation of xenobiotic chemicals (Hult & Berglund, 2007; Sharma et al., 2017). Hence, it has been reported a novel approached generated by combining the cheminformatics and machine learning approach for the determination of the metabolic enzyme and the respective bacterial species enable of metabolizing a provided xenobiotic compound at the initial step.

Methods For the development of a tool to determine the gut microbial enzymes that can highly biotransform a xenobiotic compound, two major information are needed (1) a array of the identified metabolic enzymes of microbes with their EC numbers and (2) their respective substrate compound. The above knowledge is implicated for the designing of predictive machine learning random forest (RF) modules (Sharma et al., 2017). Approximately 491 available gut bacterial genomes sequences have been taken from various sources such as NCBI genomes (http://www. ncbi.nlm.nih.gov/genome/), HMP reference genomes (http://hmpdacc.org/reference_genomes/ reference_genomes.php) and EMBL-EBI bacterial

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genomes (http://www.ebi.ac.uk/genomes/). All efficient metabolic enzymes of every gut bacterial genome have been characterized and authorized with their respective four-digit EC employing the following approaches. The enzymatic protein sequences with their EC have been retrieved UniProt database (http://www.uniprot.org/uniprot/), and a standard database having the EC with their respective protein sequences has been designed. This database has been implicated as the reference database for performing the BLAST-linked protein alignment of all the proteins of several gut bacterial genomes. The best hit for a gut bacterial protein has been recognized employing the cut-of values of Identity .40%, Query coverage .80% and E-value ,10 2 15. The best hit can be recognized for 324,697 (12.39%) proteins among 1,571,442 total proteins, and the final protein sequences of metabolic enzymes has been authorized with a four-digit EC. The recognized metabolic enzymes with their EC and bacterial genome annotation have been merged together to synthesis a database of metabolic enzymes for the gut bacterial metagenome (Sharma et al., 2017).

Construction of gut bacterial substrate database For every bacterial metabolic enzyme, the metabolic reactions have been retrieved from the KEGG database (http://www.genome.jp/ kegg). The substrates for the above reactions have been merged and labeled with their respective EC number. For preparing the substrate database, cofactors and other aiding chemicals for enzyme activity like water, metal ions, ATP, etc. have been eliminated by manual creation and only the primary substrate compounds have been recruited. This has been obtained among 2324 molecules in the substrate database. Again, the substrate database has been comprised into subsets associated

with their respective EC tags. Such subsets have been referred as “EC class-specific databases and EC subclass-specific databases.” An all-against-all structural resemblance search has been carried out for all 2,324 molecules employing Open Babel (v2.3.2) to eliminate redundancy and select the representative molecules for exercising. This step was essential to generate a nonoverlapping training array that is a need for the advancement of RF classification models. Further, the substrates that can be metabolized by enzymes categorized into several EC classes have also been eliminated. Hence, among 2324 molecules, 1609 main molecules have been recruited for the development of the RF models that will be employed in predication of biotransformation of xenobiotics compounds by human gut microbial activity (Sharma et al., 2017).

Conclusion The multiple roles of gut microbes in human system during metabolism of toxic xenobiotics compounds are very complex. The reservoirs of enzymes for microbials have been enticed toward metabolism of xenobiotic compounds which might be unique from host metabolism. The metabolism of xenobiotics through microbial system leads to bioactivation, detoxification, or in other conditions cases with glucuronidases, which might even alter the host detoxification. The environmental chemicals also alters the composition and/or optimal activities of the human microbes, with high impacts on the health of the host. Hence, it has been envisaged that the gut microbes are a main player in the toxicity of environmental pollutants. However, there are several challenges to reduce in order to understand the extent of risk related with environmental chemicals in interaction with gut microbes. The modes of interaction between gut microbes and endogenous enzymes in detoxification of toxic xenobiotics must be explored. This is

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necessary to assess the effect of human gut microbes’ variations on endogenous xenobiotic metabolism and overall sensitivity to environmental factors. Future endeavors in toxicology require more studies of how toxicants of xenobiotics interplay with the microbes to completely explain how a single chemical would influence a diverse, real-world population.

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498. Available from https:// doi.org/10.1093/bioinformatics/bts705. Zhang, J., Empl, M. T., Schwab, C., Fekry, M. I., Engels, C., Schneider, M., Lacroix, C., Steinberg, P., & Sturla, S. J. (2017). Gut microbial transformation of the dietary imidazoquinoxaline mutagen MelQx reduces its cytotoxic and mutagenic potency. Toxicological Sciences, 159(1), 266
276. Available from https://doi.org/10.1093/toxsci/kfx132. Zhang, L., Nichols, R. G., Correll, J., Murray, I. A., Tanaka, N., Smith, P. B., Hubbard, T. D., Sebastian, A., Albert, I., Hatzakis, E., Gonzalez, F. J., Perdew, G. H., & Patterson, A. D. (2015). Persistent organic pollutants modify gut microbiota
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467. Available from https://doi.org/10.1038/s41586-019-1291-3.

Xenobiotics in Chemical Carcinogenesis

C H A P T E R

13 Mechanism of resistance to toxic xenobiotics in humans Introduction The presence of a myriad of exogenous xenobiotics in nature and endogenous toxic metabolic compounds entails that all organisms have molecular and cellular events to detoxify and release harmful molecules. Detoxification activities support survival even under adverse environmental circumstances. This is a basic biological concept from unicellular to multicellular organisms, like mammals and human beings (Efferth & Volm, 2017). In this case, the question is raised as to whether or not evolutionarily conserved detoxification mechanisms might be present that are able to identify and excrete various structurally and functionally different toxic chemicals. When organisms cannot envisage to which toxins and how often they would be exposed during their life span, these mechanisms have to carry out high range detoxifying activities to reliably prevent mechanisms from the harmful impacts of toxic compounds (Efferth & Volm, 2017). Every time, organisms have always been unmasked to naturally-sourced xenobiotic chemicals. For instance, host-plant resistance approaches usually use defensive secondary metabolites, referred to as allelochemicals like alkaloids (nicotine, caffeine, morphine, colchicines, strychnine,

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00011-X

and phenolics), to impact the behavior, growth, or endurance of herbivores. Herbivorous insects and mammals have generated typical protective defenses against the consumption of allelochemicals. For instance, Australian marsupials are naturally exposed to a different set of toxic xenobiotics that come from several plant sources like Eucalyptus terpenes. Marsupials exhibit various important xenobiotic processing pathways biochemically to increase terpene detoxification which is essential for survival with their different Eucalyptus-based diets (Kennedy & Tierney, 2013). The adaptive event of organisms has been modified (to several extents) to xenobiotic exposure of natural sources by developing chemical defense/ protective/resistance processes (Table 13.1). The comparatively present phenomenon of industrial pollution and the discharge of essential synthetic substances into the environment at greater levels and relatively short periods has not supported much evolutionary adaptation to synthetics. Many organisms depend on the elemental chemical defense process to guide against new chemical armaments. The substantial and catastrophic impacts of pollution on several species are noted in the incapacity of these defenses; however, in certain conditions the protection managed by these mechanisms does work uniformly well for anthropogenic substances. For instance, the Great Lakes

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TABLE 13.1 Potential mechanisms of resistance to xenobiotic compounds. Molecular alterations

Possible resistance events

Anticipated physiological impacts

Constitutive overproduction of a gene product:

Increased defense role

Distribution of resources

Diminishing the xenobiotics target

Loss of activity

Self-reliant or recognition compounds

“Aberrant” identification of compatible xenobiotic compounds

Recognition of other xenobiotic compounds

Cellular apparatuses or excreted components

Omission of xenobiotics to exploit host internal problems like carcinogenesis or to interact with defense events

Modified role

Membrane receptor

Altered xenobiotics target

Changed activity

Stimulating regulation of gene expression

Inducible defense

Possibly none

Gene amplification Gene overtranslation Constitutive underproduction of a gene product Mutations causing the structural modifications in:

and Puget Sound, WA, have high concentrations of PCBs, PCDDs, and PCDFs. Despite these chronic exposures at high concentrations that provide toxic effects to mammals and birds, populations of fish can thrive in highly polluted regions. However, species variations at such polluted regions are less, indicating apparent toxicity, with the exception of carcinogenesis, which is uncommon. It has been considered that populations ironically exposed to maximal or even moderate extents of such pollutants have originated or developed resistance processes to such xenobiotic chemicals (Wirgin & Waldman, 2004). There are two plausible ways by which organisms can decrease their sensitivity to xenobiotics: those that develop at the extents of the individual via adaptive methods (sometime known as tolerance) and those that occur at population levels of organisms in which the genetic composition of a population is altered to reflect the

chemical, so that a higher number of individuals are capable of combat in comparison to the unexposed population (often known as resistance). Acclimation is an individual process, thereby organisms can become highly tolerant as an outcome of an initial exposure via genetic or epigenetic events. Tolerance occurring via acclimation is not transferred over several generations, hence it is considered to abate when exposure is eliminated, for instance, in remediated environments (Kennedy & Tierney, 2013). Adaptation is the intergenerational genetically associated recruitment of highly resistant persons in the population, which leads to individuals contributing, comparatively, more offspring to consecutive progenies. For adaptation, resistant phenotypes should exist in sensitive populations prior to exposure, even at low frequencies. Upon remediation, adaptations might also stray from populations due to the elimination of selective

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Introduction

pressure, though this happens more slowly in comparison to acclimation processes. Heavy metal tolerance in plants are common instances and elucidate substantial alterations to susceptibilities across some generations. The formation of industrial melanism in moths is an instance of resistance which is highly cited as an instance of pollution as a selective pressure for evolution (Kennedy & Tierney, 2013). Insect resistance to pesticides has been a widely studied field because of its scientific, economic, ecological, and health consequences. Pesticide resistance is a common cause for failure in agricultural and pest management schemes. Resistance to insecticides was first described in 1914 by A. L. Melander for scale insects to an inorganic insecticide. From 1914 to 1946, 11 more other cases of resistance to inorganic insecticides were accounted. Since 1945, it has been determined that around 500 1000 species of pests have generated a resistance to a pesticide. It had been considered that the formation of organic insecticides like dichlorodiphenyltrichloroethane (DDT) will protect insecticide resistance; however, by 1947, DDT resistance had been revealed by houseflies. With the amendment of each new insecticide class: cyclodienes, carbamates, formamidines, organophosphates, pyrethroids, even Bacillus thuringiensis-cases of resistance have been over the past 2 20 years (Mallet, 1989). Xenobiotic resistance is also relevant in the field of human health. It is a main cause of failure in human treatment as antibacterial, anticancer, antipaludic, and anti—human immunodeficiency virus-1 (HIV-1) regimens. The process behind such resistance is conserved across bacteria, eukaryotic cells, parasites, and viruses (Saves & Masson, 1998). Models of the development of resistance to xenobiotics and pathogens sometimes share the core presumption that resistance is linked with a fitness outcome. Such a presumption is associated with three areas highly derived

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from evolutionary biology, population genetics, and physiology. First, the procurement of any adaptation to a new environment like resistance has several alterations compared to the previous phenotype(s). Since these phenotypes have been developed by several selection pressures to fit the distinct environments endured by one species, any wide phenotypic alterations are therefore disputed to be detrimental within the condition of the ancestral environment. Second, however genetically oriented resistance confers a selective benefit in the presence of either xenobiotics or pathogens, resistance genes are seldomly established in natural populations. Suppose that populations have attained an evolutionary equilibrium, such a balance of polymorphism is considered as an outcome from the presence of a counterbalanced selection pressure that reduces the frequency of the resistance gene in the paucity of the respective pesticide or pathogen. Third, the information of the physiological alterations participating in xenobiotic resistance has advocated hypotheses associated with changed activity of the linked proteins (Coustau et al., 2000). All fields of xenobiotic resistance like herbicides, fungicides, insecticides, antibiotics, and plant pathogens have investigated various functional elucidations (Coustau et al., 2000; Mauricio, 1998). Generally, alterations in receptors or enzymes have appeared as normal perturbations to their normal functions; however, overexpression of an enzyme or receptor may avert energy from other fitness-increasing activities. Conditions of animal resistance to parasites, however the particular physiological pathways participated in resistance are not much explored, maximum evolutionary literature is available on the core presumption of a pricey expenses in defense roles, causing to an agreement between resistance and other fitness-related properties. Particularly, the cost of resistance is sometimes expressed as the cost to balance the immune and/or defense

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apparatus that is needed to mount a fruitful immune reaction (Kraaijeveld & Godfrey, 1997). Since the cost of resistance is important to the organism’s ability to explore the nature of resistance genes, several studies have emphasized this anticipated tradeoff between resistance and other fitness-associated traits. Though several have explored the anticipated cost of resistance, others are not able to determine it altogether (Gemmill & Read, 1998). Many causes have been put forward to explain the failure to determine a cost. First, resistance costs may only be possible under a certain array of environmental circumstances that had not been in the experimental design. Second, the related antagonistic pleiotropy may not be statistically predictable (Fry, 1993). Third, and highly exciting, there may not be an actual cost of resistance (Elard et al., 1998)-this will likely deem most advance models to be inappropriate. Therefore, this chapter will explain the various events of resistance to toxic xenobiotics in humans including drug resistance in cancer.

Cellular adaptation to xenobiotics Cells counteract exposure to xenobiotic compounds by upregulating the production of the xenobiotic metabolism apparatus viz., of protein participating in the above-described stages of biotransformation. Such adaptive cellular reaction is likely because of the interplay of xenobiotics with signaling components and transcriptional regulators like “xenosensors.” Cellular structures are determined by xenobiotics, stimulating a cellular reaction, and might be broadly classified as xenobiotic sensors (xenosensors). However, this main term may be assigned to proteins less “accidentally” interplaying with their ligands (Klotz & Steinbrenner, 2017). Biotransformation accomplishes the production of reactive oxygen species (ROS) via several reactions both directly forming ROS as part of the corresponding reaction and indirectly as an

outcome of the products formed by transformation of a xenobiotic (Kehrer & Klotz, 2015). The formation of ROS is a normal event in biotransformation employing serial redox reactions and utilizing the presence of oxygen. Electron transfer to molecular oxygen would lead to the formation of superoxide and their derivatives like hydrogen peroxide. Such ROS are understood as modulators of cellular signaling events by interacting with signaling cascades at various extents like at the level of transcriptional regulators. In addition, cells are currently explored to utilize the intermediate generation of superoxide/ hydrogen peroxide as a vital factor of signaling cascades having growth factor-relying signaling. Briefly, xenobiotics stimulate xenosensorreliant adaptations of xenobiotic metabolism, and correspondingly, via xenobiotic metabolism, be involved in the formation of ROS and ROS-based regulation of cellular signaling processes.

Evolution of resistance to toxic xenobiotics The literature and books on resistance to one or another group of toxicants have hardly met disciplinary borderlines. The prognosis of resistance, the identification of resistant phenotypes, and the genetic and often molecular exploration of resistance is generally superimposed with more hypothetical modeling of resistance evolution, with preliminary significance to an aim of management. It has been rarely seen as growth of one field impacting the other. Such disciplinary division of research on several taxa has resulted to parallel developments and idiosyncratic vocabularies. The population biology of various organisms is another origin of diversity. The transfer of genes in populations of sexually reproducing individuals like DDT-resistant mosquitoes, have complied with several rules compared to that in cloned individuals like AZT-resistant or protease suppressor resistant HIV viruses (Taylor & Feyereisen, 1996).

Xenobiotics in Chemical Carcinogenesis

Introduction

First, a molecular classification of resistance has been propose which was able to revamp rather than reinstate the basic biochemical or physiological classifications of resistance phenotypes. Second, it has been discussed how the initial population frequency of resistant genes is speculated to connect to the molecular basis of resistance. There are several plausible adaptations which allow an organism to endure lethal doses of a toxicant and could be comprised as either mechanisms of declined response to the toxicant or a process of reduced exposure. These two main groups are also often known as pharmacodynamically oriented resistance and pharmacokinetically oriented resistance. Under pharmacodynamically oriented resistance, there are several pathways of the targeted sites for insensitivity to toxicant, and under pharmacokinetically oriented resistance, there is behavioral avoidance, decreased uptake, enhanced detoxification, removal, or sequestration. A third which has not been explained via mechanism is circumvention, a process through which the organism can avert suppressed events with different metabolic mechanisms. This classification of resistance mechanisms is also highly significant based on operational aspects, and it has also been elucidated in several papers (Taylor & Feyereisen, 1996). A molecular aspect has been added, which is comprised of mutations causing resistance to the biochemical/physiological classification of resistance events. Mutations in receptors, transporters, or enzymes, might be grouped into those that change binding/catalysis by structural modification, up-regulation such as gene amplification, or down-regulation like gene disruption or silencing. Regulation could be modified either by cis- or trans-induction of expression, by duplication or amplification, or by post-translational alteration of, for instance, the extent of glycosylation, phosphorylation, or cellular localization. Such molecular biological

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aspects in the categorization of resistance event is best presented as a two-dimensional table that is an innovation in increasing the knowledge of the biology of resistance (Taylor & Feyereisen, 1996). There is not much known about posttranslational activities as a resistance event. If these alterations have any related inheritance, they are speculated to be trans-acting regulatory components. Likewise, the genetic regulation of avoidance behavior is not well-known as biochemical pathways (Sparks et al., 1989). Before the recruitment, the size and constituents of the pool of efficient resistance mutants, classifying the array of loci and the array of alleles at every locus which can confer resistance, underlying mainly on the way of action, on chemical resemblances of the toxicant to other chemicals which the organism generally contacts, and, of course, on the frequency of selection (Taylor & Feyereisen, 1996).

Impact of xenobiotics on physiology and gene expression of human gut microbiota The human gut has trillions of microbes that impact human health by metabolizing xenobiotics compounds. Presently, the diversity of the host-related community has been identified; however, it is not yet clear which microbes are playing which role and what disturbances impact such activity. In a study, it has been demonstrated by combining flow cytometry, 16S rRNA gene sequencing, and meta-transcriptomics that the gut has a different array of active microbes including Firmicutes. Shortterm exposure to a group of xenobiotics highly impacts the physiology, structure, and gene expression of such functional gut microbes (Maurice et al., 2013). A few years ago, the wealth of information explaining the organismal and genetic variation observed in the complicated microbe communities colonizing several body habitats has

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13. Mechanism of resistance to toxic xenobiotics in humans

supported better analysis of the major components impacting community assembly and metabolic efficiency. However, such highly DNA-related studies have given limited information about metabolic function of their microbe affiliates and their molecular reactions to usual disturbances like xenobiotic exposure (Maurice et al., 2013). Single-cell approaches have described bacterial physiology in different ecosystems based on physiological classification to various extents of activity and biomass (Del Giorgio & Gasol, 2008; Maurice et al., 2013; Wang et al., 2009). This method has been successfully applied to assess the physiology of cells in the gut microbes, providing evidence for four different physiological groups varying from highly active to extremely damaged cells. About half of the gut microbes are known as potentially active, with HNA proportions irrespective of the values from highly productive aquatic systems like estuaries and marshes (Bouvier & Maurice, 2011). Such high extents of activity are possibly assisted by our daily dietary composition of nutrients and the capability of the gut microbes to metabolize glycoproteins of saliva, gastric juice, and mucus (Blaut, 2013). FACS-seq assessment of cells from all physiological groups showed that the active subset was enriched for Clostridiales, and the less active subset was enriched for Bifidobacteriales, which is consistent with the outcome of complementary approaches (Gosalbes et al., 2011) and is supported by comparing the gene expression and abundance. It has been elucidated that the constituents of the potential gut microbes could not usually be described by methodological prejudices in staining, an enhanced frequency of cell division, greater cell or genome size, or higher copies of the 16 S rRNA gene. In aquatic ecosystems, several studies have explained that HNA cell population has an enhanced frequency of metabolic activity (Bouvier & Maurice, 2011; Maurice

et al., 2013). More studies on the gut microbes are further required to assess the level to which these patterns are conserved in host-linked microbes communities. Instead of greater quantities of metabolically active cells, it has also been reported that onethird of the gut microbes are made of the damaged cells with unbalanced membrane polarity. The extensively damaged cells with negotiated membrane integrity form less than one-quarter of the community, which is consistent with earlier reports (Ben-Amor et al., 2005). Such outcomes support a notion of the human gut as an ecosystem accommodating productive microbial communities, with a remarkable extent of temporal differentiation in activity and cell damage provided the complete stability of potential drivers of microbial physiology like temperature, pH, and nutrients (Blaut, 2013; Maurice et al., 2013). Still, more work is necessary to explore the components leading to such temporal dynamics such as dietary alterations, phage exposure, bile acids, host immunity, or other poorly-defined factors. The integrated exploration of the host, microbes, and environmental components regulating the activity of the gut microbes to xenobiotics can finally be employed for the construction of diagnostic tests assessing xenobiotic pharmacokinetics or therapeutic interactions. At a minimum, to know the eventual consequence of xenobiotics and their effect on human health, it is essential to know their intended, or sometimes unintended, impact on potential gut microbes (Maurice et al., 2013).

Cancer drug resistance Cancer drug resistance has been a critical issue in cancer treatment. Relatively all therapy excluding surgery, which is being employed in the treatment of cancer can develop resistance. Unfortunately, there is a large cohort of patients who would either not counter the

Xenobiotics in Chemical Carcinogenesis

Introduction

used therapy that is, intrinsic resistance or would become resistant while treated that is, acquired resistance. Often patients could become resistant to one certain drug and endure sensitivity to other drugs viz., one-drug resistance; other group of patients might be resistant to one drug and would be resistant to other unlinked drugs that is, multiple drug resistance, MDR (Peters, 2018). Statistical data reveals that about 90% mortality of cancer patients is contributed to drug resistance. MDR of cancer cells while in chemotherapy is based on several mechanisms such as increased efflux of drugs, genetic components like gene mutations, amplifications, and epigenetic modification, growth factors, enhanced DNA repair capability, and enhanced metabolism of xenobiotics. Each of these mechanisms leads to reduction of the therapeutic efficacy of administered drugs, causing more difficulties in tumor treatment (Bukowski et al., 2020; Dallavalle et al., 2020; Wang et al., 2019). Types of resistance Different responses are observed between several cancer types. Certain tumors, like in pancreatic cancer, have a fixed survival (Coppola et al., 2017) due to an integration of failures for example, to surgery and the consequent adjuvant chemotherapy, containing either a gemcitabine associate therapy or a 5-fluorouracil (5-FU) underlying combination for example, FOLFIRINOX (Caparello et al., 2016). However, the latter treatment is highly effective but at the cost of major toxicity. Therefore, pancreatic cancer is an ailment for which resistance is intrinsic. In contrast, many breast cancer patients would be treated with a combination of potential screening, advanced surgery and radiation, and potential adjuvant treatment (Shachar et al., 2018). Even triple negative patients have a more than 70% 5-year life expectancies. In this disease and in stage III and IV patients, a developed resistance is a

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main issue because of a factor: BRCA associated with breast cancer. Unfortunately, potential drug synthesis by cell and molecular biologists sometimes overlooks the pharmacology of a drug. However, poor pharmacology is a critical kind of resistance, but often it can be turned into an advantage. A drug which normally does not arrive to cancer would not be efficient. Such a condition is described for both oral and intravenous administration. For intravenous administration, the drug might be metabolized by either phase I or phase II enzymes, prior to it arriving at the cancer. A high clearance like renal clearance, also checks a drug arriving a cancer. During oral administration, more obstacles can be developed if the gut epithelial cells inhibit the uptake of xenobiotics including anticancer drugs. This could cause poor gut uptake and low plasma and cancer drug concentrations. Next, the first pass impact of the liver could protect further circulation via the body resulting in low cancer exposure (Peters, 2018). If a drug arrives at the cancer, the cancer cell has a wide array of defense pathways. A drug must be received by the malignant cells and abnormal transport is a main event of resistance. Uptake could be regulated by diffusion, a facilitated transporter or a concentrative energy underlying transporter. If a drug is to be consumed, it can be frequently thrown out by one of the ATP-binding cassette (ABC) transporters (Jaramillo et al., 2018). If a drug is to be taken up into a malignant cell, the drug would experience more obstacles causing resistance, like insufficient activation, or high levels of degradation. By employing a prodrug complex, the drug could omit the normal transporters, does not require activation, and could frequently hit its target, thymidylate synthase (TS). Such novel applications of an old drug are prepared for investigation in patients. If a drug, in such a condition as FdUMP, the functional metabolite of 5-FU strikes its target TS, and the cell could respond by altering the

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13. Mechanism of resistance to toxic xenobiotics in humans

target by enhancing the gene expression or the functionality of the target, change the drug interaction, or enable the cell to enhance the level of its target (Peters et al., 2002) to develop less sensitivity. In the condition of TS, this indicates an enhanced expression of TS that has been linked by resistance to 5-FU. 5-FU is sometimes provided by mingling with leucovorin that inhibits such increases in TS (Danenberg et al., 2016). Other methods to overlook resistance to this drug or any drug is to make smart combinations in which one drug often employs the resistance event for effectiveness (Peters et al., 2000). So 5-FU is sometimes combined with cisplatin in the curing of head & neck cancer, and with oxaliplatin in colon cancer (Grivicich et al., 2001). Novel combinations like bevacizumab inactivate the vascular endothelial growth factor and suppress angiogenesis. In another way, cetuximab suppresses epidermal growth factor (EGFR)-regulated signaling. Small molecule suppressor of EGFR like erlotinib and gefitinib, are only effective in adenocarcinoma of non-small cell lung cancer if the cancer has induced mutations, forming the malignant cell underlying EGFR signaling. More mutations like T790M cause resistance, although these cells are sensitive to the 3rd generation of EGFR suppressor (Van Der Steen et al., 2016). These results suggest that based on the target a high expression or mutated enzyme could cause either resistance or enhanced sensitivity. More mutations could cause resistance, although sensitivity to other suppressor are designed to strike the mutated region (Muller et al., 2016). Drugs, like cisplatin, can strike their target DNA by synthesizing either intra-strand or interstrand adducts. The cell eventually perishes or searches for ways to overlook its death, and for cisplatin, this is mainly regulated by apoptosis (Ballestreri et al., 2018). Abnormalities in the apoptotic apparatus might inhibit a cancer cell from dying, inducing resistance. Another defensive mechanism of the cell is autophagy, which is

either a second mode of cell kill or a survival mechanism (Go´mez et al., 2015). For surviving cells, it could also aid the cell with more nutrients like amino acids. Enzymes that mend DNA damage make an essential resistance pathway and are a main obstacle in treatment. Treatment sometimes activates repair events in the cell. It has been described that the function of apoptosis is resistance to another alkylating drug, but specifically RAS expression also participates in resistance (Sharaf Eldin et al., 2018). It has also elucidated a novel method to reverse resistance by the implication of siRNA that inhibits the survival mechanism in which RAS is involved. The siRNA (encapsulated in nanoparticles) has also been employed to downregulate the CD22ΔE12 in drug-resistant B-precursor (Uckun & Qazi, 2018). However, siRNA implication does not have sufficient model systems, but carriers like nanoparticles are being examined to resolve such issues. MicroRNAs (miRNAs) consist of 19 25 nucleotides and do not code any proteins, but they impact gene expression during posttranscriptional alterations. Epigenetics alter the miRNAs’ involvement in the generation of chemoresistance of several cancers. Presently, several studies have exhibited that miRNAs influence the susceptibility of cancer cells against anticancer regimens by altering the drug resistance-linked genes or genes involved in cell proliferation, cell cycle, and apoptosis. It has been explained that miRNAs can act as a biomarker for diagnosis of the chemotherapy in cancer treatment. Table 13.2 contains some important miRNAs that play roles in cancer progression (Bukowski et al., 2020). Mechanisms of resistance to xenobiotics

The implication of a drug is followed by the development of cellular resistance to such substances. This resistance has already been explained broadly in organisms and microbes and is the greater hurdle to failure of

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Introduction

TABLE 13.2 Major role of miRNAs in development of resistance in cancer. Tumor types

miRNA

Chemotherapy regimens

Lung cancer

miR-221/222

TKIs, TRAIL

miR-21

TRAIL

miR-34a

TKIs

miR-200c

Trastuzumab

miR-155

Paclitaxel, doxorubicin

miR-218

Cisplatin

miR-27b-3p

Tamoxifen

miR-21

Trastuzumab

miR-200c

5-FU

miR-125a/b

Paclitaxel

miR-451

Irinotecanxx

miR-384

Oxaliplatin

miR-214

Cisplatin

let-7i

Cisplatin

miR-23b

Paclitaxel

miR-125b

Paclitaxel

miR-181a/b

Fludarabine

miR-181b

Doxorubicin

let-7a

Gemcitabine

miR-29b

TRAIL

miR-29b

Gemcitabine

miR-221

Gemcitabine

miR-34a

Paclitaxel, Docetaxel, Cabazitaxel

Breast cancer

Colorectal cancer

Ovarian cancer

Leukemia

Cholangiocarcinoma

Prostate cancer

miR-217 miR-181b-5p Pancreatic cancer

Cervical cancer

miR-320amiR-146

5-FU

miR-205miR-7

Gemcitabine

miR-499a

Paclitaxel

miR-125a

Paclitaxel (Continued)

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13. Mechanism of resistance to toxic xenobiotics in humans

TABLE 13.2 (Continued) Tumor types

Gastric cancer

miRNA

Chemotherapy regimens

miR-224

Paclitaxel

miR-508 5p

Adriamycin,

miR-495 3p

Cisplatin, 5-FU Adriamycin, Cisplatin, 5-FU

5-FU, 5-Fluorouracil; TKIs, tyrosine kinase inhibitors, TRAIL, TNF-related apoptosis inducing ligand.

chemotherapy. These kinds of chemotherapies play vital roles in xenobiotic resistance, mainly antibacterial, anticancer, antipaludic, and currently anti-HIV-1 treatments, with serious clinical and economic significance (Saves & Masson, 1998). Resistance can develop from (1) decreased cellular drug levels caused from changed influx of the drug within cell, from a high drug efflux or from drug sequestration; (2) enhanced cellular detoxification; (3) qualitative and/or quantitative modification of the drug site; (4) failure to induce the prodrug to its active mode; (5) increased drug inactivation; or (6) DNA repair role. Several mechanisms might occur simultaneously in cells. Some innate pathways are usually observed in the cells prior to any therapy, whereas others could seem de novo during disease development and treatment. The modulations of some resistance events have been explained currently and reveals assurance for lucrative chemotherapy (Saves & Masson, 1998).

P-glycoproteins as universal detoxifiers A well-recognized transport protein with a high range substrate specificity is an efflux pump known as P-glycoprotein, for which encoded genes had first been cloned in multidrug resistant cancer cells in 1986 (Efferth &

Volm, 2017; Roninson et al., 1986). Just after its characterization, it explained that P glycoprotein and the MDR1 gene belong to the human gene family of ABC transporters that have 49 gene members. ABC-transporters could be observed over most—if not all—organisms from bacteria to humans and plants. The wide circulation of ABC-type pumps supports the notion that they might act as universal detoxifiers in nature. P-glycoprotein is an ATP-consuming transporter that eliminates a different type of xenobiotic chemical from cells. The areas of compounds arrive from cytotoxic anticancer regimens (conferring multidrug resistance of cancer) to other drugs in normal tissues in the body and xenobiotics regulating prevention from toxic blasphemy.

Function of P-glycoprotein for resistance to carcinogenic agents The liver is considered as a main model in understanding the functionality of ABCtransporters in cancer development due to the metabolization of xenobiotic chemicals occurring usually in the liver. The regulated events to detoxify hazardous materials can either be specific or non-specific in nature. In the view of P-glycoprotein, its expression has been stimulated by chemicals which are particularly transported by such efflux transporters. In another way,

Xenobiotics in Chemical Carcinogenesis

Link between environmental chemicals and chemoresistance

P-glycoprotein expression has also been upregulated after exposure to undefined stimulants such as chemical substances that are not substrates of P-glycoprotein (Efferth & Volm, 2017). Several environmental factors that stimulated hepatic P-glycoprotein expression point to the impressive ability to endure toxic results assimilated by the organism from the environment. The correlation between resistance to chemical carcinogens and cancer formation had been first identified by Haddow (1938). He postulated that pre-neoplastic and neoplastic cells require resistance to such cytotoxic xenobiotic chemicals. Otherwise, they cannot develop. Thus, resistance can be known as a prerequisite for cancer development. The formation of hepatocellular cancer is immediately preceded by the presence of preneoplastic lesions. Four decades later, it has been explained that cancer development in the liver might cause early recruitment of carcinogen-resistant cells (Efferth & Volm, 2017). Premalignant hyperplastic liver nodules had been activated by 2-acetylaminofluorene or ethionine. In fact, such hyperplastic nodules had developed resistance to other hepatotoxins like carbon tetrachloride and dimethylnitrosamine. Successive examinations showed that hyperplastic liver nodules had developed resistance to different kinds of carcinogenic natural products such as aflatoxins, pyrrolizidine alkaloids, isosafrol, etc. and synthetic anthropogenic toxins (carbon tetrachloride, 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, dimethylnitrosamine, 7,12 dimethylbenz(a)anthrazene 2,3,7,8tetra-chlorodibenzo-p-dioxin, phenothiazine, etc.) (Efferth & Volm, 2017). As observed in rat liver by inhibition investigations with N-nitrosomorpholine, certain carcinogen-stimulated modification in hepatocytes could be differentiated from non-specific, toxic cellular alterations that are completely reversible upon removal of the carcinogenic substances. Hence, N-nitrosomorpholine was administered for 7 weeks to rats. The

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developing tumors were examined after 80 weeks upon removal of the carcinogen for their P-glycoprotein expression. Remarkably greater mdr1 mRNA extent in hepatocellular cancer was observed in comparison to the normal livers of control animals. In normal livers, Pglycoprotein had been confined in a polarized manner at the bile canalicular plasma membrane of hepatocytes. In hepatocellular tumor, P-glycoprotein had been observed at enhanced levels in comparison to the normal liver of untreated control animals. The enhanced P glycoprotein and mdr1 mRNA expression in hepatocellular cancer irrespective to normal livers of control animals might elucidate the resistance to carcinogenic xenobiotic compounds during hepatocarcinogenesis (Efferth & Volm, 2017). It has been indicated that carcinogenic resistance during hepatocarcinogenesis is not due to only P-glycoprotein. Several more pathways also participate, such as phase I drug metabolizing enzymes (cytochrome P450 monooxygenases, aryl hydrocarbon hydroxylase), phase 2 enzymes (UDP-glucuronyle transferase, glutathione S-transferases, γ-glutamyl-transferases, sulfotransferase) and others (epoxide hydrolase, DT-diaphorase, enzymes of the pentose phosphate pathway, etc.) (Ivy et al., 1988). Such events are highly similar to the xenobiotic resistance experience in the SoltFarber model of cancer development.

Link between environmental chemicals and chemoresistance Resistance to chemotherapy has become a major issue in the treatment of most common solid tumors. However, several studies have been emphasized, in the past, to the functions of pollutants in the progression of cancer, and presently in the invasion and metastasis event. In a study, the researchers explained that BaP reversed the impact of cisplatin, 5-flurouracil, and paclitaxel in the WHCO1 esophageal

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cancer cell line by decreasing drug-stimulated cell death and apoptosis by 30% 40% irrespective to cells treated by drugs individual (Koual et al., 2020). The mechanisms involved in the development of chemoresistance in cancer cells is a matter of discussion (Eun et al., 2017; Koual et al., 2020). In 1992, the loss of epithelial markers and the increasing of vimentin expression in Adriamycin- and Vinblastine-resistant human breast cancer cell lines were elucidated and indicated the EMT cells have beneficial role in growth abilities in comparison to nonEMT cells upon drug treatment (Heckford et al., 1992). Since this first report, chemoresistance to several drugs like oxaliplatin and paclitaxel sometime have been associated with the EMT and were also explored in various cell lines and animal models (Koual et al., 2020; Singh & Settleman, 2010). However, a group of researchers has not concluded on this aspect (Diepenbruck & Christofori, 2016) and hence, experimental approaches are required to reach a conclusion on this aspect. On the contrary, the correlation between stem-cell characteristics and resistance to chemotherapy has been highly elucidated. In BC, several signaling mechanisms in cells indirectly stimulate CSCregulated chemoresistance that enhance stemness qualities and self-revival of CSCs (Koual et al., 2020; Mallini et al., 2014). The relationship between environmental components and CSC productions explained above require the unraveling of the direct association between harmful xenobiotic substances and anticancer drug resistance.

several regions of the environment in explaining sensitive and sentinel species, biomarker synthesis, underlay of water properties guidelines, generation of new chemicals, and risk analysis. There are no sufficient tools in practical uses for the prevention of the resistance to xenobiotic chemicals like pesticides and chemotherapeutic agents. More fundamental scientific knowledge of biological interaction like herbivory and allelochemicals, biological toxins and antidotes, progressive theories for resistance evolution, etc. also have significant merit. During the course of evolution, cellular and molecular pathways have been generated to ignore and repair acute or chronic issues by xenobiotic toxic chemicals. Successful security by such pathways lead to better organismal health, whereas their omission causes toxicities like hepato-, nephro-, terato-, hematotoxicity, etc. and prolonged time to develop cancer. Therefore, detoxification and carcinogenesis are considered as two parts of the same coin. Xenobiotic resistance to drugs and carcinogenesis in oncology are not separated from basic biological events. Hence, the cellular physiology and several molecular mechanisms play a major role in the detoxification of toxic xenobiotics and in increasing resistance toward anticancer drugs. Combining studies as interdisciplinary research on these aspects could be a wise approach to combat problems in medicine, environmental science, cancer biology, and others in the life sciences.

References Conclusions Knowing the protective role (tolerance and resistance) has several relevant applications for the betterment of life and the environment. It influences human health in curing diseases like chemotherapy, pharmacology, and public health prevention schemes. It is also critical for

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C H A P T E R

14 Profiling the reactive metabolites of xenobiotics in cancer Introduction Metabolism is usually known for a detoxification method through which endogenous chemicals and xenobiotics are transformed into highly hydrophilic components to expedite removal from the body. However, in several conditions metabolites are less toxic in comparison to their corresponding parent xenobiotics, it is a common process in which xenobiotic compounds undergo bioactivation to produce highly toxic reactive species (Ma & Subramanian, 2006). The explanation of the relationship between the covalent alteration of DNA and proteins by reactive metabolites and chemical-induced cytotoxicity (Ma & Subramanian, 2006; Miller, 1970) have been supported by the metabolic activation of specific xenobiotics to reactive metabolites, which could then covalently coalesce to macromolecules, causing cell damage and finally producing xenobiotic-induced toxicity (Zhou et al., 2005). Many enzymatic and non-enzymatic apparatuses contribute in the metabolism and accumulation of xenobiotic compounds that could be of several origins and classified as herbicides, pesticides, drugs, etc. Phase I xenobiotic-metabolizing enzymes (XMEs) catalyze the initial step of xenobiotic metabolism, known as xenobiotic

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00010-8

activity, in which substrates are altered by oxidation, reduction, or hydrolysis reactions. Phase II XME conjugate xenobiotics, or their phase I metabolites, to glutathione, sulfate, glucuronide, methyl or acetyl moieties, forming such highly hydrophilic compounds and, subsequently, highly applicable for removal. Transporters, usually of the solute carrier (SLC) and of ATP-binding cassette (ABC) families, regulate the influx of xenobiotic compounds into cells or support the efflux of xenobiotics or phase II metabolites from cells. The integrated expression between phase I XME, phase II XME, and transporter genes is done by nuclear receptors (NRs) that are ligand-induced transcription factors that regulate constitutive and inducible expression of several genes such as the XME and transporter genes. Three main NRs (AhR, PXR, and CAR) are induced by xenobiotics and called xenosensors (Leclerc et al., 2011). Biotransformation process are usually advantageous since they facilitate detoxification of xenobiotics and removal from cells. Although, in some conditions, such processes can induce nontoxic procarcinogens into reactive intermediates which could attach to DNA that could lead mutations for the development of cancer. The metabolic equilibrium between

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such induction and detoxification processes in a particular tissue is based on the XME activation profiles in the tissue (Castell et al., 2005). The localization of carcinogenic xenobiotic compounds inducing and detoxifying enzymes in lung tissues together with interindividual variations in their expression, is highly essential in exploring the impact of genetic and environmental components in the progression of pulmonary ailments like lung cancer and chronic pulmonary diseases. However, the explanation on systematic examinations of the xenobiotic-metabolizing capability of pulmonary cells are limited. Several earlier studies conducted on human lungs (Leclerc et al., 2011; Zhang & Cashman, 2006) emphasized only on a certain family of XME genes and determined pooled whole lung tissues that does not allow the reorganization of differentiations in gene expression between individuals, or between the two different pulmonary chamber which are bronchial mucosa (BM) and pulmonary parenchyma (PP). Although, such two tissues have several activities, they are made of several kinds of cells and distinctively exposed to stimulating xenobiotics. Hence, gene expression profiles must be separated in BM comparison to PP, to be susceptible to xenobiotic compounds. The present development of high-throughput technologies for the assessment of gene expression has made plausible the examination of several genes together with small specimen concentrations. Several xenobiotic compounds are converted into highly polar and balanced metabolites by metabolizing enzymes and the further removed from the body. However, certain xenobiotics involve metabolic activation to form the reactive electrophiles that enable covalent interactions to protein, DNA, and other biomolecules (Li et al., 2011). However, the mechanistic communication between reactive metabolites and toxicity is not cleared yet, but some results explain their association (Li et al., 2011; Rousu et al., 2009). The main proteins altered by reactive metabolites

might change the biological reaction and then lead in the direct toxicities explained by tissue necrosis and/or apoptosis (Evans et al., 2004). The interactions of reactive metabolites to DNA has the capability to develop genotoxicity (Farmer et al., 2005). Hence, exploring reactive metabolites is very important in determining the toxicity of xenobiotics chemicals exposed to humans (Guengerich & MacDonald, 2007; Li et al., 2011). Generally, reactive metabolites have been sorted into soft and hard electrophiles. Classic soft electrophiles have epoxides, α,β-unsaturated carbonyls, quinones, quinone imines, quinone methides, imine methide, isocyanate, isothiocynates, aziridinium, and episulfonium (Tang & Lu, 2010). Aldehydes and iminium ions are examples of hard electrophiles. Highly reactive metabolites are stable and hence not directly assessed. GSH and its analogs are usually employed to trap soft electrophiles (Le Blanc et al., 2010; Soglia et al., 2006). Hard electrophiles are hinged by semicarbazide, methoxylamine, or cyanide ions (Argoti et al., 2005; Kalgutkar et al., 2005). The reaction of trapping components and reactive metabolites synthesize stable adducts, but it is difficult to remove such adducts from an intricate biological matrix. Multiple mass spectrometry (MS) approaches like neutral loss (Wen & Fitch, 2009), precursor ion (Wen & Fitch, 2009), multiple reaction monitoring (MRM) (Zheng et al., 2007), and mass defect filtering (MDF) (Zhu et al., 2007) have been used to characterize reagent-trapped reactive metabolites. Although effective, they are also prejudiced approaches and preset criteria are required to perform data assessment. For instance, transition lists are needed for MRM that determine the envisaged reactive metabolites, although avoid the undesired metabolites (Zheng et al., 2007). A prejudiced method is essential for the identification of trapped reactive metabolites. Metabolomics explains an integrative method for determining metabolic alteration counter to dietary, lifestyle, and environmental factors.

Xenobiotics in Chemical Carcinogenesis

Experimental methods for the assessment of reactive metabolites

Non-targeted and targeted metabolomics underlying methods have highly advanced screening of hundreds of metabolites altogether based on several metabolic mechanisms. Instead of recommendations of comprehensive metabolic assessment in human nutrition to provide parameters of health, its implication remains limited (Al-Khelaifi et al., 2018). Several researchers have explored gene expression in human intestinal cells. But there has been no absolute study analyzing intestinal cell lines with both human ileum and colon, mainly for systems participating in metabolism and the accumulation of xenobiotic molecules. This knowledge will increase capability to determine the efficient pharmacological and toxicological results of xenobiotic exposure in the intestinal mucosa and can produce data translation to in vivo conditions (Bourgine et al., 2012). With the onset of high-resolution sequencing methods, the study of genome-wide epigenetic alterations has been fascinating, for which gene expression mechanisms of a certain cell or tissue are regulating. There is now increasing evidence that disturbances to the epigenetic landscape happen under a host of cellular methods like normal proliferation/differentiation and aberrant results for development of cancer. Further, epigenetic disturbances have been related with exposure to a range of xenobiotic compounds (drugs and toxicants) such as non-genotoxic carcinogens (NGCs). However, several epigenetic alterations stimulated by NGCs have been explored earlier, present genome-wide associated epigenomic and transcriptomic studies exhibiting for the first time the level and changing nature of the epigenetic modifications causing xenobiotic exposure. The examination and association of one epigenetic impression, the advanced explored 5-hydroxymethylcytosine (5hmC) alterations, shows that drug treatment based on disturbances of the epigenome could result in different epigenetic signatures (Thomson et al., 2014). The above

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demonstrations show that the screening of xenobiotics irrespective of those active molecules responsible for mechanistic patterns in cells; therefore, this chapter will provide an overview on the reactive metabolites of xenobiotics in carcinogenesis.

Experimental methods for the assessment of reactive metabolites Reactive metabolites can be highly comprised into electrophiles and free radicals (Mackenzie et al., 2017). Most reactive metabolites are electrophilic nature and react with nucleophiles. Electrophiles could be divided as “hard” or “soft”; a restricted positive charge will produce the electrophile “hard,” whereas a delocalized charge will make it “soft.” Likewise, nucleophiles could also be described as “hard” or “soft.” For instance, a sulfur-containing nucleophile is known to be softer than a nitrogencontaining nucleophile, due to a larger sulfur atom, and the lone pair electrons again move away from the nucleus and disseminate more. Usually, hard electrophiles contribute to interactions with hard nucleophiles, whereas soft electrophiles have a tendency to react with soft nucleophiles (Mackenzie et al., 2017) Free radicals are identified by having an unpaired electron and they mainly extract a hydrogen atom from molecules, leading to a new free radical and hence start a chain reaction. Reactive metabolites are sometimes short-lived and not usually observable in distributing blood/ plasma. In vitro methods are usually implicated to investigate the bioactivation potential of xenobiotic species that might give some indirect but important knowledge in toxicity determinations. Several techniques are available to analyze reactive metabolite production, and these have: (1) investigation of covalent interacting to proteins, (2) trapping and identifying reactive metabolites, and (3) time and cofactor-underlying cytochrome P450 (CYP) suppression.

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Analysis of covalent binding to proteins A critical approach for addressing and evaluating the production of reactive metabolites is the implicated of radiolabeled (3H-or14C-) compounds to determine irreversible binding of reactive metabolites to macromolecules. The liver is the vital part of xenobiotic metabolism, where in vitro covalent binding is mainly analyzed from incubations of the drugs with liver microsomes in the existence of particular cofactors or newly derived hepatocytes. The extent of covalent adducts are predicted based on the quantity of unextractable radioactivity present in the protein pellet and expressed in pmol equivalents/mg protein (Ma & Subramanian, 2006; Pohl & Branchflower, 1981). From a quantitative aspect, it has been explained that xenobiotics molecules with a covalent binding of .50 pmol equiv. mg21 of proteins might have highly toxic issues. Such value had been planned based on the data from normal extents of covalently integrated protein adducts present in the livers of animals provided a prototypic hepatotoxin divided by a factor of 20 to

provide a conservative site upper limit. It is mentioned that the aim of such covalent binding approaches is hardly to help in the recruitment of drug synthesis candidates with a low propensity for bioactivation in animals and humans (Ma & Subramanian, 2006).

Trapping and identifying reactive metabolites Chemical trapping has been highly employed in the identification of reactive metabolites which synthesis stable adducts that could be screened by UPLC-TOFMS (ultra performance liquid chromatography-time-of-flight mass spectrometry), LC
MS/MS and/or nuclear magnetic resonance (NMR) spectroscopy. Such experiments are sometimes performed in liver microsomes with NADPH (nicotinamide adenine dinucleotide phosphate) and certain nucleophilic trapping components like thiols (glutathione: GSH), its ethyl ester derivative, or N-acetylcysteine, amines (semicarbazide and methoxylamine), or cyanide anion (Fig. 14.1)

FIGURE 14.1 Diagrammatic presentation of the metabolomic approach for the profiling of absorbed reactive metabolites. Xenobiotics could be incubated in a reaction apparatus having enzymes, with or without NADPH and trapping reagents that may be assessed by UPLC
TOFMS. A data matrix could be developed by MarkerLynx which MDA could be performed to screen absorbed reactive metabolites. MDA, Multivariate data analysis; NADPH, Nicotinamide adenine dinucleotide phosphate; UPLC-TOFMS, ultrahigh-pressure liquid chromatography-time-of-flight mass spectrometry.

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Time and cofactor-based cytochrome P450 suppression

(Kalgutkar & Soglia, 2005; Ma & Subramanian, 2006). GSH has a free sulfhydryl class, a soft nucleophile able of interacting with a wide range of reactive electrophiles like Michael acceptors, epoxides, arene oxides, nitrenium ions, and alkyl halides. Basically, the GSH is found in all mammalian tissues and, hence, acts as a natural protective for chemically reactive metabolites. The implication of the ethyl ester analog of GSH has been exhibited to escalate the MS susceptibility of the prediction of reactive metabolites (Soglia et al., 2004). Semicarbazide and methoxylamine are hard nucleophiles that primarily react with hard electrophiles for example, aldehydes (Chauret et al., 1995). The cyanide anion is a hard nucleophile which could be implicated to potentially trap iminium components (Argoti et al., 2005). Instances of several trapping reactions that are mainly employed in vitro to screen reactive intermediates for structural identifications are exhibited in Scheme 1. The approaches for trapping free radicals employing spin-trapping components have been heavily studied. Spin traps are mainly C-nitroso molecules or nitrones which would immediately react with free radicals to produce stable nitroxide radical adducts. For instance, a free radical trapped by 5,5 dimethylpyridine-oxide (DMPO) have been exhibited in Scheme 2. Whereas, the other employed spin traps have tert-nitrosobutane (tNB), phenyl-tert-butylnitrone (PBN), and ˛-(4-pyridyl Noxide)-N-tert-butylnitrone (4-POBN). Presently, the approaches have integrated LCelectron spin resonance (ESR) spectroscopy, and LC
MS/MS has been developed to separate and characterize spin-trapped radical adducts in vivo and in vitro (Guo et al., 2004).

Time and cofactor-based cytochrome P450 suppression CYP inhibition assessment is usually performed in vitro employing human hepatic

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microsomes treated with drug and CYP isozyme-based model substrates. Metabolites of model substrates have been further determined by LC
MS/MS (Dierks et al., 2001; Qin et al., 2014) or fluorescence (Kenaan et al., 2013) processes to analyze the impact of the test xenobiotic specimens on the metabolism of the model substrate. In other conditions, CYP-regulated bioactivation of xenobiotic produces a reactive intermediate that is highly reactive and irreversibly interacts to the active core of the enzyme, leading in the loss of enzymatic potential (Kent et al., 2005). Such method has been comprised as mechanism-related inhibition. In mechanism-based inhibition, the enzyme activity could be not restored by the elimination of inhibitors; sometimes, at least one cycle of CYP-catalyzed reaction is essential to restore its activity. Mechanism-based inhibition also needs the NADPH cofactor and the inhibition continues with time; therefore, it is also known as time-dependent inhibition (TDI). The studies of time and cofactor-based CYP inhibition aid in analyzing the equilibrium dissociation constant of the inactivator (KI), the rate constant for mechanistic suppression to produce the inactive complex (kinact), and the partition ratio of kcat/kinact. The kinact/KI ratio is usually considered as an indicator of the in vitro efficiency of a mechanism-associated inhibitor (Mayhew et al., 2000). A positive TDI assessment suggests the production of reactive intermediates which are covalently integrated to metabolizing enzymes. Thus, the study of time and cofactor-dependent CYP inhibition study is very essential in vitro profiling assessment for reactive metabolites.

NMR spectroscopy for identification of xenobiotic toxicity Global profiling technologies are needed to completely unravel the effect of genetic

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14. Profiling the reactive metabolites of xenobiotics in cancer

alterations and toxicological interferences on the organizations of transcripts, proteins and metabolites in a cell, tissue or organism. Highresolution 1H NMR spectroscopy integrated with statistical ways characterization is one such technique, known as metabonomics or metabolomics that is highly used worldwide to profile metabolites. This has supported the methods to recognize genetically altered yeast strains and differentiate both disease presence and severity to organisms (Griffin, 2003). Eventually, the main aim of metabolomics is to identify each small-molecule metabolites of xenobiotics compounds found in a biofluid, tissue or even organism, further MS has a several profit in relation of sensitivity across 1H NMR spectroscopy. Such imbalance is being explained by the synthesis of magnets with enhanced field strength, cryogenically cooled probes, and microprobes (Griffin, 2003). Further, one benefit which is intrinsic to NMR spectroscopy in comparison to other tools, is that the technique is highly non-invasive, resulting to several medical implications of the NMR impact to identify molecules in vivo like magnetic resonance imaging and magnetic resonance spectroscopy.

High-throughput NMR in xenobiotics toxicology To increase the knowledge of multivariate datasets, a high-throughput approach is essential in developing data matrices completely explaining both the variation related with a disorder and the innate variation linked with the biological system whereas decreasing false positives related with such global multivariate assessments. This is usually true for the use of functional genomic approaches in safety analysis for xenobiotics toxicity studies. Here, target chemicals are usually dosed at pharmacological level, well below assessed LD50 concentrations, and

therefore would impact only a minority of animals. In this respect, NMR-based metabolomics is specifically fascinating due to its low cost on a per-sample basis. With advancements both in automated shimming of samples and flow marker tools, sample throughput for metabolite containing fluids like urine and blood plasma is as much as 300 samples per day, with no relevant costs or time related with sample synthesis (Griffin, 2003). Employing such a method, the Consortium for Metabonomic Toxicology (COMET) constituting of Imperial College London, UK, BristolMyers Squibb, Eli Lily and Company, Hoffman LaRoche, NovoNordisk, Pfzier Incorporated, and the Pharmacia Corporation, are presently examining 150 model liver and kidney toxin via NMR-associated assessment of urinary metabolites over a three years (Lindon et al., 2003). To obtain this, it has been essential in addressing how reproducible the database will be in relation to both the collection of samples and the resultant NMR assessment. Investigating hydrazine toxicity in the rat, Lindon and colleagues explained that the alterations in NMR-based metabolomics as a result of performing a study over seven different laboratories had minimum in respect to the variation related with the toxic lesion. It is believed that this method would support the creation of oracle systems where liver and kidney toxicity could be determined for model xenobiotic molecules with the databases being conveniently interchangeable between laboratories. To completely investigate the high multivariate datasets which are immediately generated by studies like COMET, mode of identification technologies have been an essential section of such methods (Lindon et al., 2001; Valafar, 2002). Both unsupervised and supervised tools could be employed to determine metabolic profiles (Lindon et al., 2001). To examine the innate differentiation in a dataset,

Xenobiotics in Chemical Carcinogenesis

High-throughput NMR in xenobiotics toxicology

unsupervised technologies like principal component analysis (PCA) or hierarchical cluster analysis (HCA) are employed. Although, where certain queries are being raised, supervised tools like “prediction to latent structures through partial least squares” (PLS), genetic programming and neural webs might be highly accurate (Griffin, 2003). PLS, the regression expansion of PCA, could also be employed as a means of data filtering, known as orthogonal signal correction (OSC) (Wold et al., 1998). Variation which is orthogonal to the tendency of concern is eliminated by employing PLS. For all the supervised tools, it is essential to investigate the robustness and predictability of the models formed, however the biological role of the explored metabolites might also suggest the success of the certain way of recognition technology of generating a metabolic profile against specific disease. The comfort of automation for NMR-associated metabolomics also synthesizes it a novel technology for profiling human populations for general metabolic ailments. Expert systems have been made which determine both the existence and severity of carcinogens employing blood plasma samples (Griffin, 2003). If these systems could be implicated to the clinical case, relevant economical savings could be made over other technologies, presently the novel standard for prognosis.

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Characterization of xenobiotic metabolites by LC/HRMS/MS MS detection approaches are potential tools for understanding xenobiotic metabolism (Fig. 14.2). Currently, xenobiotic metabolites have been predominantly detected and characterized in biological samples due to the frequent formation of high-resolution MS (HRMS) containing time-of-flight MS, Fourier transform ion cyclotron resonance MS, and Orbitrap MS and data assessment software (Takahashi et al., 2018). For instance, 24 troglitazone metabolites have been explored in rat plasma and bile employing liquid chromatography integrated with HRMS (LC/HRMS) and a backgroundsubtraction method with a mock-treated sample (Zhu et al., 2011). It has been characterized 23 triclosan metabolites in horseradish hairy root-cultured cells employing an orthogonal projection to latent structures discriminant analysis (OPLS-DA) method with LC/HRMS data generated from both mock-treated and xenobiotic-treated samples (Seiwert et al., 2015). Other data-processing approaches employing LC/HRMS data like a MDF, has also been explained (Zhang et al., 2009) owing to several xenobiotic metabolites have same mass defects to that of the parent chemicals. The MDF method has been then advanced for the comprehensive

FIGURE 14.2

The potential tool for detection and identification of xenobiotic metabolites formed during xenobiotic metabolism.

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determination of xenobiotic metabolites with different MDFs associated with structural templates of several groups of conjugated xenobiotic metabolites (Zhang et al., 2009). Employing statistical assessment methods with LC/HRMS data is powerful, but such approaches face various problems. First, false positive peaks might be observed if employing background-subtraction and OPLS-DA methods with LC/HRMS data received from mocktreated and xenobiotic-treated samples and this could be avoided. Second, when candidate metabolites are observed, it often faces several difficulties in identifying their structures. One of the highly believable means of determining xenobiotic metabolites is to analyze the chromatographic retention time (RT) and HRMS spectrum of the known metabolites observed in vivo with those of the accurate chemical; although in several conditions, it is very challenging to have accurate chemicals for xenobiotic metabolites. Hence, detecting the xenobiotic metabolites employing LC/HRMS data is usually conducted implicating correct mass information and exploring chemical structure databases implicating Pubchem, Chemspider, etc. However, implicating chemical structure databases is not presently beneficial in the area of xenobiotic study due to limitation of the registered xenobiotic metabolites in databases. Stable isotopes like 2 H, 13 C, 15 N, and 34 S, of elements contain the equal atomic number and hence likely similar physicochemical characteristics but vary mass-to-charge ratios (m/z). Hence, LC/HRMS assessment integrated with in vivo labeling employing a stable-isotopelabeled xenobiotic has potential for resolving the first problem such as removing false positive peaks from endogenous metabolite variation due to exposure to a xenobiotic. The merging stable isotope-labeling approaches with MS support for the immediate collection and analysis of data for xenobiotic metabolism (Mutlib, 2008). Moreover, various software technologies like

MetExtract and Hi TIME1, have been used for the automatic and potentially correct determination of xenobiotic metabolites employing nontarget LC/HRMS data (Takahashi et al., 2018). But such software technologies are limited to the removal of “twin ions” that are xenobiotic metabolites obtained from a 1:1 mixture of unlabeled and 13C-labeled xenobiotics. 2 H-labeled compounds are highly practical than 13C-labeled chemicals. Although, in reverse phase LC, the RTs of 2H-labeled chemicals are readily speedy in comparison to those of the unlabeled substances; the unlabeled chemicals and 2H-labeled compound are not coeluted (Guo et al., 2007). Hence, implications of the MetExtract and HiTIME software are presently limited because 2H-labeled chemicals could not be applied. Implicating in silico metabolism software has the potential for high throughput and exact identification of xenobiotic metabolites. In silico metabolism software packages like Meteor (Lhasa, UK) and MetabolExpert (CompuDrug, USA), have been constructed (Mu¨ller et al., 2002). The software could determine the metabolic fate of a known chemical structure by employing knowledge-related structure-metabolism guidelines that is, biotransformations. Many groups have explored the xenobiotic biotransformed compounds employing in silico metabolism determining software. For instance, various metabolites of quetiapine, an antipsychotic drug, have been explored in autopsy urine through LC/HRMS assessment and implicated knowledge on phase I metabolites such as oxidation, dealkylation, and hydroxylation, as predicted by Meteor software (Ojanpera¨ et al., 2006). Although, earlier studies for xenobiotic metabolism employing in silico metabolism software are not enough for drug metabolism in humans and animals, and it has no implications to pesticide metabolism in plants. Further, to explore the xenobiotic metabolites in plants, it is essential to extend the in silico metabolic process to explain phase I metabolism, phase II

Xenobiotics in Chemical Carcinogenesis

High-throughput NMR in xenobiotics toxicology

metabolism that is, conjugation of xenobiotics or xenobiotic metabolites to endogenous chemicals, and phase III metabolism (transfer of phase II metabolites into secondary conjugates). HRMS/MS spectra are very important in identifying the molecular sub-structures. The assessment of temporal alterations in xenobiotics and their metabolites is also significant for unraveling the xenobiotic metabolism. Hence, an integration of in silico metabolism determination, HRMS/MS spectral assessment, and time-dependent screening of the xenobiotic and its metabolites would enhance the accuracy of characterization for xenobiotic metabolites and explain the event of xenobiotic metabolism.

Screening of xenobiotics in by UHPLCHRMS/MS Recently, it has been well established that about three quarters of human diseases are associated with exposure to xenobiotic compounds (Musatadi et al., 2021). Observing the exposome can turn out as an effective technology to assess potential health incidence and open new boundaries in the comprehension of external, internal and non-specific exposures and their results on the health of organisms, mainly of humans (Escher et al., 2017). Monitorization of biological fluids and tissues to determine the potential biomarkers from the epidemiological aspects can explore potential subpopulations to experience negative health impacts (Vineis et al., 2017). In this aspect, biomonitorization has become essential in epidemiological studies (Andra et al., 2017) and the European Union is encouraging the biomonitorization of xenobiotic compounds in humans to apprise the unraveling of exposure response relationship (Musatadi et al., 2021). With regards to biological fluids, urine and blood are most used (Yusa et al., 2015).

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However, the bioaccumulation of organic compounds in breast milk has also enticed certain attentiveness in the last decade, since it is the main exposure origin of contaminants to breastfed newborns (Yusa et al., 2015) and a well-known incidence component for breast cancer in women (Siddique et al., 2016). But the enhancing requirement for human breast milk has led to a hasty development of milk banks which do not pursue regulations associated with organic microcontaminants due to the lack of specific analytical technologies, emphasizing only on the removal of microbes (Garcı´a Lara & Pen˜a Caballero, 2017; Irazusta et al., 2020). Since breast milk is usually constituted with adipose tissue and the lipids of the milk could increase up to 5%, the presence of high contents of lipid soluble chemicals can accumulate in breast milk (Stefanidou et al., 2009). Anyway, the presence of water in milk could also allow for the accumulation of more polar and water-ionizable xenobiotic compounds (Stefanidou et al., 2009). Instead of human breast milk, animal source milk has also been the core of attention in the last decade, mainly bovine milk. Milk is a crucial component of the human diet over world and the enormously implication of drugs and pesticides in dairy farming and agricultural processes, mainly pollute it with their components (Jadhav et al., 2019). In addition, the enhancing application of illegal or off-license drugs and pesticides in dairy industries further escalates health incidence to consumers (Beyene, 2015). Of the analytical methods to assess xenobiotics in milk, liquid
liquid extraction (LLE) employing non-polar solvents like diethyl ether, hexane, or dichloromethane, is one of the most prevalent extraction approaches (Lopes et al., 2016). By adding ethanol to the non-polar solvents or taking more polar solvents like acetonitrile or methanol, removal of the more polar xenobiotics is advocated (Rodrı´guez-Go´mez et al., 2014). Although, the addition of salts like anhydrous magnesium sulfate (MgSO4) or

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14. Profiling the reactive metabolites of xenobiotics in cancer

sodium chloride (NaCl) increases phase partition and assures larger recoveries via salting-out impact. Several researchers elucidated that the potentiality of LLE is advanced by rapidly handshaking or employing a vortex (Baduel et al., 2015). By adopting above approaches, some works have used greater speed solvent separation methods that also employ solvent mixtures to achieve medium polarities like acetone/hexane mixtures and salts [anhydrous sodium sulfate (Na2SO4)] to separate non-polar and lightly polar chemicals (Asante et al., 2011; Devanathan et al., 2012). In non-selective extraction cases, a relevant level of proteins and lipids is co-extracted along with the organic xenobiotics (Jime´nez-Dı´az et al., 2015; Lopes et al., 2016). However, a protein precipitation phase is sometimes done just after the extraction step (Jime´nez-Dı´az et al., 2015; Lo´pezGarcı´a et al., 2018), next clean-up of the extracts is necessary to overcome the matrix-impact at the prediction step. In this aspect, solid phase extraction (SPE) has been usually examined for the elimination of intrusions. In view of the larger polarity of analytes, polymeric associated sorbents like Oasis hydrophilic-lipophilic balance (HLB) have been enormously implicated (Calafat et al., 2004; Musatadi et al., 2021). Clean-up processed related to size exclusion like miniaturized gel permeation chromatography (Malarvannan et al., 2009) or Captiva ND-Lipids filters (Baduel et al., 2015) are enough for eliminating larger biomolecules. In the exploration of polar organic chemicals, LC is highly implicated since it supports the partition of a broad spectrum of xenobiotic molecules as far as polarity is vital that could be fascinating in the assessment of evolving/ new molecules and their metabolites and/or biotransformed compounds (Jamin et al., 2014). As for the observation step, MS is the selected alternative in the maximum present works since it figures out coelution issues which are appeared in other detectors (Hermo et al., 2008). Electrospray ionization (ESI) is ideally

employed to combine the MS to LC since it has capability of determining ionizable xenobiotic chemicals within a greater molecular weight range (Mass spectrometry: a textbook, 2011). HRMS is also a highly useful technology to explore unknown components present in milk and to have a more comprehensive information of the exposome. Hybrid detectors like quadrupole time of flight (qTOF) or quadrupole-Orbitrap (qOrbitrap) grant conducting tandem MS at high resolution having both the MS1 (pseudomolecular ion and isotopic profile) and MS2 (fragmentation spectra) at high resolution that elucidates the unknown xenobiotics chemicals (Corte´jade et al., 2016).

Example for determination of unknown xenobiotic compounds Reagents Two hundred forty-five target analytes had been recruited to imitate as realistically as possible actual exposure to xenobiotic compounds that organisms endure over their complete lifespan, including different analytes in regards of polarity, acidity/basicity, functional groups, structures, molecular weight and usage. Standard stock solutions had been made in the 100
10,000 μg g21 range by MeOH (99.9%, UHPLC-MS), AcN (ChromAR HPLC), acetone (ChromAR HPLC), EtOH (ChromAR HPLC), dimethyl sulfoxide (DMSO) and/or Milli-Q water (H2O , 0.05 μS cm21), based on the target molecules. Solutions up to 2 μg g21 having all the target components had been made in MeOH and stored at 220 C in the dark condition. A surrogate mixture solution of 1 μg g21 having [2H5]-atrazine, [13C3]-caffeine, [2H8]ciprofloxacin, [2H6]-diuron and [2H5] enrofloxacin had been separately made in MeOH and kept in the same conditions as the target analytes. All solutions were freshly made following to the specific experimentation needs (Musatadi et al., 2021).

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Target analysis and suspect screening

Extraction of xenobiotics Before extraction, all milk samples had been defrosted at room temperature. The optimization of the extraction process had bee performed by spiking bovine milk samples with 214 target analytes to have final concentrations of extract nearly 300 ng g21. Extractions had been conducted employing a vortex at speed for 1 minutes, and the extraction solvents tested were: (1) AcN, (2) could with several combinations of MgSO4, Na2SO4, and NaCl, (3) AcN:water (95:5, v/v) with 0.1% EDTA, (4) MeOH:HOAc (95:5, v/v) and (5) MeOH with TFA or trichloroacetic acid (80:20, v/v) (Musatadi et al., 2021). UHPLC-qOrbitrap Analysis The extracts derived upon clean-up had been evaporated to dryness and again solvated in 200 μL MeOH. All samples and solutions had been sieved prior to the assessment employing 0.22 μm polypropylene filters in chromatography vials and stored in the freezer. A UHPLC integrated to a high-performance Q Exactive Focus Orbitrap mass analyzer with a heated ESI (HESI) source had been employed for the assessment of the xenobiotic compound (Musatadi et al., 2021). Analyte separation had been conducted in an ACE UltraCore XB-C18 column with a prefilter from Phenomenex. Milli-Q water (A line) and AcN (B line) were implicated as mobile phase, both having 0.1% HCOOH and 5 mM ammonium acetate for positive and negative ionization modes, respectively. Column flow had been fixed at 0.3 mL min21 and the temperature was kept at 50 C. Gradient elution initiated with 13% B was altered to 50% B in 10 minutes. Further, the constituents of the B line had been enhanced to 95% in 3 minutes and stored for 3 minutes. Eventually, the mobile phase constituents had been modified to the initial phase in 3 minutes. With regard to the HESI parameters, sprinkle voltage had been fixed at 3.2 kV for positive

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and 3.5 kV for negative ionization patterns. For positive ionization, the capillary temperature had been fixed at 320 C, the scabbard gas at 40 arbitrary units (au), the auxiliary gas at 15 au and 310 C, and the sweep gas at 1 au. For negative ionization, the capillary temperature had been fixed at 300 C, the sheath gas at 40 arbitrary units (au), the auxiliary gas at 15 au and 280 C, and the sweep gas at 1 au. External calibration of the qOrbitrap mass analyzer had been performed once each day for three days by employing Pierce LTQ ESI calibration solutions. Measurements had been accomplished in negative and positive ionization ways in the Full scan data dependent MS2 discovery acquisition way in the m/z 70
1050 Da range. Upon an entire scan at 70,000 FWHM resolution at m/z 200, three scans had been conducted in the m/z 100
600 Da range at 17,500 FWHM at m/z 200 with an isolation window of 3.0 m/z with a stepped collision energy (SCE). The ddMS2 scans had been run with an automatic intensity threshold and dynamic exclusion (Musatadi et al., 2021).

Target analysis and suspect screening Target assessment and quantification had been done by employing TraceFinder 5.0 software that had a homemade database with the RT, exact mass, isotopic mode, and essence MS2 fragments of all target chemical. Concerning the parameter for target exploration and consecutive quantification, a 60 seconds window had been allowed for the RTs whereas a 5 ppm error had been supported for monoisotopic masses and fragment ions. In addition, 70% fitting had been approved for experimental and theoretical isotopic modes (Musatadi et al., 2021). The suspected screening had been performed by using the Compound Discoverer 3.1 program and the compounds of the suspected list the mzCloud library had been employed.

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From the explored xenobiotics, endogenous chemicals had been repudiated employing The Human Metabolome Database (HMDB, https://hmdb.ca/). To screen suspects, first, only properties with a Lorentzian chromatographic peak area and a minimum peak area of 107 had been taken. In addition, the properties should be in the three replicates conducted for every sample and the group differentiation should be lower than 30%. The ratio in regarding to the procedural blanks must be same or greater than 10 as well. The Compound Discoverer 3.1 program explained all the properties that, owing to their accurate mass and isotopic profile, paired with one or various of the chemicals in the suspect list. Next, fitting greater than 70% in the condition of the fragmentation spectrum had been taken employing the mzCloud library. Eventually, RT had been taken prior to the confirmation: (1) since the pure standard was present, and (2) if not available, a determination of the theoretical RT had been conducted implicating the RT index platform (http://rti.chem.uoa.gr/) (Musatadi et al., 2021).

Profiling of seasonal variation in and cancer risk assessment of benzo(a)pyrene and heavy metals in drinking water Aquatic contaminants usually have trace elements, fertilizers, microscopic organisms, and toxic organic compounds (Nambatingar et al., 2017). Water pollution produces direct impacts on human health, whereas sewage and industrial effluents develops indirect impacts on human health via consumed foods irrigated with polluted water. The World Health Organization 2011 suggested that more than 80% of human health problems are associated with water. Heavy elements in surface and ground water having Mn, Cr, Fe, Cu, Ni, Cd, and Zn produce

adverse impacts on human physiology (Singh et al., 2011). Polycyclic aromatic hydrocarbons (PAHs) in the environment have parent components and alkylated homologs. These chemicals (PAHs) are of main environmental issue with their persistence, bioaccumulation and toxic impacts (Badawy & Emababy, 2010). The health impact of single PAHs might be possible in case of high exposure. Long-term exposure might be more significant in order to overall public health (Carpenter et al., 2002).

Materials and methods Extraction and analysis of benzo(a)pyrene in water samples The LLE process explained by UNEP, 1989, showed the isolation of B(a)P from two liters of water sample with 60 mL of CCl4. This process had been conducted twice, and the combined extracts had been put into a flask for next step. Organic extracts had been further evaporated to dryness by a rotary evaporator. Upon evaporation, the residue had been liquified in 5 mL acetonitrile and next concentrated to 1 mL under N2 treatment. The extract had been further kept at 220 C till assessed by highperformance LC. About 12 μL of extract had been injected into a capillary column of stationary phase and then detected employing a UV detector at 254 nm wavelength. Water was used as the mobile phase, and the flow rate of acetonitrile was 1.5 mL minute21. Peaks on the chromatogram had been detected and matched with control RT and spectra. Enzyme-linked immunosorbent assay (ELISA) test kit method B(a)P are present at very low extents in drinking water. To obtain high recovery, high susceptibility, and high reproducibility, a B(a)P ELISA test kit had been employed as other approach for determining levels and further

Xenobiotics in Chemical Carcinogenesis

Profiling of seasonal variation in and cancer risk assessment of benzo(a)pyrene and heavy metals in drinking water

collated with HPLC. This is a competitive enzyme immunoassay approach. A 1.5 mL water sample had been used at a pH range (6.5
7.5) and regulated by 0.1 M HCl or NaOH. A B(a)P conjugate layering had been employed in the plate wells. If the target exists in the sample, it would compete for antibody interaction by checking the antibody from binding to the B(a)P adhered to the wells. Upon adding the substrate, the color of the secondary antibody tagged with a peroxide enzyme intensified, and the target primary antibody related with the B(a)P covering the plate wells, leading to an opposite relationship with the target level in the sample. Extraction and analysis of heavy metals The polyethylene containers had been taken for collection of heavy metal (HM) samples and then digested the sample using concentrated HNO3. Heating had been balanced by adding concentrated HNO3 till a light-colored, transparent solution appeared. Digested samples had been sieved employing glass fiber filters and next transferred to a 100-mL volumetric flask. Samples had been cooled, diluted to the right mark and mixed rigorously. Standard solutions with various concentrations of every HM had been made to get a standard curve. An AAS9000 Flame/Graphite Furnace Integrated Atomic Absorption Spectrophotometer of Skyray Company had been used. The detection limit for the determined parameters was 0.001 mg L21. Main contaminants like lead, manganese, copper and cobalt, had been assessed in collected water samples. Cancer risk assessment PAHs are natural environmental pollutants which play a vital role in carcinogenesis. PAH chemicals are biotransformed enzymatically, and some of them are reactive. The CYP1A1, CYP1A2, CYP1B1, and CYP3A4 cytochrome P450 enzymes are essential in the metabolism process for PAHs. PAHs undergo metabolic

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activation to diol-epoxides that covalently attach to DNA. The DNA binding of activated PAHs is necessary for the carcinogenic impact and has been explored in a several human tissues. A significant relationship between epidemiological results has observed a link between PAH exposure and the detection of PAH-DNA adducts (Jedrychowski et al., 2013). For human exposure to xenobiotic compounds (PAHs and HMs) in drinking water through several routes like ingestion and dermal absorption had been determined by below Equation, taken from Exhibits 1
3, USEPA. CDI 5

CW 3 IR 3 EF 3 ED 3 CF BW 3 AT

where CDI denotes for chronic ingestion of chemicals (mg kg21 day21), CW denotes chemical level in water (mg L21), IR denotes ingestion rate of water (L day21), EF denotes exposure rate, 350 days year 180 1, ED denotes exposure duration (year), CF denotes conversion factor (1, 106 kg mg21), BW denotes body weight in (kg), and AT denotes average time (day), 25,550 da. The exposure dose of B(a)P via the dermal uptake mechanism while bathing was estimated using an equation taken from “Dermal Absorbed Dose per event for Organic Compounds-Water Contact,” (USEPA, 2004). rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi στ event 3 t event DA event 5 2FA 3 kP 3 Cw π where DA event denotes for dermal absorbed dose of B(a)P per event, FA is the fraction absorbed water, kp denotes the dermal permeability coefficient of B(a)P, τ event explains the lag time per event (h event21), for B(a)P. B(a)P quantification is more authentic with HPLC than ELISA kits, and measured points were greater during the misty season in comparison to the dry season. Lower carcinogenic incidence risks (oral and skin exposure) had been observed with the ELISA kit than the

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HPLC approach. Carcinogenic incidence for both processes had admissible ranges and did not exceed standards, with maximum extents observed in children irrespective to adults. The maximum relevant contributors to alterations in overall cancer incidence seem to be changes in the concentration of B(a)P in several sampling sites, adopted by exposure length. Higher concentrations of lead had been detected in the drinking water. The incidence from HM exposure like lead is generally imperceptible with respect to incidence from B (a)P. Therefore, such approach might open an alternate way to future endeavors with respect to xenobiotic compounds involving in cancer development.

Toxicological analysis of anthropogenic xenobiotics associated with environmental metabolomics Currently, it has long been a major issue with increasing anthropogenic pollutants and their ecological and toxicological impact on organisms and the surrounding environment for decades. Metabolomics, a highly prevalent approach for readout of cellular activity, could explore organism reflections to several pollutant-associated stressors, having direct impressions to explain the environmental responses to toxic xenobiotic compounds (Zhang et al., 2021). Metabolomics, one of the recent “omics” methods, can identify several small molecules viz. metabolites in an organism when exposed to external stressors (Mathew & Padmanaban, 2013). Advancement and implication of metabolomics has increased rapidly for two decades, as returned by the ever-escalating publications in a different research area. The biological effects of metabolomics have been broadened beyond conventional characterization of simple biomarkers for exploring the molecular pathways (Johnson et al., 2016).

With the advantages of discerning of relationship between organism and environment at the molecular extent, metabolomics has exhibited its potential in environmental science that is known as environmental metabolomics.

Environmentally relevant organisms and anthropogenic contaminants There are two main factors: organism and environment, to study in environmental metabolomics field. The classical implications of environmental metabolomics are the examination of organismal reactions to different environmental biotic and abiotic stressors. Biotic stressors are those stressors that are obtained from other species or organisms inhabiting alike ecological niche like predators or male competitors in the same class. Abiotic stressors differ from natural components such as light, temperature, salinity and drought to anthropogenic components like environmental contaminants. In view of the increasing effects of environmental contaminants produced by anthropogenic activities, recently environmental metabolomics especially emphasizes the toxic impacts of anthropogenic pollutants on the ecosystem. Such studies are typically used in the area of environmental toxicology (Zhang et al., 2021). The initial step of environmental metabolomics methods is to recruit a model organism such as in the field or from the laboratory, and a different kind of environmental pollutants. At present, environmentally significant organisms employed for environmental metabolomics usually have animals (rodents, fish, crustacean and earthworms) and microbes (bacteria, yeast and microalgae). Such studies usually examined the ecotoxicity of anthropogenic components containing HMs, nanomaterials, pesticides, pharmaceuticals and personal care products (PPCPs), persistent organic pollutants (POPs) and other environmental contaminants Table 14.1. The succeeding

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Toxicological analysis of anthropogenic xenobiotics associated with environmental metabolomics

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TABLE 14.1 Some examples of detection of toxic xenobiotic compounds using animal models (Zhang et al., 2021). Xenobiotic compounds

Detection methods

Organism

Altered metabolic pathway

Pesticides

GC
MS

Brachydanio rerio

Amino acid metabolism; TCA cycle; neurotransmitter balance (glutamic acid, taurine and glycine)

Imidacloprid

NMR

Eisenia fetida

Maltose, glutamate, malate, fumarate, ATP, tyrosine, leucine, phenylalanine, isoleucine, betaine, valine, alanine, tryptophan and scyllo-inositol

Acetochlor, carbofuran, chlormequat, ethephon, fenpropimorph, and glyphosate

NMR

Wistar: rats

TCA cycle; energy production and storage; lipid, carbohydrate and amino acid metabolism

Bisphenol A

NMR

Chironomus riparius

Energy metabolism; protein biosynthesis; gluconeogenesis; methionine pathways

Fluoxetine, N,N-diethyl-metatoluamide, 17 alphaethynylestradiol and diphenhydramine

GC
MS

Crassostrea virginica

Cellular energetics (Krebs cycle intermediates), amino acids and fatty acids; osmotic stress; oxidative stress

Sulfamethoxazole

HPLC
HRMS

Mytilus Amino acids (aspartate, phenylalanine, valine galloprovincialis and tryptophan) participated in osmotic regulation and energy metabolism, nucleotides (guanosine and inosine) and a carboxylic acid

Persistent organic pollutants

LC
MS/

Benzo[a]pyrene

MS

Murine hepatoma Hepa1c1c7 cells

Amino acids, acylcarnitines and glycerophospholipids

2,20 ,4,40 tetrabromodiphenyl ether

LC
Orbitrap
MS

C57BL/6 mice

Purine, aspartate, glutamate, phenylalanine, tyrosine, and tryptophan

Nanomaterials

GC/LC-Q-TOF-MS

Daphnia similis Amino acid (serine, threonine and tyrosine), fatty acid (arachidonic acid) and sugar (D-allose) metabolism; protein digestion and absorptionGlutathione metabolism; carbohydrate, protein and lipid production

AgNPsTiO2 NPs

GC
MS

E. fetida

Acetamiprid and halosulfuronmethyl

ATP, Adenosine triphosphate; GC, Gas chromatography; HPLC, high-performance liquid chromatography; HRMS, high resolution mass spectrometry; LC, liquid chromatography; MS, mass spectrometry; NMR, nuclear magnetic resonance; NPs, nanoparticles; Q, quadrupole; TCA, tricarboxylic acid; TOF, time of flight.

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14. Profiling the reactive metabolites of xenobiotics in cancer

experimental step is to confirm the pattern of pollutants exposure. The exposure view of pollutants generally happens in laboratory and imitates those under natural circumstances, although there is an increasing interest in employing environmental metabolomics to the intricates ecosystems. Identification of metabolites and pathways The instrumental assessment is the highly crucial step in metabolite screening and exploring the corresponding pathway. Instruments that are applicable to determining a large number of metabolites are MS and NMR. Highly advanced MS analyzers can qualitatively, or even quantitatively, screen xenobiotic metabolites from a compound mixture with maximum selectivity and sensitivity (Dettmer et al., 2007), among which TOF and Orbitrap are mainly implicated in environmental metabolomics. MS tools could be assembled with gas chromatography (GC), LC and capillary electrophoresis, or used alone by direct infusion (Po¨ho¨ et al., 2019). The assembled chromatographic isolation and MS determination of metabolites have been highly utilized to understand environmental organisms which reflect to environmental stressors. GC
MS is made for the assessment of volatile and thermally durable components after derivatization, whose detection limits could attain nmol/pmol extent with maximum interpretive reproducibility (Dunn & Ellis, 2005). It is a bit useful for assessments of small molecule organic acids, amino acids, fatty acids, sugars and amines (Roessner-Tunali et al., 2003; Zhang et al., 2021), surpassing LC
MS and NMR in low instrument cost. Recently, the LC
MS has been highly accepted in metabolomics studies as it does not need sample derivatization, and is plausible for the assessment of polar, semi-polar and non-polar metabolites. The ultrahigh-pressure LC MS (UPLC
MS) is highly used in high-throughput metabolomics studies because the small pore size (2 mm) in the column which relevantly

reduces the time for assessment, during balancing high separation potential (Nu´n˜ez et al., 2012). Presently, important technologies of MS are influentially advanced to develop the separation and measurement methods, accomplishing it an auspicious technology tool in the field of metabolomics, achieving highly attention. NMR is a non-invasive method which provides great knowledge on metabolite structures in the liquid phase. There is no essential for isolation and derivatization of metabolites like MS-based metabolomics, where exhibiting intensive superiority in the assessment of sugar, amines and volatile ketones. The acquisition time (2
5 minutes) of a high-field NMR spectrometer is lesser than that of GC/LC
MS, whereas the accuracy and precision have revealed approx. 1% in a quantitative 1H NMR detection (Burton et al., 2005). Such characteristics explain NMR as a potential technology for toxicological analysis of environmental organisms from polluted fields (Melvin et al., 2018). Although, the limitations of NMR have low sensitivity, nonselectivity and the overlapping resonances (Emwas, 2015), indicating it not plausible for the focused metabolomics. The low sensitivity challenge might be reduce by the current advancement of higher field magnets (900 MHz) and cryogenically cooled markers (Wishart, 2008). The issues related with overlapping resonances could be overcome by two-dimensional addition methods (Ludwig & Viant, 2010). Therefore, by integrating MS and NMR, it is possible to have a high comprehensive array of metabolic exploration.

Conclusions Primarily, proteomics, metabolomics, toxicogenomic, and pharmacogenomics elucidate the advanced experimental methods to explore the functions of the biological system after interaction with xenobiotic compounds.

Xenobiotics in Chemical Carcinogenesis

References

Their interactions naturally recognize main targets for the development of the toxicity effect in organisms. In such conditions, enormous, trapped reactive metabolites were explored, which indicated that the metabolomic method is a potential tool for profiling the trapped reactive metabolites of xenobiotics. The various benefits of this method include: (1) escaping tedious method of determining the major reactive metabolites and explores knowledge on unpredictable reactive metabolites; (2) ignoring the implication of isotope-labeled substances; and (3) it is not only specified to the GSH conjugated groups, but also beneficial for other kinds of electrophiles like aldehydes and iminium ions. In future research on the function of reactive metabolites in toxicity, it has been proposed that (1) treatment with reactive metabolites in mice or other animal models, (2) structural alterations of a xenobiotic to stop the metabolic mechanism that produces reactive metabolite (s), and (3) genetic knockout or downregulation of the enzyme(s) which play a crucial role in production of reactive metabolites. Moreover, a multi-target approach capable of predicting about 200 xenobiotics in commercial and breast milk samples had been made, further increasing the determination of profiling by employing a database containing approximately 18,000 xenobiotic chemicals. The expeditious development of HRMS and data mining tools has led to exploring and profiling xenobiotic metabolites. Advanced approaches to explore extensive xenobiotic metabolites employing an integration of isotope labeling, nontarget assessment with LC/HRMS, data mining approaches, in silico metabolism determination, time-dependent profiling, and description of molecular sub-structures underlying HRMS/MS spectra have been studied. Such approaches can be used to the comprehensive assessment of several kinds of xenobiotic chemicals such as pesticides, drugs, and environmental hazards. Another approach is that environmental

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metabolomics is a promising ecotechnique to assess the effects of pollutants associated with stressors developed by anthropogenic activities based on xenobiotic compounds. Above all, the decades of research in the field of metabolic activities and xenobioticinduced toxicity does not unravel explain the generation and fate of reactive intermediates responsible for cellular damage. The generation of reactive metabolites and covalent interaction to macromolecules could be a signal for xenobiotic toxicity; however, it requires further studies to explain underlying mechanisms responsible for xenobiotic toxicity reactions.

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15 Toxicogenomics for the prediction of carcinogenicity of xenobiotic substances Introduction Chemical carcinogenesis is a multievent procedure involving modification of genome integrity observed as vital genes and chromosomal aberrations, malignant transformation of cells, and finally progression of cancer upon exposure to chemical agents. Owing to the relationship between DNA damage and formation of cancer, the preclinical security assessment pattern for drugs and chemicals consists of analyzing their genotoxicity such as their efficiency to lead DNA damage, and carcinogenicity, after prolonged exposure to chemicals developing tumors in animals (Fig. 15.1) (Ellinger-Ziegelbauer et al., 2009). The present development in sequencing, genomic techniques and system biology approaches has facilitated investigating cellular responses to toxic impetus of the complete genome through observing gene expression profiles and assessing toxic impacts in relationship to molecular mechanisms (Nuwaysir et al., 1999). The practicability of employing “fingerprints” to unravel molecular webs linked with toxicity have also been explained by using active genomic methods which exploited several yeast mutants or malignant cell lines (Weinstein et al., 1992). The potential

Xenobiotics in Chemical Carcinogenesis DOI: https://doi.org/10.1016/B978-0-323-90560-2.00005-4

of toxicogenomic assessment for determining genotoxic events to accomplish risk prediction of genotoxicity results in in vitro systems had been highly elucidated (Aubrecht & Caba, 2005). Several studies have explored associations of chemical exposure, toxicity, and disease conditions. The long-term animal model bioassay, the typical approach to detect carcinogenic factors of xenobiotic compounds to humans, is very expensive, so to save time and chemical resources, interest has emphasized short or medium-term bioassays (Tsujimura et al., 2006). One method is to explore alterations in gene expression in animal models in contrast to chemical exposure. Signatures of genetic changes cannot be explained by employing classical approaches for examinations of single genes but with the emergence of toxicogenomics, and the implication of cDNA microarrays, the potential functions of several genes in conjunction could now be possibly examined in high-throughput assessment which are highly sensitive and anticipative than, for instance, cell death analysis. Presently, uses of such methods for predictive toxicology employing gene expression profiles has been described by various groups (Boess et al., 2003; Hong et al., 2003).

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FIGURE 15.1 Investigation of genotoxicity and carcinogenicity. The genotoxicity testing permits a simple and correct analysis of DNA damage generated by application of the tested chemicals. In another way, carcinogenicity prediction assesses the ability to stimulate cancers in animals.

The emergence of genomics occurred more than a decade ago simultaneously with the sequencing of the human genome. Genomic, or “omics,” technologies describe all about the biological systems at the level of mRNA, proteins, or metabolites (Schmitz-Spanke, 2019). The implication of genomics approaches to study the toxicity of materials is known as toxicogenomics (Mahmud et al., 2016). Toxicogenomics is the field of science that explains the compilation, interpretation, and repositories of knowledge based on gene and protein activity, even within an individual cell or tissue of an organism in counter to chemicals. Toxicogenomics integrates genetics, genomic-level mRNA expression (transcriptomics), cell- and tissue-level protein expression (proteomics), metabolite screening (metabolomics) and bioinformatics with typical toxicology in an endeavor to unravel the function of gene environment interactions in impact and disease, respectively (Omenn, 2004). Usually, toxicogenomics is implied in two horizons: (1) to understand mechanisms based on toxicity and (2) to obtain modes of molecular expression like molecular biomarkers which determine toxicity or the genetic sensitivity to it. Toxicogenomics determine how the complete genome participates in an organism’s reactions to chemical agents such as drugs and

environmental factors. This gained growing consciousness in genetics with the accelerated development of high-throughput molecular profiling methods like transcriptomics, proteomics and metabolomics (Ancizar-Aristiza´bal et al., 2014). Statistical algorithms or machine learning approaches in combination with such high-throughput tools can recognize toxicogenomic biomarkers (Chung et al., 2015; Hasan et al., 2018). The toxicogenomic biomarkers are such genes or proteins or metabolites that are influenced by up/downregulated exposure to chemicals. In another way, from the notion of central dogma, the expression of a gene controls the expression of its products like proteins and metabolites (Zhu et al., 2005). Hence, chemicals toxicity could be detected from the gene expression assessment of target organs prior to the phenotypic alteration has been observed (Igarashi et al., 2015). Toxicogenomics integrate high-throughput molecular methods with statistical and machine learning techniques to explore an identical class of doses of chemical compounds (DCCs) and genes to identify toxicogenomic biomarkers and their administrative DCCs. This is also highly vital in the toxicity study of environmental factors, synthetic compounds and drug discovery and development event.

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Introduction

Cancer is one of the major reasons for mortality all over the world. Several chemicals including toxic xenobiotics can cause cancer. Given the rising number of new chemicals that are manufactured every year, prior going to the marketing, it is highly essential to examine chemicals for their carcinogenic potential. For such investigations of chemicals, the lifetime bioassay employing rats and mice is generally used. Although, over the years such analysis has apparently appear to show various limitations: plenty numbers of animals are employed, and the assessment are lethargic, unresponsive and costly. Beyond this, there is major scientific ambiguity about the authenticity of the assessment, since a number of false positive outcomes (so-called rodent carcinogens) have been detected. Hence, alternative approaches to determine carcinogenic potential of compounds are in demand (Schmitz-Spanke, 2019). In such views, new technologies like toxicogenomics play vital roles in improving the current test method. Toxicogenomics emphasize that molecular mechanisms are associated with a toxicological impact and must explore molecular biomarkers for the toxicity prediction (Schmitz-Spanke, 2019). The advancement in biotechnologies would now help in the prediction of higher mutations, epigenetic modifications, and alterations in gene expression in cancer cells. The authentic, economical, and hasty exploration of mutations, gene expression profiles, and epigenetic changes in cancer genome has resulted to insights in knowing cancer biology and to upgraded cancer diagnosis and treatment. Over the past decades, germline mutation prediction methods have rapidly advanced from low throughput, low resolution approaches such as restriction fragment length polymorphism (RFLP) assess nextgeneration sequencing (NGS) tools that contribute to very high-resolution genetic knowledge associated with cancer development (Ning et al., 2014). The potentiality of molecular epidemiological studies of several kinds of cancer has

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emerged from single marker association assessment employing RFLP to various marker association assessment implicating TaqMan assays (Hartikainen et al., 2006), and to genome-wide association studies (GWAS) employing microarray approaches (Hunter et al., 2007). Coinciding with the disclosure of Illumina MiSeqDx in November, 2013 which was the first NGS program to obtain marketing approval by the FDA, Collins and Hamburg explained the ample power of high-throughput sequencing method to revolutionize biomedical science and clinical medicine (Collins & Hamburg, 2013). Presently, NGS approaches are implemented in exploring the details of higher level of molecular activities with a relatively inexpensive, leading the ambient assessment of human and cancer genomes. The complete genome sequencing of integrated cancer and adjoined normal tissue reveals a conclusive image of the cancer genome. Further, NGS brings the opportunity to understand the activities of mutational signatures in cancer development which could be related with plausible etiologies like exposure to genotoxic component or aberration in DNA repair (Alexandrov et al., 2013). The comparative studies of somatic and germline mutations at basepair resolution clearly explains how the cancer genome varies from the normal genome and sheds light on the pathways/events of cancer development (Banerji et al., 2012). Many international consortia, like The Cancer Genome Atlas, the Cancer Genome Project (at the Wellcome Trust Sanger Institute), the International Cancer Genome Consortium, and Catalogue of Somatic Mutations in Cancer (COSMIC) have made enormous endeavors to explore cancer markers and mutations. Mutations, translocations, and certain therapeutic targets have been explored in several cancer subtypes by employing NGS approach (Xie et al., 2014). Microarray is a novel approach in profiling the expression of hundreds to thousands of genes in malignant tissues, allows classifying of cancers (like gastric cancer) into clinic subtypes, and determining

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cancer reiteration and response to various treatment methods (Sotiriou & Piccart, 2007). NGS contributes enough greater resolution and enhanced intensities of cancer gene expression by describing features of transcriptional barriers, differential expressions, mutations, uncommon transcripts, and abnormalities in alternative splicing (Kaur et al., 2013). Another molecular alteration related to cancer could be predicted by NGS. It has been used NGS approach to detect copy number variations for nuclear, mitochondrial, and telomeric DNA sequences with high precision (Castle et al., 2010). Similarly, NGS is a potential technology for determining the epigenetic alteration leading to alterations in gene expression. For instance, chromatin immunoprecipitation integrated with NGS (ChIP-Seq) had been applied to explain epigenome maps based on the developed mechanisms for drug resistance in breast cancer while endocrine therapy (Magnani et al., 2013). Toxicogenomics data collect details about role of gene/protein in response to the exposure to chemicals and have been highly unraveled in the past decades (Su et al., 2021). Several wide parameters for toxicogenomics screens have been explored to acquire relevant knowledge about the molecular profiles and the toxicity of chemicals (Su et al., 2021; Uehara et al., 2010). Toxicogenomics data have been used in designing of computational models to assess organ-specific toxicity or overall toxicity. Uehara et al. (2011) worked gene selection and toxicity classification and recognized candidate biomarkers for both genotoxic and nongenotoxic carcinogenic compounds in the rat liver; Su et al. (2019) made a multidose model for the determination of hepatotoxicity; Yamane et al. (2016) used a gene network, the gene-to-gene interactions, to assess progression chemical toxicity. Some studies also integrated another kind of information with toxicogenomics such as with the QSAR to analyses the drug based liver toxicity; Sutherland et al. (2018) made a coexpression model TXGMAP

and integrated it with the pathological data to predict the events of hepatotoxicity. Maximum studies used the gene expression precisely. However, the extents of gene expression might not be highly impacted by certain drugs and the noise might command the transcriptional signals (Alexander-Dann et al., 2018). The biological assessment highly aids in differentiating the signals from the noise and also facilitating the enhancement of predictive potential (Su et al., 2021). Until now, toxicogenomic methods have highly increased the unraveling of mechanistic disturbances developed by several chemical agents including xenobiotic compounds (Schmitz-Spanke, 2019). Mainly, the complementary implication of omics data and cellular and molecular assessment accomplishes it plausible to connect alterations in omics profiles to adaptive or adverse impacts. Although, this area of area is only an instance of the toxicogenomic ability, and it is highly relied, that toxicogenomics is not only helpful to enhance mechanistic knowledge, but would also aid several advantages for risk analysis. Risk assessment methods contain, among others, analysis of scientific knowledge on the hazardous features of xenobiotic agents (hazard identification) and the dose response relationship (dose response analysis) (Schmitz-Spanke, 2019). The several xenobiotics compounds develop distinct cancer by perturbing or following different molecular mechanism which toxicity levels are predicted precisely by molecular methods. Hence this chapter will explain the assessment of xenobiotic toxicity at the genomic level by emphasizing the toxicogenomics.

Mechanistic inference to toxicogenomics Recently, various computational approaches have shown exemplary accomplishment in detecting toxicity impacts of compounds (Luechtefeld et al., 2018; Pu et al., 2019; Tripodi

Xenobiotics in Chemical Carcinogenesis

Introduction

et al., 2020). Computational methods usually develop mechanistic hypotheses to explore why such chemicals produce a toxic effect. It is a novel context in knowing the event of toxicity for a chemical which observes to explore an adverse response. A small molecule development is one instance, where a chemical that failed early screening of toxicological impacts can be analyzed to determine the original mechanism of toxicity, highly decreasing research time and costs on subsequent ones. The principle of a mechanistic knowledge of toxicity also implicated to pharmacovigilance, since researching rare negative impacts of a drug in subgroups of the population. The progression of oncological chemotherapeutics is other instance, where particular events of cytotoxicity could really be advantageous to remove several kinds of malignant cells. Notably, the expenses, time consumption, and ethical issues of toxicity animal models, entice toward alterative procedure particularly in vitro and in silico methods. Presently, it has been accessed to a wealth of biological, chemical and medical structured data presented in domain-specific ontologies. These ontologies explain distinct relationships between its components such as protein protein interactions, or involvement of enzymes or chemicals in biological pathways, at certain cellular chamber. The Gene Ontology (Ashburner et al., 2000; Tripodi et al., 2020) (GO) is highly employed, and several types of tools are used to search enrichment of specific concepts (Martin et al., 2004; Mi et al., 2019) or even certain mechanisms (Tarca et al., 2009). The implication of artificial intelligence (AI) to discuss mechanistic modes in biological science or other fields is still at an early stage. Maximum computational researches on biological events has been emphasized on their representation (Tripodi et al., 2020), and approaches focused at explaining a event of toxicity have usually been targeted to particular chemicals, or limited groups of them. Prior work in

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discovering enrichment of adverse outcome pathways (AOPs) (Ankley et al., 2010) had been emphasized on targets such as pulmonary fibrosis (Nymark et al., 2018) or fatty liver (Bell et al., 2016). Computational methods are often encountered with skepticism, especially as the tools turn into “black boxes” (Castelvecchi, 2016). A hypothesis generation tool which makes mechanistic descriptions backed by curated existing information, although, will lead to more fascinating alternatives as scientists can confirm the possible explanations. In addition, scientists can spot any major errors, regulating web of knowledge properly with all community gain from it. If considering toxic xenobiotics in the environment, a mechanistic, general description of toxicity might be selected over a statistical or machine learning-based detection by itself. Describing an event of toxicity is, although, an expensive and time-taking method which needs the involvement of experts from a different area, usually depending on animal models. One newly developed tool for mechanistic inference framework (MechSpy) is implicated as a hypothesis generation for understanding the mechanistic toxicology associated with human biology and biochemistry along with gene expression time course on human tissue. Employing vector presentations of biological components, MechSpy explores enrichment in a manually curated list of high-level events of toxicity, exhibited as biochemically- and causally-associated ontology views. Instead of detecting the approved event of toxicity for various well-explored chemicals, it had been experimentally confirmed some predicted compounds without known mechanisms of toxicity. Such mechanistic inference framework is a helpful technique for determining toxicology, and the first of its kind to develop a mechanistic description for every detection. MechSpy is improved to add more mechanisms of toxicity, and is generalizable to another kinds of event of human biology (Tripodi et al., 2020).

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Onset of system toxicology Over the past fifty years, biological sciences have become advance after the discovery of gene, genome and genetic code, role of genes and mutation of genes. By this, the researchers have invented the genetic code which is the building block and principle of all molecular function in biological system. According to this, various molecular tools have been explored to unravel molecular mechanism, impacts of chemical exposure within organisms and environment. For this assessment, the need of toxicogenomics is very important, which deals with the impact of chemical in altering the genetic modes along with mutation into gene. Toxicogenomics also explains the transcription of proteins and metabolite profiling to examine the interplaying of genes and environment stress in several diseases including cancer. Toxicogenomics also explained the modified expression of genes developed by mutation and chemical exposure which led to the development of various diseases and reveals toxicant role in cell. Therefore the main aim of toxicogenomics is to eliminate such exposure of toxic chemicals and xenobiotics and contribute to mitigate several diseases associated with toxicity. The utilization, implementation, correlation, integration and association of several relevant, crucial, advance biological areas such as proteomics, transcriptomics, bioinformatics, microarray and many more other molecular events are performed by toxicogenomics which are constantly emerging in systems toxicology (Mahmud et al., 2016). Emergence of molecular toxicology After revelation of DNA structure by Watson and Crick, the history of molecular biology has been subdued. The potential of complete translating the codes into functional is absolutely challenging for past six decades. The precise development of molecular biology to toxicology contributes to deciphering

molecular aspect to organism health. Southern blotting is a technique to visualize the genetic materials in a way of feasible which has been entrenched in 1975. Further, the modified form of southern blotting has been entrenched as northern blotting which determines RNA transcript (Alwine et al., 1977). Hence a technological breakthrough happened that certified the toxicologists to determine the way of alteration within the DNA transcript and explores the modifications of gene expression in cells exposing to toxicants. The first implication of northern blotting had been designed to detect lactate dehydrogenase transcript exposing to materials (Mahmud et al., 2016). Now, the more advance methods have been established which are capable to measure small amount of sample and also track the molecular mechanisms in genomic level. For instance, the Microarray chip is a highly modern technology for studying of molecular events published first in mid-1990s. DNA microarray comprises two kinds of roles, one that had been generated with “onchip formation” of short oligo sequences having technologies from semiconductor industry (Chee et al., 1996). The purification of lengthy DNA “spots” developed by PCR is the next activity of microarray chip (Hughes et al., 2000; Mahmud et al., 2016). The outcome for either floor was a very simple array which can uniquely grant the probing the complete DNA transcript profile and investigate the expression of functional genes in host for biological hybridized RNA and it developed a different area in toxicogenomics. Presently, “toxicogenomics” explains the interface of various functional genomic methods which are employed to explore the condition of toxicity (Brown & Botstein, 1999). The National Academy of Sciences and also scientists have deciphered the need and disadvantages of toxicology to calculate individual sensitivity and incidence, assessment of exposure, description of mechanism (Mahmud et al., 2016). The lucrative performance of microarray technology requires

Xenobiotics in Chemical Carcinogenesis

Introduction

the progression of interdisciplinary sciences across various rules like chemistry, engineering, mathematics, computer science, molecular biology and engineering (Afshari et al., 2011). Emergence of the field of toxicogenomics Toxicogenomics has three principal objectives: it explains the relationships between environmental factors and human disease sensitivity, it predicts novel biomarkers for diseases and exposure to toxic compounds; and it describes the molecular events of toxicity (Waters & Fostel, 2004). In toxicogenomics study, animal experiments are generally considered. This experiment has three treatment groups: high-dose and low-dose treatment groups and a control group which has obtained the solvent mainly along with the test agent. Such groups are experimentally determined at two or three points in time that are accomplished three to five animal models per group, therefore toxicogenomics study explains a simple and acute-toxicity level (Hamadeh, Knight, et al., 2002). These two groups have variations in their scope of the response from which they are determined and, in the methods, implicated. The high-dose treatment is revealed under toxic impact of compound, the toxicogenomics research could detect such toxic response employing the all-comprehensive measurement techniques. Toxicogenomics study has made a list for all sample genes which are expressed distinctively. Whether it is not plausible, profileassessment approaches are used to doseassociated and time periods studies for the exploration of genes and gene profile of sample individual (Hamadeh, Knight, et al., 2002). By employing the knowledge that is derived and collected from literature assessment a comparative investigation and modeling of molecular expression datasets has been developed to identify the adaptive responses of biological systems (Zweiger, 1999). It also explains those alterations which are related with clinical or discernible

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adverse impact. For 5 years, the area of toxicogenomics has highly expanded within the view of gene expression profiles as “signatures” of toxicant groups, disease related or other biological effects. Via analytical research, such signatures are developed for prognostic biomarkers of toxicant impacts and such signature are now help to explore the dynamic changes in molecular events which are related with toxic and adaptive activities. Recently, the research associated with toxicogenomics are highly developing and the content of gene expression database also enhances. For the investigation of per dose-time class, each animal tissue needs 18 45 microarrays and 2000 or higher transcripts per array needed for consequent assessment (Kaput & Rodriguez, 2004). Likewise, all animal have treatment-based data on their total body and organ-weight analysis, clinical chemistry assessment and microscopic histopathology results for various tissues (Mahmud et al., 2016; Mattes et al., 2004; Stoeckert & Parkinson, 2003). Such relevant data collection, management, and integration have been accomplished precisely and this method is highly critical for the experimental events and for depicting toxicological results. Therefore the collection of all such data is needed in terms of dose, time and severity of the toxicological or histopathological phenotype. Such experimental data are assembled to assess with toxicoinformatics techniques and computational modeling and it acquires a new significant knowledge of toxicant-based disease (Tennant, 2002). Therefore the toxicogenomics is the assemblage of the multiple data collection obtained from transcriptomics, proteomics and metabonomics through conventional toxicological and histopathological endpointassessment. Such assemblage is highly capable to generate knowledge on the linkage between toxicological impacts and molecular genetics. Now toxicology and toxicogenomics are evolved broadly on single compounds and stressors into a knowledge-based science (Waters & Fostel, 2004). Toxicogenomics is based on “predictive

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toxicology” which is the phenotypic outcome of a component on an associated strain, and this could be employed to explore the way of activities of similar compound in related strain or other species. Such outcome also implicated for other toxicogenomics works associated with genotypes and the species are comprehended for multigenome knowledgebase. Such knowledgebase are ascertained by chemical formula or kind of stressor, by gene, protein or by assessing the metabolism of metabolic molecule or by phenotypic results of other components which show the outcome of newly tested component (Tsai et al., 2009). All these factors show that toxicology is the study of information science based on genomics and proteomics (Fig. 15.2). For instance, single rodents have been exposed to different doses of chemicals and tissues have been taken at several time points and process to microarray assessment. Calculations have been accomplished to (1) analyze the relevantly modified genes in every sample and (2) map such gene modifications into annotated mechanisms. This leads for initial determination of insight to crucial events of tissue response to chemical disturbances. The expression files might also be mapped against archived files to analyze similarities of chemical action/response to other chemicals which had been explored in the database earlier (Afshari et al., 2011).

FIGURE 15.2

Genetic toxicology: transcriptomics For explaining genetic toxicology, toxicogenomics, using transcriptomics, is utilized to follow up positive genotoxicity to decipher the mechanism of action. The development of DNA array techniques and enhanced sequence information meant that gene expression microarrays can be employed to determine and identify alterations in genome-wide gene expression that is different to biosensor cell lines which cover a restricted number of biological mechanisms. Thus transcriptomics had been detected to understand major effects in the area of genetic toxicology (David, 2020). DNA damage caused in a stress response stimulates gene expression alterations in various biological mechanisms (Fornace et al., 1992), and chemicals trigger a certain mode of gene expression alterations according to their MOA (Hamadeh, Bushel, Jayadev, Martin, et al., 2002). Such distinct expression profiles for particular groups of chemicals can work as “fingerprints,” that can be employed in classifying the compounds and detect their way of action, where increasing the hazard identification method (Hamadeh, Bushel, Jayadev, DiSorbo, et al., 2002). One field of specific focus has been the differentiation of genotoxic from nongenotoxic carcinogens employing gene expression fingerprints, and this has been

Schematic presentation of toxicogenomics.

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Genetic toxicology: transcriptomics

explained by a several groups. For instance, mRNA transcriptomic profiles suggesting exposure to genotoxic and nongenotoxic carcinogens have been explored for human peripheral blood mononuclear cells, mouse liver, rat liver, HepG2 cells and TK6 cells (David, 2020). For instance, it has been detected transcripts modified by genotoxic but not nongenotoxic carcinogens participated in pathways like immune response, apoptosis and cell cycle, whereas for nongenotoxic carcinogens, signaling transduction and protein phosphorylation had been regulated (Hochstenbach et al., 2012). And mRNA expression profiles being capable to differentiate MOA, microRNA (miRNA) profiles have also been explored as contributing mechanistic views consecutive exposure to genotoxic and epigenetic hepatocarcinogens (Koufaris et al., 2012) as well as genotoxic and nongenotoxic carcinogens (Melis et al., 2014), and cDNA microarrays have been revealed to differentiate between various MOA in several cell lines (Amundson et al., 1999). Looking to the usage of such signatures in genotoxicity examination, it had been successfully classified the mixed samples employing gene expression profiles developed from known chemicals, and signatures from genotoxic and nongenotoxic carcinogens had been successfully implicated to identify carcinogens which provided obscure genotoxicity outcomes. To assess if even gene expression profiles can be related with the event of action, various model genotoxins had been examined by the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) group. These encompassed a DNA methylator [methyl methane-sulfonate (MMS)], DNA cross-linkers [mitomycin C (MMC) and cisplatin] and nucleotide pool perturbators (hydroxyurea). Only some reproducible gene alterations had been detected at low concentrations and less time periods (4 hours), and alterations .threefold were not frequent, even at greater genotoxic level of chemicals.

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However, alterations had been determined at greater doses and a longer time-period (24 hours), and a few biologically significant genes, like GADD45 (Growth Arrest and DNA Damage) family, were actively upregulated at cytotoxic concentrations. Expression alterations of the GADD45 gene also related with the extent of DNA-platinum adducts and DNA protein cross-links. Exposure to MMC stimulated genes participated in other mechanisms like endoplasmic reticulum stress and the unwind protein response in addition to DNA damage recovery genes. It had been concluded that during gene expression alterations predicted were not as susceptible as conventional outcomes, the significance of gene expression profiling for genotoxicity is to distinguish chemicals which interplay directly with DNA from those that are genotoxic through a secondary pathway (David, 2020). After showing the promising outcomes by such transcriptomics studies, this technique has not highly revolutionized the area of toxicology in the way it had been envisaged. There are several issues associated with gene expression microarrays like giving an indirect assessment of relative concentration, integrating of several related sequences to the same probe, and only being capable to determine sequences the array had been made to detect (Bumgarner, 2013). Although, new sequencing technologies, known as NGS, have the capacity to revolutionize genetic toxicology by increasing knowledge of DNA from a sequence and also mutation aspects.

Next-generation sequencing So far, NGS techniques have revolutionized genomics because of the fact that hundreds of billions of base pairs could be sequenced at the same time in lower cost and faster than conventional Sanger processes (Schmitt et al., 2012). Such processes have highly developed

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over the automated Sanger techniques; NGS libraries are synthesized in a cell-free system, thousands to millions of sequencing reactions are conducted in parallel and the sequencing result is direct, with base investigation done cyclically and in parallel (Thermes, 2014). In reality, the millions of sequencing reactions are done in parallel and the capability to sequence every base several times enhances the depth and so accuracy of the data (Behjati & Tarpey, 2013). “Deep sequencing” has been implicated in a several areas such as metagenomics, forensics, and human genetics, and clinical implications include determination of fetal aneuploidy (Schmitt et al., 2012). Various different NGS programs which employ several sequencing technologies have been designed and are continuing to make advance (Thermes, 2014).

Artificial intelligence and machine learning Machine learning is a kind of AI in which computers could cognize from data and do prognostic studies (Wu & Wang, 2018). It could be rapid, cost-effective, and more accurate, and machine learning is being employed to explore toxicity (Yang et al., 2018). The accuracy of the predictions done by machine learning is based on the extent and quality of data implicated to instruct the algorithms. NGS develops maximum number of datasets which are useful to machine learning and can be implicated to classify chemicals and envisage toxicity. For instance, machine learning as a support vector machine (SVM) had been employed to screen compounds according to toxicity stimulated in 3D-cultured human pluripotent stem cellisolate neural cells (Schwartz et al., 2015). In other study, it had been performed transcriptomic assessment ensuing treatment of embryonic stem cells with various compounds, which they were capable to comprise into groups like genotoxic and nongenotoxic carcinogens, and implication of SVM enabled the researchers to assess late

chemical toxicity (Yamane et al., 2019). Machine learning has also been used to detect somatic mutation like MutationSeq, SomaticSeq, SNooPer, and Cerebro. Presently, these have several issues like investigating on small training datasets, problems with places which are rigorous to map, have ultra-high coverage or low complexity and not appraising detection of low-frequency mutations. As machine learning algorithms develops, and maximum datasets responsible to machine learning are created to teach the algorithms and certify such methods, this could be a potential technique for mutation determination (David, 2020).

High-throughput screening Microarray- or RNA-seq-based TGx approaches give beneficial knowledge about how thousands of genes in living systems counter to xenobiotic compounds, though they are highly costly to present as high-volume screening examinations for the impacts of thousands of compounds in different cells at a range of dose levels and time periods. Whereas, single high-throughput screening (HTS) approach consider only one or some genes at a time, but permits thousands of compounds to be screened in a single day over a wide range of concentrations. In contrast to highly costly conventional toxicology and TGx examinations, in vitro screening investigations as employed in the triage of molecular libraries for specific molecular or biological functions usually apply larger and fewer doses of the compounds, some test materials, smaller investigation duration, and lower extensive assessments of the toxic results. Hence, HTS creates a practical approach to examine more than 100,000 chemicals per day in decreased in vitro assessment to explore those causing for potential adverse impacts. For safety assessment and toxicity examining “hits” in the screening analysis in order to biological mechanisms which are understood to cause for adverse effects. With

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Genetic toxicology: transcriptomics

ample collected data, it might be plausible to implicate structure-activity assessment to determine HTS hits, in order that potential targets could be anticipated before to screening. The implication of robotic HTS as a beneficial accompaniment to conventional toxicology has been increasing (Waters, 2016). HTS assessment has been widely categorized into two methods: biochemical analysis and cellbased assessment. Biochemical (cell-free) assessment usually accounts direct impacts on particular molecular targets of interest. Such assessments are employed to determine enzymatic activity, integration of compounds to receptors, ion channel role, nuclear receptor activity, and protein protein interactions. As they participate in homogenous reactions, biochemical assessments are highly decreased. Although, not all targets can be made adequately for biochemical assessments. Further, a chemical’s activity determined in cell-free analysis is not highly related to its activity in the intact cell that might be influenced by the appearance of intracellular cofactors, issues of membrane permeability, cytotoxicity, and other impacts on the target components. However, cell-based assessment determines the impacts of compounds on mechanisms of interest in the physiological condition of a cell without considering the specific a molecular target. There are several instances like functional analysis, reporter-gene assessment, and phenotypic studies for processes like cell migration or division. Cell-based assessments determine impacts on complete mechanisms, and alterations can be analyzed at more than one step in a pathway. Cell-based HTS in 1536- or even 3456-well plate arrangement is not exceptional that is required more explanations (Waters, 2016).

Predictive toxicology Predictive toxicology is described as how toxic impacts are determined in model systems/humans could be applied to predict

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pathogenesis, analysis of incidence, and thwart human disease. Developing risk analysis is a major objective of predictive toxicology. Knowledge gaps and deviations consist of: The requirement of larger toxicity screening data, data on impacts in humans and on human exposure extents; knowledge on the significance of animal data to humans; exposureresponse data (mainly at low, environmental exposure extents); data on various paths of exposure; data on the impacts of co-exposure to more than one compound; data on human variations in sensitivities to toxicants; and knowledge to unravel or describe disparities in data from several animal models. TGx approaches are able of explaining several, if not all, of such knowledge gaps. Although, completely associating TGx techniques into predictive toxicology would need a coordinated endeavor to explore major datasets and to extract the necessary data and information which could be implicated for predictive determination. For this approach, it is a more requirement for better bioinformatics, statistical, and computational methods and software (Waters, 2016).

Toxicogenomics-related exploration of pathways for immunotoxicity Direct immunotoxicity is explained as direct detrimental impacts of a xenobiotic on the active immune system, while indirect immunotoxicity is an allergic affect that leads tissue injuries after exposure to a xenobiotic compound. Direct immunotoxicity is produced by either inhibition or by stimulation of the immune system, referred as immunosuppression and immune enhancement, respectively (Corsini et al., 2013; Galbiati et al., 2010; Shao et al., 2013). Several chemicals with direct immunotoxic impacts develop highly human health incidences exposing to food (Nyarugwe et al., 2020), drinking water, and the environment.

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Direct immunotoxicants are metals, mycotoxins, agricultural pesticides, industrial compounds, and specifics drugs. Presently, the molecular events of direct immunotoxicity are not well explored for the maximum xenobiotic chemicals (Shao et al., 2013). Currently, the implications of genomics approaches have led to advanced mechanistic knowledge for a specific array of direct immunotoxic chemicals. The rodent in vivo studies revealed that several direct immunotoxicants can have overlapping event of function at the extent of gene expression: cell cycle arrest had been exhibited by the polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP), the immunosuppressive drug cyclosporine A (CsA; calcineurin inhibitor), and the industrial chemical tributyltin oxide (TBTO; organotin) in murine spleens (Baken et al., 2007), while T-cell receptor and CD28 signaling had been modified in murine thymocytes by the immunosuppressive drugs cyclophosphamide (CP; alkylating agent), diethylstilbestrol (estrogen), and dexamethasone (glucocorticoid) (Frawley et al., 2011). The implication of immunotoxicogenomics in in vitro condition has led to advanced insights into the mechanism of action (MOAs) of direct immunotoxic chemicals. For example, transcriptome assessment of human lymphocytes exposed in vitro to immunotoxicants have led to the recognition of calcium-based activation of endoplasmic reticulum (ER) and oxidative stress by the organotin chemical TBTO (Katika et al., 2011, 2012) and the trichothecene mycotoxin deoxynivalenol (DON) (Katika et al., 2012). Hence, the recent work focused to obtain insights into the molecular event associated with direct immunotoxicity. It has been analyzed in vitro the impacts of 31 test chemicals on the transcriptome of the human Jurkat T-cell line. Such chemicals were direct immunotoxicants, immunosuppressive drugs with various mechanism of actions, and nonimmunotoxic regulating compounds. Pathway assessment of the microarray data led to explore canonical

mechanisms and Gene Ontology methods which had been transcriptionally mediated in general by immunotoxicants (1) with structural resemblance like tributyltin chloride and tributyltin oxide which induced the retinoic acid/X receptor signaling mechanism and (2) without structural resemblances like As2O3, dibutyltin chloride, diazinon, MeHg, ochratoxin A (OTA), S9-treated OTA, S9-treated cyclophosphamide, and S9-treated benzo[a]pyrene that induced unfolded protein response, and FTY720, lindane, and propanil that stimulated the cholesterol biosynthesis mechanism. Moreover, procedures strangely impacted by single immunotoxicants had been explored like activation of Notch receptor signaling and the suppression of acute-phase response genes by OTA. Such outcomes had been confirmed by quantitative realtime PCR assessment of genes participated in these methods. This study suggested that different mechanisms of action have participated in direct immunotoxicity and that an array of pathways or genes, in spite of one individual gene, could be employed to screen chemicals for direct immunotoxicity (Shao et al., 2013). It has been concluded by employing in vitro toxicogenomics methods that the explored cellular pathways and procedures which are transcriptionally regulated upon exposure to direct immunotoxicants. The value of the Jurkat T-cell line as a sensitive system has also been deciphered for identification of mechanisms associated with direct immunotoxicity. The involvement of diverse MOAs indicated that an assay underlying an array of mechanisms or genes, rather than one single gene, would allow to screen chemicals for direct immunotoxicity. Hence, the Jurkat cell model might not be applicable to test chemical which mainly target immune cells other than T cells. So, the assessment method could be advanced based on the outcomes of the recent study should not be used as a universal screening assessment but as a potential assay to complement animal-free immunotoxicity testing technologies (Shao et al., 2013).

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Prediction of carcinogenicity effects of xenobiotics by toxicogenomics methods

Prediction of carcinogenicity effects of xenobiotics by toxicogenomics methods Genotoxic and nongenotoxic carcinogenesis Following the move in the compound recruitment approach used by the National Toxicology Program (NTP), it was a progressive identification of the increasing numbers of presumptive nongenotoxic carcinogens. A decreasing particularity of the short-term genotoxicity test battery had been determined together owing to the fact that reference sets of National Cancer Institute/NTP (NCI/NTP) carcinogens moderately encompassed maximum nongenotoxic carcinogens. From a regulatory context, the identification of nongenotoxic events of carcinogenesis has detailed the well-known associations between genotoxicity and carcinogenicity. Nongenotoxic carcinogens are not determined in regular short-term genetic bioassays and the significance of some nongenotoxic event of rodent carcinogenesis to chemically stimulated cancer development in humans has been questioned (Waters et al., 2010). Among all chemicals tested in rodents, approximately 50% compounds are carcinogenic (Kinoshita & Miyata, 2002) and about half of these are presumably nongenotoxic (Snyder & Green, 2001). Rat liver elicits mainly susceptible to nongenotoxic carcinogens, and

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has been highly studied to explore the major mechanisms participated. It is confirmed that both genotoxic and nongenotoxic compounds develop cancers in a distinct target region in rodents. The eight highly frequent target regions in both rats and mice are liver, lung, mammary gland, stomach, vascular system, kidney, hematopoetic system and urinary bladder (Fig. 15.3) (Gold et al., 1993). Some species have different target organs like the liver, Zymbal’s gland and kidney. Although, there is no evidence for any methodical interspecies variations in tissue distribution and pharmacokinetics between genotoxic and nongenotoxic compounds, and nor for the concept that such two groups of compounds generate cancer in several target organs (Gold et al., 1993). The outcomes of predictive toxicogenomics examinations over the past 6 years have covered new light on the major implication of molecular expression assessment to more accurately classify putative carcinogens. Toxicogenomics, that is, mRNA transcription profiling to explore genes which counter to groups or categories of compounds, and statistical classification approaches apparently have developed in their capability to detect carcinogenicity. The researchers cited in this report have explored cancer-inducing gene arrays which differentiate genotoxic carcinogens versus nongenotoxic carcinogens versus noncarcinogens. The approach used recruits a training FIGURE 15.3 Assessment of xenobiotic exposures can be performed at each dose/time point/organ separately.

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set of the identified carcinogenic (genotoxic or nongenotoxic) and noncarcinogenic chemicals to which to expose mice or rats in vivo or cultured cells in vitro from 1 to 90 days. Statistical classification tools are employed to determine expressed genes which differentiate the probable results groups. The training set genes are further implicated in classifying uninvestigated compounds. In other way, the genes expressed by the chemicals in the “‘training sets”’ are employed to exhibit the major mechanism of action of unidentified compounds and classified as DNA reactive, or a carcinogen or noncarcinogen (Waters et al., 2010). Analysis of genotoxic carcinogenicity by toxicogenomics methods The presence of cDNA and oligonucleotide microarrays has facilitated the exploring of pertinent genes, mechanisms and networks which are based on genotoxic events at the genomic extent (Aubrecht & Caba, 2005). Ionizing radiation had been employed as a model treatment in understanding the genotoxic stress impact at the gene expression extent (Amundson & Fornace, 2001; Amundson et al., 2003; Waters et al., 2010). The cellular response to ionizing radiation is stimulated through the p53 pathway and participates in cell cycle arrest and apoptosis, as well as the stimulation of MAPK cascades, NF-kB, and the AP-1 transcription complex. The changed mRNA extents determined employing this method reflect in controlling of genes participated in the cell cycle (CDKN1A, GADD45, Cyclin E), apoptosis (BAX, BCL-XL), DNA repair (XPC, DDB2, GADD45) and in intracellular signaling and other physiological events (FOS/JUN, MDM2, FRA-1 IL-8, HSP70) (Snyder & Morgan, 2004). The DNA damage response stimulated by exposures of rodents to compounds leads induction of the ATM-p53 pathway that causes expression of the p53 target genes p21, cyclin G1 (CCNG1) and Mgmt (Ellinger-Ziegelbauer

et al., 2005). Mgmt is a DNA repair protein which eliminates alkyl groups and resynthesis of intact DNA. Expression of Mgmt is suppressed by wild-type p53 and upregulated by mutant type p53 (Grombacher et al., 1998). CCNG1 is a p53-downstream gene which interplays with Mdm2, a regulator of p53 in a adverse impact loop (Kimura & Nojima, 2002; Momand et al., 2000). Upon DNA damage, cyclin G1 binds with the Mdm2-ARF complex, and inhibits p53 ubiquitination by Mdm2. This helps in arresting the cell cycle and DNA repair. Cdkn1a, Bax, and Btg2 are antiproliferative p53 depending factors of the DNA damage cellular feedback mechanism (Kohn, 1999). Such genes stimulate growth arrest and/or apoptosis with highly DNA damage facilitating the activation of apoptosis. Hence, the pathways which are responsive to certain DNA damaging components are apparently explained and profiling such pathways gives comprehensive information on the major DNA reactivity of a toxicant. It has been explained the examination of four components for every two groups of hepatocarcinogens (Ellinger-Ziegelbauer et al., 2004). Gene expression stimulated by the genotoxic components, 2 nitrofluorene (2-NF), dimethylnitrosamine (DMN), 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone, and aflatoxin B1 (AB1), had been compared to that activated by the nongenotoxic hepatocarcinogens methapyrilene HCl (MPy), DES, Wy-14643 (Wy) and piperonylbutoxide (PBO). The two exceptions were DES, an Ames test negative genotoxic carcinogen which stimulated chromosomal abnormalities and aneuploidy in vitro and chromosome abnormalities in bone marrow in vivo, and Wy, also an Ames test negative chemical, that the NTP explored as positive in the mouse lymphoma assessment. Hence, such two chemicals can be divided as Ames test negative genotoxic carcinogens. The accession number for microarray data set had been submitted in the European

Xenobiotics in Chemical Carcinogenesis

Prediction of carcinogenicity effects of xenobiotics by toxicogenomics methods

Bioinformatics Institute (EBI) ArrayExpress database (Brazma et al., 2003) is E-TOXM-16 and the experiment has been conducted on the entitled, “Transcription profiling of rat liver response to genotoxic carcinogens at doses known to induce liver tumors in the 2year rat bioassay-short-term in vivo study.” Gene expression had been assessed on Affymetrix RGU 34A microarrays employing liver RNA obtained from male WistarHanover rats ensuing treatment of five rats per class for 1, 3, 7, or 14 days at the maximum tolerated dose (MTD). Early, the doses studied had been explained to stimulate liver cancer and the anticipated initial histopathological alterations were proved (EllingerZiegelbauer et al., 2005). Ellinger-Ziegelbauer et al. (2005) had explored significantly deregulated genes first on a per chemical basis, and then they had functionally classified as carcinogen group. The assessment of the microarray dataset showed different gene expression profiles for the two distinctive groups of carcinogens. In the condition of the genotoxic carcinogens, a robust DNA damage response at the gene expression extent explained direct DNA alteration with survival/proliferation signaling, while in the case of the putative nongenotoxic carcinogens, expression counters to widespread oxidative stress suggested potential secondary DNA damage with regeneration and cell cycle regression. The DNA damage stimulated by the genotoxic carcinogens participated upregulation of p53 target genes. The researchers explained that the debilitated upregulation of the similar genes by the nongenotoxic carcinogens may be because of oxidative stress; other oxidative stress responsive genes had also been upregulated by such components and p53 is known to be stimulated by both DNA damage and oxidative stress. They suggested that secondary DNA damage by generation of reactive oxygen species after treatment with

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nongenotoxic carcinogens also was highly linked by the enhanced expression of apurinic/apyrimidinic endonuclease 1 (APEX1). Assessment of nongenotoxic carcinogenicity by toxicogenomics methods It has been explained that the nongenotoxic carcinogens act through several events such as induced mitogenesis, reduced apoptosis, intervention with gap junction intercellular communication, intervention with tubulin polymerization, etc. (Combes, 2000). Kramer et al. have mainly identified the potential nongenotoxic hepatocarcinogens (Kramer et al., 2004). Such group subjected transcription profiling in studies of five possible rodent nongenotoxic carcinogens (bemitradine, clofibrate, doxylamine, methapyrilene, and phenobarbital), and two genotoxic carcinogens (2-acetylaminofluorene and tamoxifen), a mitogenic carcinogen (isoniazid) as well as a noncarcinogen (4-acetylaminoflurene). Male SpragueDawley rats had been treated with one of three dose extents of every such chemicals. Microarray gene expression profiles had been related with a predicted carcinogenic impact of every chemical and dose level in order to explore various individual candidate genes to act as molecular markers of rodent nongenotoxic carcinogenicity. The researchers emphasized transforming growth factor-ß induced clone 22 (TSC-22) and NAD(P)H cytochrome P450 oxidoreductase (CYP-R) as correlating the best with nongenotoxic carcinogenicity. The prognostic value of rat counterparts of such two genes had been assessed by Fielden et al. (2007) who did not obtain them as mainly helpful for the classification of possible nongenotoxic carcinogenicity. Furthermore advancement of gene signatures for predictive carcinogenicity underlying molecular pathways of nongenotoxic carcinogenesis had been highly studied by Nie et al. (2006) who had created a large gene expression database employing cDNA microarrays.

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Transcription profiling had been performed on liver samples of male Sprague-Dawley rats treated for 24 hours with 100 distinct chemicals, and the generating database was mined for gene expression signatures properties of nongenotoxic carcinogens (Nie et al., 2006). To explain molecular events of nongenotoxic carcinogenesis, it had been recruited 125 distinctively expressed genes employing Student’s t-test. Among 125 genes, 71 had been wellannotated with biologically significant activities and 62 were highly expressed in five biochemical pathways, most of them associated with cancer development (Nie et al., 2006). Intriguingly, these pathways had been centrally connected by one gene, c-myc. The proto-oncogene, c-myc, is highly thought to commence or promote cancer development leading to the virus infection, mutation, DNA hypomethylation etc. Genes which were either up- or downregulated by nongenotoxic carcinogen treatments were highly expressed in various gene groups such as cancer, cellular growth and proliferation, cell cycle, cell death, and immune and lymphatic system development and action. Expression profiles in a study had been used to recruit a gene signature for prognostic and assessment for pathway or functional group (Nie et al., 2006). A semiexhaustive, nonredundant, gene recruitment algorithm produced six genes which determined nongenotoxic carcinogens with 88.5% prediction accuracy. This gene signature had been confirmed by employing GE Codelink Rat Whole Genome microarrays. These six genes are mainly: liver uridine diphosphate glucuronyltransferase, phenobarbital-inducible form, UDPGTr2; methionine adenosyltransferase 1, alpha, Mat1a; progesterone receptor membrane component 1, Pgrmc1; nuclear transport factor 2, NUTF2; suppressor of lin-12 homolog, Sel1h; and metallothionein 1A, MT1A. The researchers explained that the six genes in the last signature set do not observe coordinately regulated, and different mechanisms are explained by their various regulation. After

annotation on the six genes, the phenobarbitalinducible UDP glucuronyltransferase (UDPGTr2) is a nongenotoxic carcinogen signature gene involving in mechanism of action for thyroid carcinogenesis: thyroxine levels in the rat are usually detected by confirming the glucuronidation by UDPGT (Nie et al., 2006). Plasma extents of thyroid hormone decline if UDPGT is stimulated and this eliminates feedback inhibition of thyroid stimulatory hormone (TSH) formation and release by the pituitary gland. The enhanced TSH extent trigger enhanced formation of thyroid hormones that are eliminated by glucuronidation. Finally, the chronic TSH production, overstimulation, and hyperplasia of the thyroid gland could be responsible for cancer development (Wilson et al., 1996). Another nongenotoxic carcinogen signature gene with a possible function in cancer development is methionine adenosyltransferase 1 alpha (Mat1a). Mat1a is the hepatic-based isozyme; Mat2a is present in extra-hepatic tissues and is highly antagonistic to Mat1a. The output of methionine adenosyltransferase activity, level of S-adenosyl-L-methionine (SAM), is found at much higher in liver in comparison to other tissues. The greater concentration of SAM or its metabolites are known to be critical for DNA methylation and hepatic gene silencing that is the crafted basis for anticarcinogenic impact in the liver. Most such genes are not ones that are highly altered in magnitude, but the researchers shows that they will provide enough analysis of pathways participating in nongenotoxic carcinogenesis to the extent. Fielden et al. (2007) had suggested that various genes are needed for meticulous classification because of the multiple modes of action (MOA). This suggests that the same expression profiles over the signature genes will be observed for compounds with similar MOA. The output of the log10 ratio and weight (impact scores) for the 37 genes in the signature had been hierarchically assemblage over

Xenobiotics in Chemical Carcinogenesis

Conclusions and future prospective

the 25 nongenotoxic hepatocarcinogens in the training set employing Pearson’s correlation as the similarity metric (Fielden et al., 2007). Positive impact scores provide the way of alteration leading to positive prediction and the relative significance of a provided gene in classification; hence, compound similarity is obtained by the expression most significantly altering the prediction. The 25 compounds were sorted into four different clusters, and some subclusters, indicating the 37-gene signature is catching at least four different MOA associated with identified chemicals having: (1) regenerative proliferation, (2) proliferation based on xenobiotic receptor induction, (3) peroxisome proliferation, and (4) steroid hormone-regulated carcinogenesis. Such outcome explained that the signature could be implicated to determine the capability of a xenobiotic chemical to trigger hepatic cancer in rats and to illustrate the potential MOA associated with the resemblance of the signature profile to compound with the explored mechanism.

Conclusions and future prospective Presently, the development of advanced technologies for molecular studies has facilitated the exploration of intricate webs of cellular mechanisms in carcinogenesis at the genomic level in response to xenobiotic compounds. The new field “toxicogenomics” has led to the exploration of the area of genetic toxicology. Such new sequencing technologies and techniques have been important parts of genetic toxicity testing. The main aim of toxicogenomics is to explore insights into the molecular functions of several kinds toxicants through assessing the gene expression profiles by linking present and future aspect (Fig. 15.4). Several xenobiotics belonging to environmental chemicals are pro-carcinogens which metabolizes to active carcinogen in vivo in the

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target organ. Maximum in vitro examinations procedures do not have significant metabolic activation, although, a few might be capable in in vitro systems subjected to further study. Several carcinogens are cytotoxic and stimulate for cell proliferation. For study of such phenomenon of carcinogens in vitro, the appropriate toxicogenomics approaches are applied to explore the important and predictive mechanism. However, the published datasets in vitro and in vivo show relevant variations, general properties develop in response to molecular pathways indicating the necessitate for a systems toxicology method for data interpretation. The DNA damage in carcinogenesis is highly stimulated both by DNA reactive genotoxicants in vitro and genotoxic carcinogens in vivo, revealing and elaborating the molecular information of what has been explored before. The capability to determine inducing of important biological events in respect of DNA damage in the in vitro assessment and in vivo studies contribute in synthesizing of translational biomarkers for genotoxic carcinogenicity by targeting particular tissues. Other xenobiotics groups, mainly in vitro exemplified DNA nonreactive genotoxicants and in vivo nongenotoxic carcinogens, the published articles have revealed the participation of generic events in their mechanisms of action such as common stress reaction, signaling and cell cycle genes in vitro, or several oxidative stress response and cell cycle genes in vivo. Until now, several studies have explained that there is no direct in vitro-in vivo relationship as present for the DNA reactive genotoxicants and genotoxic carcinogens. Although, the toxicogenomics might reveal a differentiation of DNA reactive versus DNA nonreactive genotoxins in vitro and genotoxic versus nongenotoxic carcinogens in vivo. Hence, the toxicogenomics approach highly enables improved cancer risk analysis for xenobiotic compounds like drugs and

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FIGURE 15.4 Connection of present and future aspects of genetic toxicology. The present method to genetic toxicology employs standalone assessment whereas a future aspect link together rates of mutation and its regulating patterns, gene expression profiles, and “omitted” data from machine investigation, to make a “fingerprint” of genotoxicity.

environmental factors. The advancement of toxicogenomic methods is very challenging required various resources and time. Hence, it needs developing of pertinent investigating protocols and affirmation. So, the collective endeavors which have researchers/scientists from academia, industry, and regulatory agencies like ILSI HESI Genomics Committee, the Critical Path Initiative in the US or the forthcoming Innovative Medicines Initiative in Europe are required for making experimental protocols and investigating models. Allinclusive, toxicogenomic research has highly elaborated its capacity to explore and analyze the incidence to that xenobiotic’s compounds cause to adverse effect for human health. The continuous works on toxicogenomics could solve the several mysteries associated with

xenobiotic compounds involving in chemical carcinogenesis and also become alternative testing tools in future approved by administrative bodies.

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Xenobiotics in Chemical Carcinogenesis

Index

Note: Page number followed by “f” and “t” refer to figures and tables, respectively.

A Absorption, Distribution, Metabolism and Excretion or Elimination (ADME), 61 Acceptable Daily Intake (ADI), 63 2-Acetylaminofluorene, 10 2-Acetylaminofluorine-induced bladder cancer, 4 5 Acid rains, 37 39 Additional Protocol, 53 Adverse drug reactions (ADRs), 71 73 Adverse outcome pathways (AOPs), 66, 129 130, 287 Aflatoxins, 58 59 Ah receptor nuclear translocator (ARNT), 117 118 Air, 161 Alcoholic liver disease (ALD), 135 Alkylbenzyl sulfonates, 41 Aminocarbolines (ACs), 30 Aminoimidazoazarenes (AIAs), 30 Androgens, 182 183 Antibiotics, 1 Anticancer drug therapy, 28, 93 94 and oxidative stress, 93 94 Antiestrogens, 180 181 Antioxidants, 44 preventive and therapeutic potential of, 94 Aromatic amines, 58 59 Artificial intelligence and machine learning, 292 Aryl hydrocarbon receptor (AhR), 24 26, 88, 116, 232 as a cofactor in carcinogenesis, 25 26 mechanisms associated with cancer initiation, 25 26 in humans, 25

Asn487Asp variant, 25 Aspergillus flavus, 45 46 Ataxia telangiectasia mutated (ATM), 90 91 Atrazine and triazine herbicides, 190 Azoxymethane (AOM), 14

B Bayesian population methods, 68 in risk analysis, 69 B-cell lymphoma 2 (Bcl-2) expression, 94 96 Bench mark dose (BMD), 3 1,2,5,6-Benzanthracene, 4 Benzene, 58 59 Benzo(a)pyrene (BaP), 4, 30, 88 in water samples, 272 Bioassay of carcinogens, 9 10 long-term, 11 13 Biotransformation, 48 49 Bisphenol A (BPA), 46, 159, 184 185 and breast cancer, 202 chemical properties and main sources of exposure to, 201 202 epigenetic impacts of, 204 estrogenic potential of, 203 204 Bisphenol A-induced breast cancer, 202 205 changes of breast microenvironment, 205 DNA damage, 204 205 epigenetic impacts of bisphenol A, 204 estrogenic potential of bisphenol A, 203 204 Breast cancer bisphenol A-induced, 202 205 breast microenvironment, changes of, 205

307

DNA damage, 204 205 epigenetic impacts of bisphenol A, 204 estrogenic potential of bisphenol A, 203 204 due to endocrine disrupting chemicals, 186 188 case studies of endocrine disrupting chemicals associated with breast cancer, 187 endocrine disrupting chemicals, 187 188 identification of problems associated with the mode of action of EDCs, 186 187 multiple combinations of risk components, 186 role of pesticides in breast cancer progression, 31 Breast cancer, xenoestrogens and risk for, 197 202 bisphenol A and breast cancer, 202 bisphenol A and phthalates, chemical properties and main sources of exposure to, 201 202 bisphenol A-induced breast cancer, 202 205 changes of breast microenvironment, 205 DNA damage, 204 205 epigenetic impacts of bisphenol A, 204 estrogenic potential of bisphenol A, 203 204 phthalates, 205 209 exposure via diet, 206 208 risk factors as models for environmental chemicals, 200 201

308 Breast microenvironment, changes of, 205 Breast milk (BM), 197 198

C Cadmium, 137 138 epigenetic effect of, 137 138 Cancer caused by mutation/environmental factors, 2 genetic modifiers of, 14 role of environmental agents in, 58 59 Cancer-associated fibroblasts (CAFs), 92 Cancer cells, 83 Cancer development endocrine disruptors on cancer development in women atrazine and triazine herbicides, 190 chlorpyrifos and other pesticides, 190 dichlorodiphenyltrichloroethane, 189 dioxins, 188 189 methoxychlor (MXC), 189 190 toxicokinetics and toxicodynamics of xenobiotics in, 65 67 Cancer drug resistance, 250 254 resistance to xenobiotics, 252 254 Cancer microenvironment and oxidative stress, 96 99 Cancer risk assessment, 273 274 Carcinogenesis data associated with exposure to endocrine disruptors in, 184 185 pesticides in, 57 58 Carcinogenesis models, 5 6 Carcinogenic and noncarcinogenic categorization of chemicals, 10 11 Carcinogenic chemicals, identifying the mode of action of, 112 116 alkylating compounds arising from endogenous processes, 115 background DNA lesions, 114 carcinogenic mode of action, 115 116 formation of DNA adducts in endogenous processes, 114 115 Carcinogenic impacts of nanomaterials, 165 168 nano-metal elements, 165 166

Index

nickel NPs, 165 166 silver NPs, 166 nano-metal oxides, 166 168 titanium dioxide NPs, 166 167 zinc oxide NPs, 167 168 Carcinogenic Potency Database (CPDB), 11 Carcinogens bioassay of, 9 10 early studies for identification of, 3 5 potential of, 3 CD4 1 T cells, 119 120 CD8 1 T cells, 92 Cell adaptability, 49 50 Cell transformation assays (CTAs), 116 Cellular adaptation to xenobiotic compounds, 48 50, 248 Cellular physiology, function of gut microbes in, 224 225 Cellular uptake and intracellular consequences of nanoplastic materials, 161 163 Chemical carcinogenesis, theories for, 6 9 Chemotherapeutic compounds, 58 59 Chloroform, 40 41 Chlorpyrifos, 232 and other pesticides, 190 Chromosomal abnormalities, 183 Circadian clock, 143 144 Classic Sex Hormone Paradigm, 71 72 Constitutive androstane receptor (CAR), 130 131 Cumulative dose, 10 Cyclin-dependent kinase inhibitor p27 (CDKN1B), 13 14 CYP1A1 expression, 25 26 CYP3A4, 71 CYP expression, 74 75 CYPs genes, 26 27 Cytochrome P450 (CYP), 21, 24, 26 28, 71 75, 87 88 Cytotoxicity and immune inhibition, 120

D Data Protection Directive 95/46/EC, 53 Deep sequencing, 291 292 DEREK, 77

Dermal exposure, 161 Dichlorobiphenyl dichlorophenylethane (DDD), 230 Dichlorodiphenyltrichloroethane (DDT), 117, 158, 230, 247 Dichlorodiphenyltrichloroethane, 189 Dichloromethane (DCM), 69 Diethylstilbesterol in pregnant women, 187 188 Diethylstilbestrol (DES), 25 26 Dihydrotestosterone (DHT), 182 183 Dihyroxydihydro epoxide, 4 5 4-Dimethyl-aminoazobenzene, 4 5 7,12-Dimethylbenz[a]anthracene (DMBA), 13 1,2-Dimethylhydrazine (DMH), 14 2,4-Dinitrotoluene, 230 Dioxins, 188 189 DNA/chromatin remodeling enzyme function and expression, 142 143 DNA damage, 9, 183 184, 204 205 DNA methylation, 57 mode of alterations in, 137 DNA methylation in development of cancer, 131 146 alteration of epigenome by chemical carcinogens, 134 135 cadmium, epigenetic effect of, 137 138 carcinogenicity of ochratoxin A through complex network of epigenetics, 132 134 epigenetic impacts of ethanol on liver and gastrointestinal system, 135 137 alcohol-stimulated epigenetic modifications, 135 136 DNA methylation, mode of alterations in, 137 miRNAs, changes in, 136 137 epigenetic remodeling altering donors for, 141 142 xenobiotic-induced, 141 lung cancer of smokers, epigenetics modification in, 138 141 model systems and biomarkers to assess epigenetic effects, 144 146 natural genetic variation and interaction with epigenome, 144 145

309

Index

nonrodent models for epigenetic assessment, 145 146 novel epigenetic biomarkers for safety assessment, 146 stem cells and reprogramming, 146 modifying DNA/chromatin remodeling enzyme function and expression, 142 143 regulation of the epigenome by xenobiotics, 132 xenobiotic epigenetic toxicity and circadian clock, 143 144 Drinking water, 160 Druckrey-Ku¨pfmu¨ller model Dynamic energy budget (DEB) theory, 63 65

E ECVAM research group, 76 77 Effective biomarkers, systematical implication of, 69 70 Electrospray ionization (ESI), 270 Endocrine disrupting chemicals (EDCs), 175 177, 177f, 188f Endocrine disruption, 75 Endocrine disruptor activity of xenobiotics in carcinogenesis antiestrogens, 180 181 breast cancer due to, 186 188 case studies of endocrine disrupting chemicals, 187 endocrine disrupting chemicals, 187 188 identification of problems associated with the mode of action of EDCs, 186 187 multiple combinations of risk components, 186 on cancer development in women atrazine and triazine herbicides, 190 chlorpyrifos and other pesticides, 190 dichlorodiphenyltrichloroethane, 189 dioxins, 188 189 methoxychlor (MXC), 189 190 carcinogenesis, data associated with exposure to endocrine disruptors in, 184 185 endocrine disruption of xenobiotic exposure, 179

estrogen and androgen, endocrine disruptors action on mechanism of, 182 184 chromosomal abnormalities, 183 DNA damage, 183 184 micro RNAs (miRNAs), 184 food chain, endocrine regulators in, 181 future prospective, 191 192 health issues, 190 191 xenoandrogens, 180 xenoestrogens, 180 Endocrine disruptors (EDs), 37 39, 176 177 Endocrine modifiers, 116 118 mode of action for, 116 non-receptor regulators endocrine modifiers, 118 Endogenous processes alkylating compounds arising from, 115 formation of DNA adducts in, 114 115 Enhancer of Zeste Homolog 2 (EZH2), 185 Enterohepatic circulation, 225 226 Environmental agents’ role in human cancer, 58 59 Environmental chemicals and chemoresistance, link between, 255 256 Environmental pollution, 39 Environmental xenobiotics for inducing cancers, 57 60 exposure of biomarkers and assessment of human exposures, 59 pesticides in carcinogenesis, 57 58 role of environmental agents in human cancer, 58 59 Enzyme-linked immunosorbent assay (ELISA) test kit method, 272 273 Epigenetic effect of cadmium, 137 138 Epigenetic effects, model systems and biomarkers to assess, 144 146 natural genetic variation and interaction with epigenome, 144 145 nonrodent models for epigenetic assessment, 145 146

novel epigenetic biomarkers for safety assessment, 146 stem cells and reprogramming, 146 Epigenetic impacts of ethanol on liver and gastrointestinal system, 135 137 alcohol-stimulated epigenetic modifications, 135 136 changes in miRNAs, 136 137 mode of alterations in DNA methylation, 137 Epigenetic remodeling, altering donors for, 141 142 Epigenetic remodeling molecular pathways by xenobiotics, 141 Epigenetics carcinogenicity of ochratoxin A through complex network of, 132 134 defined, 127 modification, in lung cancer of smokers, 138 141 Epigenome alteration of epigenome by chemical carcinogens, 134 135 regulation of epigenome by xenobiotics, 132 Epithelial mesenchymal transition (EMT), 92 Estradiol, 182 Estrogen hormones, 116 Estrogen receptors (ERs), 28 29, 116, 199 Estrogen response elements (ERE), 117, 182 Ethanol, 137 N-Ethyl-N-nitrosourea (ENU), 14 Exposure, 75

F Fanconi anemia (FA), 90 5-Fluorouracil (5-FU), 251 Food carcinogens exposure to, 45 47 assessment of, 47 48 Food chain, 160 161 endocrine regulators in, 181 Food processing, formation of carcinogenic xenobiotics during, 29 31 Formaldehyde, 115 Fossil fuels, 39

310 Fourier transform infrared spectroscopy (FTIR), 158 159 FOXO (forkhead box), 49 50 Freons, 40 41 Future of chemical carcinogenesis, 14 15

G GABAA receptor, 71 Gap-junctional intercellular communications (GJICs), 117 Gap-junction intercellular communications, suppression of, 120 122 Gastrointestinal (GI) microbes effect of environmental chemicals on the activity of, 231 232 organic pollutants, 232 pesticides, 232 metabolism of environmental chemicals by, 229 231 nitrated PAHs or nitro-PAHs, 229 230 nitrotoluenes, 230 pesticides, 230 polychlorobiphenyls (PCBs), 231 polycyclic aromatic hydrocarbons (PAHs), 229 Genetically engineered mouse models (GEMMs), 2, 9 10, 13 14 Genetic modifiers of cancer, 14 Genotoxic and non-genotoxic activities of xenobiotics in carcinogenesis identifying the mode of action of carcinogenic chemicals, 112 116 alkylating compounds arising from endogenous processes, 115 background DNA lesions, 114 carcinogenic mode of action, 115 116 formation of DNA adducts in endogenous processes, 114 115 identifying the mode of action of non-carcinogenic compounds, 116 120 cytotoxicity and immune inhibition, 120 endocrine modifiers, 116 118 mode of action for endocrine modifiers, 116

Index

suppression of gap-junction intercellular communications, 120 122 toxicity and inflammation at the tissue level, 119 120 tumor promotion, 118 119 Genotoxic and nongenotoxic mechanisms of xenobiotics in carcinogenesis, 75 77 advanced approaches in the science of xenobiotic toxicology, 76 77 Genotoxic carcinogenicity by toxicogenomics methods, 296 297 Genotoxic compounds, 83 84 Glucose-6-phosphate dehydrogenase (G6PD), 90 Glutathione (GSH), 90 Glutathione S-transferases (GSTs), 87 88 Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), 90 91 Greenhouse gases, 37 39 Growth hormone, 74 75 Gut microbiota, 249 250 Gut microbiota, biotransformation of toxic xenobiotics by complementary chemistry of microbial xenobiotic metabolism, 226 computational method, 235 factors affecting the rate and level of gut microbes in xenobiotic metabolism, 232 234 function of gut microbes in cellular physiology, 224 225 gastrointestinal (GI) microbes, effect of environmental chemicals on the activity of, 231 232 organic pollutants, 232 pesticides, 232 gastrointestinal (GI) microbes, metabolism of environmental chemicals by, 229 231 nitrated PAHs or nitro-PAHs, 229 230 nitrotoluenes, 230 pesticides, 230 polychlorobiphenyls (PCBs), 231 polycyclic aromatic hydrocarbons (PAHs), 229

gut bacterial substrate database, construction of, 236 gut microbial interactions with xenobiotics, 225 226 habitat of microbes in human body, 221 222 metabolome of microbes, 224 microbiome regulation of toxicity, 222 223 role of microbes in health and disease, 222 xenobiotic-degrading microbes, identification of, 234 235

H Halocarbons, 40 41 Heat shock protein 90 (HSP90), 94 96 Heat shock proteins (HSP), 182 183 Heavy metals, 39 40 extraction and analysis of, 273 HeLa cells, 25 Hepatocyte growth factor, 97 98 Heterocyclic amine (HCA) food mutagens, 22 24, 30 Heterogametic sex determination, 74 High grade serous ovarian carcinoma (HGSC), 94 96 High-throughput screening (HTS) approach, 292 293 Histone acetyl transferase (HAT) function, 143 Historical review and future prospective of chemical carcinogenesis bioassay of carcinogens, 9 10 cancer caused by mutation or environmental factors, 2 carcinogenesis models, 5 6 chemical carcinogenesis and genetically engineered models, 13 15 future of chemical carcinogenesis, 14 15 genetic modifiers of cancer, 14 early studies for identification of carcinogens, 3 5 issues with carcinogenic and noncarcinogenic categorization of chemicals, 10 11 long-term bioassays, 11 13 potential of carcinogens, 3 theories for chemical carcinogenesis, 6 9

Index

Hormone replacement therapy (HRT), 201 Human AhR (hAhR), 25 Human biomonitoring (HBM), 51 52 challenges of, 52 53 Human gut microbiota, 249 250 100-fold default factor, 63 100-fold uncertainty factor, 63 Hydrogen peroxide, 84

I Identification of carcinogens, early studies for, 3 5 Immunotoxicity, toxicogenomicsrelated exploration of pathways for, 293 294 Inflammation, 164 Ingestion, 160 Inhalation, 161 Insect resistance to pesticides, 247 In silico approach to risk assessment, 67 68 Interleukine-6, 97 98 International Agency for Research on Cancer (IARC), 3 4 International Commission on Radiological Protection (ICRP), 73 International Program on Chemical Safety’s (IPCS) project, 65 66

L LADME paradigm, 66 Leukemia, 58 Liver and gastrointestinal system, epigenetic impacts of ethanol on, 135 137 alcohol-stimulated epigenetic modifications, 135 136 changes in miRNAs, 136 137 mode of alterations in DNA methylation, 137 Long-term bioassays, 11 13 Lung cancer of smokers, epigenetics modification in, 138 141 Lys401Arg variant, 25 Lysosomal-associated membrane protein 3 (LAMP3), 204

M Machine learning, artificial intelligence and, 292 Malignant lymphoma, 58

Marine products, 160 161 Mass defect filtering (MDF), 262 Maximum tolerated dose (MTD), 12 Mechanism of action, 66 MechSpy, 287 Mesenchymal mesenchymal transition (MMT), 97 98 Messenger RNA (mRNA) expression, 129 130 Metabolic homeostasis, 165 Metabolome of microbes, 224 Methoxychlor (MXC), 189 190 Microbes habitat of microbes in human body, 221 222 metabolome of, 224 role of microbes in health and disease, 222 Microbial xenobiotic metabolism, complementary chemistry of, 226 Microbiome regulation of toxicity, 222 223 Microbiota, 219 Micro RNAs (miRNAs), 184 changes in, 136 137 MMT (microbiome modulation of toxicity), 223 Mode of action, 66 Molecular initiating event (MIE), 66 68, 71 Monte Carlo simulations, 69 Multiple reaction monitoring (MRM), 262 Mutation/environmental factors, cancer caused by, 2 Mutations, 8 Myeloid-derived suppressor cells (MDSCs), 93

N Nanomaterials, 155 174 carcinogenic impacts of nanomaterials, 165 168 nano-metal elements, 165 166 nano-metal oxides, 166 168 cellular uptake and intracellular consequences of nanoplastic materials, 161 163 generation of nanoplastic in the environment, 158 159 effect of nanoplastics on human health, 158 159

311 human exposure to, 160 161 dermal exposure, 161 drinking water, 160 food chain, 160 161 inhalation, 161 major toxic impact of nanoplastics on human health, 163 165 inflammation, 164 metabolic homeostasis, 165 oxidative stress and apoptosis, 164 165 Nano-metal elements, 165 166 nickel NPs, carcinogenic impacts of, 165 166 silver NPs, carcinogenic impacts of, 166 Nano-metal oxides, 166 168 titanium dioxide NPs, carcinogenic impacts of, 166 167 zinc oxide NPs, carcinogenic impacts of, 167 168 Nanotoxicology, 160 National Cancer Institute (NCI), 9 10 National Research Council (NRC), 52 National Toxicology Program (NTP), 9 10 NcRNA, 96t Next-generation sequencing (NGS), 291 292 Nickel NPs, carcinogenic impacts of, 165 166 Nitrated PAHs or nitro-PAHs, 229 230 Nitrates, 45 46 2-Nitrofluorene (NF), 229 230 Nitroso compounds, 45 46 Nitroso dimethylamine (NDMA), 45 46 Nitrotoluenes, 230 N-nitroso compounds, 5 N-nitrosodiethylamine (DEM), 5, 14 N-nitrosodimethylamine (DMN), 5 Non-carcinogenic compounds, identifying the mode of action of, 116 120 cytotoxicity and immune inhibition, 120 endocrine modifiers, 116 118 mode of action for, 116 non-receptor regulators endocrine modifiers, 118 suppression of gap-junction intercellular communications, 120 122

312 Non-carcinogenic compounds, identifying the mode of action of (Continued) toxicity and inflammation at tissue level, 119 120 tumor promotion, 118 119 Non-dioxin-like PCBs, 118 Nongenotoxic carcinogenesis (NGC), 130 Nongenotoxic carcinogenicity by toxicogenomics methods, 297 299 Nongenotoxic carcinogens, 83 84 Non-Hodgkin’s lymphoma (NHL), 58 Non-small cell lung carcinoma (NSCLC) cells, 94 96 Nonylphenol, 186 No-observed-adverse-effect-level (NOAEL), 63 Nuclear receptor (NR), 71

O Ochratoxin A (OTA), 132 134 Oil mixtures, 41 Organic anion transporter (OAT), 74 Organic pollutants, 232 Organochlorine insecticides, 58 Orthogonal signal correction (OSC), 266 267 Oxidative stress, 83 85, 93 94 anticancer drug therapy and, 93 94 antioxidants, preventive and therapeutic potential of, 94 and apoptosis, 164 165 arrays of, 87 88 -associated mechanisms with xenobiotics in anemia cells, 90 in cancer cells via gene expression, 100 102 cancer microenvironment and, 96 99 and ER activity, 99 100 future prospective, 102 gene expression, modification of, 86 linked with xenobiotic compounds in carcinogenesis, 88 89 oxidative DNA damage, 85 86 reactive oxygen species (ROS) endogenous factors of, 86 87 exogenous sources of, 87 relationship of ROS, ncRNA, and p53, 94 96

Index

time-dependent cellular adaptations to, 90 91 in tumor microenvironment, 97f xenobiotic-induced ROS generation in embryos, 89

P p27 protein, 13 14 p53 gene, 8, 13 14, 94 96, 95f, 96t P450 expression, 5, 21 Papain, 44 Pentose phosphate pathway (PPP), 90 Peptide-major histocompatibility complex (pMHC), 93 Perchloroethylene (PCE), 121 122 Perfluorinated compounds (PFCs), 183 Perfluorooctanoic acid (PFOA), 74 Peroxisome proliferator-activated receptors (PPARs), 85, 209 Peroxisome proliferator-induced receptor-a (PPARa), 28 29 Persistent organic pollutants (POPs), 58, 74, 163 Pesticides, 39, 58, 230, 232 in breast cancer progression, 31 in carcinogenesis, 57 58 insect resistance to, 247 P-glycoproteins for resistance to carcinogenic agents, 254 255 as universal detoxifiers, 254 Phenobarbitalstimulators, 118 Phenytoin, 120 Phosphate fertilizers, 39 Phosphorus, 1 Phthalates (PAEs), 201, 205 209 and breast cancer, 208 209 chemical properties and main sources of exposure to, 201 202 exposure via diet, 206 208 toxicological aspects and human health effects, 207 208 Physiologically-based pharmacokinetic modeling (PBPK), 73 Polychlorinated biphenyls (PCBs), 41 Polychlorobiphenyls (PCBs), 231 Polycyclic aromatic hydrocarbons (PAHs), 4, 22 24, 30, 46 47, 88, 229, 272 Polyvinyl chloride (PVC), 201 202 POPs (persistent organic pollutants), 40

Population model of chemical carcinogenesis, 7f Posterior probability distributions, 68 Potential of carcinogens, 3 Predictive toxicology, 293 Pregnant women, diethylstilbesterol in, 187 188 Progesterone receptor (PR) expression, 99 100 Progesterone receptor, 116 Programmed death-1 (PD-1), 92 Propachlor, 230 Proteins, analysis of covalent binding to, 264 Pseudomonas genus, 43 Pyrolytic amines, 30 Pyruvate kinase M2 (PKM2), 90 91

Q Quantitative structure activity relationships (QSARs), 77

R Reactive metabolites, 261 263 analysis of covalent binding to proteins, 264 cancer risk assessment, 273 274 environmentally relevant organisms and anthropogenic contaminants, 274 276 metabolites and pathways, identification of, 276 enzyme-linked immunosorbent assay (ELISA) test kit method, 272 273 experimental methods for the assessment of, 263 extraction and analysis of benzo(a) pyrene in water samples, 272 extraction and analysis of heavy metals, 273 high-throughput NMR in xenobiotics toxicology, 266 271 characterization of xenobiotic metabolites by LC/HRMS/MS, 267 269 screening of xenobiotics in by UHPLCHRMS/MS, 269 270 unknown xenobiotic compounds, determination of, 270 271 target analysis and suspect screening, 271 272

Index

time and cofactor-based cytochrome P450 suppression, 265 266 NMR spectroscopy for identification of xenobiotic toxicity, 265 266 trapping and identifying, 264 265 Reactive oxygen species (ROS), 25 26, 37 39, 84, 183 184 endogenous factors of, 86 87 exogenous sources of, 87 Reactive oxygen species (ROS) and reactive nitrogen species (RNS) on tumor microenvironment (TME), 92 100 cancer microenvironment and oxidative stress, 96 99 oxidative stress and ER activity, 99 100 quantitative determination of oxidative stress in cancer cells via gene expression, 100 102 relationship of ROS, ncRNA, and p53, 94 96 role of oxidative stress in the treatment and prevention of cancer, 93 94 anticancer drug therapy and oxidative stress, 93 94 preventive and therapeutic potential of antioxidants, 94 Recalcitrant toxic xenobiotics, 40 41 alkylbenzyl sulfonates, 41 cellular adaptation to xenobiotic compounds, 48 50 exposure to food carcinogens, assessment of, 47 48 food carcinogens, exposure to, 45 47 future prospective, 53 54 halocarbons, 40 41 hazards from xenobiotic molecules, 42 human biomonitoring, 51 52 challenges of, 52 53 oil mixtures, 41 polychlorinated biphenyls (PCBs), 41 removal of xenobiotics molecules, 43 44 risk assessment for exposure of humans to toxic compounds, 44 45 routes of xenobiotic exposure, 41 42

ingestion, 42 inhalation, 41 42 injection, 42 skin (or eye) absorption, 42 synthetic polymers, 41 xenobiotic-induced toxicity, detection of, 50 51 xenobiotics in carcinogenesis, 42 43 Receptor, 66 Reference Dose (RfD), 63 Resistance to toxic xenobiotics, 248 249 Resistance to xenobiotics, 252 254 Risk assessment (RA), 44 in silico approach to, 67 68 role of toxicokinetics and toxicodynamics in, 65 67

S S-adenosylmethionine, 115 Senescence-activated secretory pathways (SASPs), 97 98 Sex differentiation in human and animal toxicology, 71 75 adverse drug reactions, 72 73 body composition, 73 endocrine disruption, 75 exposure, 75 growth hormone, 74 75 sex hormones and their exemplification, 74 Silver NPs, carcinogenic impacts of, 166 Single nucleotide polymorphisms (SNPs), 44 45, 87 88 Smokers, epigenetics modification in lung cancer of, 138 141 Soft tissue sarcoma (STS), 58 Solid phase extraction (SPE), 270 SOT II (solid oil treatment), 43 44 South all And Brent Revisited (SABRE) cohort, 139 140 Sry gene, 74 Stem cells and reprogramming, 146 Support vector machine (SVM), 292 Synthetic polymers, 41 Systems toxicology, 50, 51f

T TCDD (2,3,7,8,-tetrachlorodibenzo-pdioxin, 88 89, 117 118, 120 121 T cells, 92

313 Tert-butylhydroquinone (TBHQ), 121 122 Tertbutylquinone (TBQ), 121 122 2,3,7,8-Tetrachlorodibenzofuran (TCDF), 232 2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD), 143, 188 189 12-o-Tetradecaoylphorbol-13-acetate (TPA) protocol, 13 Thalidomide, 61 62 Thioredoxins (TXN), 90 Thymidylate synthase (TS), 251 252 Thyroid hormone receptors (TRs), 116, 118 Thyroid stimulating hormone (TSH), 118 Titanium dioxide NPs, carcinogenic impacts of, 166 167 Tobacco chemicals, 58 59 Tolerable Daily Intake (TDI), 63 Toxicodynamics, 61 63, 65 67, 283 290, 290f emergence of field of, 289 290 future prospective, 299 300 genetic toxicology, 290 294 artificial intelligence and machine learning, 292 high-throughput screening (HTS) approach, 292 293 next-generation sequencing (NGS), 291 292 predictive toxicology, 293 toxicogenomics-related exploration of pathways for immunotoxicity, 293 294 mechanistic inference to, 286 287 molecular toxicology, emergence of, 288 289 Toxicogenomics methods genotoxic carcinogenicity by, 296 297 nongenotoxic carcinogenicity by, 297 299 Toxicokinetic and toxicodynamic models of xenobiotics in cancer development, 61 65 Bayesian population methods, 68 in risk analysis, 69 effective biomarkers, systematical implication of, 69 70 genotoxic and nongenotoxic mechanisms of xenobiotics in carcinogenesis, 75 77

314 Toxicokinetic and toxicodynamic models of xenobiotics in cancer development (Continued) in silico approach to risk assessment, 67 68 in risk assessments, 65 67 sex differentiation in human and animal toxicology, 71 75 adverse drug reactions, 72 73 body composition, 73 endocrine disruption, 75 exposure, 75 growth hormone, 74 75 sex hormones and their exemplification, 74 Toxicokinetics, 61 62, 65 67 Toxicokinetic-toxicodynamic (TKTD) models, 63 65 Toxicology, 61 Toxic xenobiotics, resistance to, 245 255 cancer drug resistance, 250 254 mechanisms of resistance to xenobiotics, 252 254 cellular adaptation to xenobiotics, 248 environmental chemicals and chemoresistance, link between, 255 256 evolution of resistance to toxic xenobiotics, 248 249

Index

impact of xenobiotics on physiology and gene expression of human gut microbiota, 249 250 P-glycoproteins for resistance to carcinogenic agents, 254 255 as universal detoxifiers, 254 Toxic xenobiotics, resistance to, 248 249 Transcription factors, modulation of xenobiotic-metabolizing enzymes by, 28 29 Transforming growth factor-b (TGFb), 120 Translational toxicology, 61 62 Tributyltin (TBT), 181 Trichloroacetic acid (TCA), 121 122 2,4,5-Trichlorophenoxypropionic acid, 190 2,2,4-Trimethylpentane, 76 Tumor-associated macrophages (TAMs), 92 Tumorigenic dose rate, 3

U UHPLC-qOrbitrap analysis, 271 Unknown xenobiotic compounds, determination of, 270 271 extraction of xenobiotics, 271 reagents, 270 UHPLC-qOrbitrap analysis, 271

Urethane, 14 Urinary bladder cancer, 3 4

V Vascular endothelial growth factor, 97 98

W Water and cosmetics, 161

X Xenoandrogens, 180 Xenobiotic compounds, 85 Xenobiotic epigenetic toxicity and circadian clock, 143 144 Xenobiotic-induced toxicity, detection of, 50 51 Xenobiotic metabolizing enzymes (XMEs), 24, 42 43 Xenoestrogens, 178, 180, 198 Xenosensors, 48

Y Y chromosome, 74

Z Zebrafish, 146 Zinc oxide NPs, carcinogenic impacts of, 167 168