Environmental Endocrinology and Endocrine Disruptors: Endocrine and Endocrine-targeted Actions and Related Human Diseases [1 ed.] 3030390438, 9783030390433, 9783030390440

Citation preview

Endocrinology Series Editor: Andrea Lenzi Series Co-Editor: Emmanuele A. Jannini

Rosario Pivonello Evanthia Diamanti-Kandarakis Editors

Environmental Endocrinology and Endocrine Disruptors Endocrine and Endocrine-targeted Actions and Related Human Diseases

Endocrinology Series Editor Andrea Lenzi, Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy Series Co-Editor Emmanuele A. Jannini, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Roma, Italy

Within the health sciences, Endocrinology has an unique and pivotal role. This old, but continuously new science is the study of the various hormones and their actions and disorders in the body. The matter of Endocrinology are the glands, i.e. the organs that produce hormones, active on the metabolism, reproduction, food absorption and utilization, growth and development, behavior control, and several other complex functions of the organisms. Since hormones interact, affect, regulate and control virtually all body functions, Endocrinology not only is a very complex science, multidisciplinary in nature, but is one with the highest scientific turnover. Knowledge in the Endocrinological sciences is continuously changing and growing. In fact, the field of Endocrinology and Metabolism is one where the highest number of scientific publications continuously flourishes. The number of scientific journals dealing with hormones and the regulation of body chemistry is dramatically high. Furthermore, Endocrinology is directly related to genetics, neurology, immunology, rheumatology, gastroenterology, nephrology, orthopedics, cardiology, oncology, gland surgery, psychology, psychiatry, internal medicine, and basic sciences. All these fields are interested in updates in Endocrinology. The aim of the MRW in Endocrinology is to update the Endocrinological matter using the knowledge of the best experts in each section of Endocrinology: basic endocrinology, neuroendocrinology, endocrinological oncology, pancreas with diabetes and other metabolic disorders, thyroid, parathyroid and bone metabolism, adrenals and endocrine hypertension, sexuality, reproduction, and behavior.

Rosario Pivonello • Evanthia Diamanti-Kandarakis Editors

Environmental Endocrinology and Endocrine Disruptors Endocrine and Endocrine-targeted Actions and Related Human Diseases

With 40 Figures and 23 Tables

Editors Rosario Pivonello Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES) Università Federico II di Napoli Naples, Italy

Evanthia Diamanti-Kandarakis Medical School National and Kapodistrian University of Athens Athens, Greece

ISSN 2510-1927 ISSN 2510-1935 (electronic) Endocrinology ISBN 978-3-030-39043-3 ISBN 978-3-030-39044-0 (eBook) https://doi.org/10.1007/978-3-030-39044-0 © Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This book is dedicated to you, who inspired it

Series Preface

Is there an unmet need for a new MRW series in Endocrinology and Metabolism? It might not seem so! The vast number of existing textbooks, monographs, and scientific journals suggest that the field of hormones (from genetic, molecular, biochemical, and translational to physiological, behavioral, and clinical aspects) is one of the largest in biomedicine, producing a simply huge scientific output. However, we are sure that this new series will be of interest to scientists, academics, students, physicians, and specialists alike. The knowledge in endocrinology and metabolism limited to the two main (from an epidemiological perspective) diseases, namely hypo/hyperthyroidism and diabetes mellitus, now seems outdated and perhaps closer to the practical interests of the general practitioner than to those of the specialist. This has led to endocrinology and metabolism being increasingly considered as a subsection of internal medicine rather than an autonomous specialization. But endocrinology is much more than this. We are proposing this series as the manifest for Endocrinology 2.0, embracing the fields of medicine in which hormones play a major part but which, for various historical and cultural reasons, have thus far been “ignored” by endocrinologists. Hence, this MRW comprises “traditional” (but no less important or investigated) topics: from the molecular actions of hormones to the pathophysiology and management of pituitary, thyroid, adrenal, pancreatic, and gonadal diseases, as well as less usual and common arguments. Endocrinology 2.0 is, in fact, the science of hormones, but it is also the medicine of sexuality and reproduction, the medicine of gender differences, and the medicine of well-being. These aspects of endocrinology have to date been considered of little interest, as they are young and relatively unexplored sciences. But this is no longer the case. The large scientific production in these fields coupled with the impressive social interest of patients in these topics is stimulating a new and fascinating challenge for endocrinology. The aim of the MRW in Endocrinology is thus to update the subject with the knowledge of the best experts in each field: basic endocrinology; neuroendocrinology; endocrinological oncology; pancreatic disorders; diabetes and other metabolic disorders; thyroid, parathyroid, and bone metabolism; adrenal and endocrine

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hypertension; and sexuality, reproduction, and behavior. We are sure that this ambitious aim, covering for the first time the whole spectrum of Endocrinology 2.0, will be fulfilled in this vast Springer MRW in Endocrinology Series. Andrea Lenzi Emmanuele A. Jannini

Volume Preface

The endocrine system encompasses a complex network of interconnected structures and functional pathways across multiple organs and tissues, which cooperate in modulating each other and to drive virtually all biological and vital processes within an individual, through production of hormones. Global industrialization and the contemporary lifestyle determined the occurrence in the environment of several natural and man-made factors, known as endocrine disruptors, recognized to adversely affect the normal functioning of the endocrine system, by mimicking or interfering with production, transport, signaling, and clearance of endogenous hormones. Moreover, other environmental cues, including chemical factors and physical factors such as climate, temperature, photoperiod, radiation, and nutrition, are also known to ultimately affect the endocrine function, directly or indirectly. Because of their intrinsic characteristics, endocrine disruptors display complex pharmacokinetics with a non-canonical, non-monotonic, dose-response pattern and frequent additive or synergistic effects. Growing concerns on the health effects of exposures to such compounds in humans have triggered extensive efforts in deciphering their concrete impact, leading to production of extensive data, particularly in experimental models. Novel evidence on mechanisms of endocrine disruption continues to rapidly accumulate in the literature; nevertheless, environmental endocrinology is still a “relatively recent” area of investigation, encompassing quite a few challenges with respect to establishing causative relationships in humans. The urgent need to organize and to provide an overall exhaustive overview of all the evidence, by trying to deliver some straightful take-home messages, was the rationale for developing the current textbook. The volume Environmental Endocrinology and Endocrine Disruptors: Endocrine and Endocrine-targeted Actions and Related Human Diseases comprises chapters written by outstanding international researchers operating in the field of environmental endocrinology and is aimed at gathering evidences from preclinical and clinical studies encompassing the pathogenetic role of exposure to endocrine disruptors, as a major focus of the volume, as well as to other environmental cues targeting the endocrine system by alternative nonendocrine mechanisms. The volume provides a comprehensive overview of all aspects of environmental endocrinology, spanning from sources and patterns of exposure, to the identification of endocrine and non-endocrine targets, and to description of the underlying ix

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mechanisms of action, by examining potential causal pathways of downstream endocrine and endocrine-related diseases. The volume exhaustively and critically examines the impact of the environment on endocrine axes, particularly, on the hypothalamus-pituitary unit function and the development of pituitary tumors, and on the hypothalamus-pituitary-thyroid, the hypothalamus-pituitary-adrenal, the hypothalamus-pituitary-ovary, and the hypothalamus-pituitary-testis axes. A major segment of the volume covers the area of male and female reproductive function, which has been long time characterized as a noteworthy target of endocrine disruption by lifestyle and environmental components, due to compelling evidences deriving from both experimental and epidemiological studies, and also encloses chapters disserting the role of the environment in the risk of developing specific reproductive conditions/syndromes, such as testicular dysgenesis syndrome and ovarian or uterine diseases. The volume also comprises a focused chapter on the impact of the environment on sexual response, encompassing the potential link between exposures and disorders of reproductive organs development and of secondary sexual characteristics, as well as sexual function and sexual orientation/core gender identity. Other major topics of the volume concern the role of the environment in the pathogenesis of endocrine cancers, endocrine-related cancers, and neuroendocrine tumors, as well as a dissertation on incipient new targets of endocrine disruptors, such as metabolic and immune disorders and bone metabolism. Volume editors wish to sincerely thank and congratulate with all of the authors for their commitment and relevant contribution to this major reference work dedicated to endocrinologists, andrologists, urologists, gynecologists, and sexologists, as well as to all professionals involved in environmental health and interested in deepening their knowledge of this alarming and complex field of investigation, and in increasing public policy and awareness. Naples, Italy Athens, Greece April 2023

Rosario Pivonello Evanthia Diamanti-Kandarakis

Contents

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Environmental Endocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sriram Gubbi, Rachel Wurth, Fady Hannah-Shmouni, and Christian A. Koch

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Environmental Impact on the Hypothalamus–Pituitary Axis Giuseppe Giuffrida, Francesco Ferraù, Marta Ragonese, and Salvatore Cannavò

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Environmental Endocrinology and the HypothalamusPituitary-Thyroid Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leonidas H. Duntas

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Environmental Impact on the Hypothalamus–Pituitary– Adrenal Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Krystallenia I. Alexandraki, Ariadni Spyroglou, Lorenzo Tucci, and Guido Di Dalmazi Environmental Impact on the Hypothalamus-PituitaryOvary Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olivera Stanojlović, Dragan Hrnčić, Danijela Vojnović-Milutinović, Dušan Mladenović, and Nikola Šutulović

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Environmental Impact on Female Fertility and Pregnancy . . . . . . Anastasia-Konstantina Sakali, Alexandra Bargiota, Maria Papagianni, Aleksandra Rasic-Markovic, and George Mastorakos

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The Role of the Environment in Female Reproductive Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olga Papalou and Eleni A. Kandaraki

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Environmental Impact on the Hypothalamus-Pituitary-Testis Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andrea Di Nisio, Christian Corsini, and Carlo Foresta

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Environmental Impact on Semen Quality and Male Fertility Francesco Pallotti, Marianna Pelloni, Stefano Colangelo, Daniele Gianfrilli, Andrea Lenzi, Francesco Lombardo, and Donatella Paoli

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The Role of the Environment in Testicular Dysgenesis Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renata S. Auriemma, Davide Menafra, Cristina de Angelis, Claudia Pivonello, Francesco Garifalos, Nunzia Verde, Giacomo Galdiero, Mariangela Piscopo, Annamaria Colao, and Rosario Pivonello

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Environmental Impact on Sexual Response . . . . . . . . . . . . . . . . . . Carlotta Cocchetti, Dominik Rachoń, and Alessandra D. Fisher

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Environmental Impact on Bone Health . . . . . . . . . . . . . . . . . . . . . M. Grammatiki, V. Antonopoulou, and K. Kotsa

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Environmental Impact on Immune System . . . . . . . . . . . . . . . . . . Andrea M. Isidori, Valeria Hasenmajer, Francesca Sciarra, and Mary Anna Venneri

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Environmental Impact on Metabolism . . . . . . . . . . . . . . . . . . . . . . Giovanna Muscogiuri, Luigi Barrea, Evelyn Frias-Toral, Eloisa Garcia-Velasquez, Cristina de Angelis, Carlos Ordoñez, Gabriela Cucalón, Marwan El Ghoch, Annamaria Colao, and Rosario Pivonello

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The Role of the Environment in Neuroendocrine Tumors . . . . . . . Aleksandra Zofia Rutkowska, Aleksandra Olsson, Jacek Rutkowski, and Andrzej Milewicz

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The Role of the Environment in Endocrine Cancers . . . . . . . . . . . Melpomeni Peppa and Ioanna Mavroeidi

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The Role of the Environment in Hormone-Related Cancers . . . . . Alzbeta Bujnakova Mlynarcikova and Sona Scsukova

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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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About the Editors

Rosario Pivonello, MD, PhD Università Federico II di Napoli Naples, Italy Rosario Pivonello is now Full Professor of Endocrinology at Università Federico II di Napoli, Italy. In 2003, Prof. Pivonello received a Ph.D. in Neuropsychopharmacology and Toxicology at Università Federico II di Napoli, and, in 2005, a Ph.D. in Internal Medicine (Basic and Clinical Endocrinology) at Erasmus University, Rotterdam, the Netherlands, on the role of the dopaminergic system in pituitary and adrenal tumors. Prof. Pivonello’s major clinical interests and scientific research include pituitary and adrenal diseases, with a focus on Cushing’s syndrome, of which he is recognized as an expert by the scientific community. Prof. Pivonello is principal investigator of international multicenter studies on Cushing’s syndrome, acromegaly and adrenal diseases, and of national research projects in endocrinology funded by the Italian Ministry of University and Research (MIUR) and the Italian Ministry of Health. In the last decade, Prof. Pivonello’s clinical and research interests included the study of andrology and reproductive and sexual medicine. In 2011, Prof. Pivonello pursued a Master in Andrology and Sexual Medicine at the University of Florence, Italy and, in 2016, a Master in Andrology and Seminology at the University of Rome “La Sapienza,” Italy. Prof. Pivonello is Director of the Unit of Andrology and Medicine of Male and Female Reproduction and Sexuality “FERTISEXCARES” (Excellence Centre of the Italian Society of Andrology and Sexual Medicine [SIAMS]) of University Hospital

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Federico II. Prof. Pivonello is a staff member of the UNESCO Chair on Health Education and Sustainable Development at Università Federico II di Napoli (Chair coordinator Professor Annamaria Colao), with direction of the andrology program. Prof. Pivonello has several national and international committee memberships and editorships. Currently, he is a Board Member of The Pituitary Society (since 2021), coordinator of the club Endocrinology and Metabolism of Sport and Physical Exercise of the Italian Society of Endocrinology (SIE; since 2018), coordinator of the Clinical Trials Committee of SIAMS, coordinator of the Relationships with Other Scientific Societies and Institutions Committee of the Italian Society of Gender, Identity and Health (SIGIS; since 2022), and treasurer for the Foundation for Research in Endocrinology, Metabolic Diseases and Andrology Onlus (Fo.Ri.SIE; since 2022). In the past, Prof. Pivonello has been a member of the Executive Committee of the European Neuroendocrine Association (ENEA; 2016–2020). Prof. Pivonello was coordinator (2018–2021) and member (2010–2012) of the Scientific Committee, coordinator of the Drugs Committee (2017–2019), and member of the Executive Committee (2012–2016) of SIAMS. Prof. Pivonello was also a member of the Drugs Committee and of the Scientific Committee (2011–2013 and 2017–2019) of the SIE, and has established relations with the Italian Medicines Agency for drug monitoring in endocrinology (2015–2017) and the Innovative Proposals Commission (2013–2015). Prof. Pivonello is Associate Editor of Frontiers in Endocrinology (Pituitary Endocrinology section; since 2017), Editorial Advisory Board Member of the Journal of Neuroendocrinology (since 2020), and Editorial Board Member of The Journal of Clinical Endocrinology and Metabolism (since 2022). Furthermore, Prof. Pivonello has been an expert peer reviewer for the German Research Foundation in the evaluation of funding proposals (2017–2021) and is a member of the Register of Expert Peer Reviewers for Italian Scientific Evaluation (MIUR-REPRISE; since 2015). In terms of academic achievements, Prof. Pivonello is coordinator of the second-level University Master course in Andrology and Medicine of Reproduction and Sexuality at Università Federico II di Napoli, faculty member for PhD courses, and member of the

About the Editors

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Committee of Lecturers for the PhD at the University of Rome “La Sapienza.” Prof. Pivonello authored more than 400 scientific publications (h-index: 73; citations: 17063 [Scopus]) and is ranked in the Italian Top Scientist List. Dr. Evanthia Diamanti-Kandarakis is Emeritus Professor of Internal Medicine and Endocrinology and Chairman of the Department of Endocrinology and Diabetes, Hygeia Hospital Athens. She received her M.D. from Medical School of Athens and her Ph.D. in Experimental Endocrinology on the effects of androgens in hypophysectomized rats, from the same university. Her training in Internal Medicine took place in England (1974–1980), and in Endocrinology- Diabetes, Metabolism and Obesity in USA (1980–1986). Her research interests have focused for the last 25 years on clinical, molecular, and environmental aspects of metabolic and hormonal abnormalities in obesity, diabetes, and polycystic ovarian syndrome. Recently her scientific interest has included the environmental endocrinology and specifically on the effects of endocrine disruptors in endocrinopathies. This work has generated 190 publications with approx. 24,000 citations, classifying her among the 27 worldwide best Greek scientists and the first Greek woman endocrinologist among them. In 2016, 2017, and 2018, she has received the first award of the best teacher in endocrinology in Greece, after undisclosed vote among young trainee endocrinologists in Greece. On May 22, 2017 at the European Congress of Endocrinology in Lisbon, the European Society of Endocrinology has awarded her with the European Hormone Medal for her outstanding contribution in the field of Endocrinology and Metabolism, among 49 candidates from all European endocrinological societies. She is the inspirator and organizer of the monothematic and interactive training COMBO ENDO, international course which takes place yearly in Athens Greece. She is the author of several chapters and editor of 20 books of endocrinology. She currently is the editor of the following books under publication: The applied

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endocrinology 2020, Environmental endocrinology by Elsevier 2023 and Polycystic ovarian syndrome by Elsevier 2022, which are in the publication process. Dr. Diamanti-Kandarakis has been invited by the international academic community as a speaker and tutor and has given more than 250 lectures, literally around the globe (Europe, Asia, Africa, North and South America).

Contributors

Krystallenia I. Alexandraki Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece V. Antonopoulou Division of Endocrinology and Metabolism – Diabetes Center, 1st Department of Internal Medicine, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Renata S. Auriemma Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Alexandra Bargiota Department of Endocrinology and Metabolic Diseases, Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece Luigi Barrea Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia e Andrologia, Università Federico II di Napoli, Naples, Italy Centro italiano per la cura e il benessere del paziente con obesità (C.I.B.O) Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy Alzbeta Bujnakova Mlynarcikova Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic Salvatore Cannavò Department of Human Pathology of Adulthood and Childhood, University of Messina, Sicily, Italy Endocrine Unit, “G. Martino” University Hospital of Messina, Sicily, Italy Carlotta Cocchetti Andrology, Women’s Endocrinology and Gender Incongruence Unit, Careggi University Hospital, Florence, Italy Stefano Colangelo Laboratory of Seminology – Sperm Bank “Loredana Gandini”, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy xvii

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Contributors

Annamaria Colao Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Health Education and Sustainable Development, Federico II University, Naples, Italy Centro italiano per la cura e il benessere del paziente con obesità (C.I.B.O) Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy Christian Corsini Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy Gabriela Cucalón ESPOL Polytechnic University, Escuela Superior Politécnica del Litoral, ESPOL, Lifescience Faculty, Guayaquil, Ecuador Cristina de Angelis Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Guido Di Dalmazi Endocrinology and Diabetes Prevention and Care Unit, Department of Medical and Surgical Sciences, S. Orsola Policlinic, Alma Mater Studiorum University of Bologna, Bologna, Italy Andrea Di Nisio Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy Leonidas H. Duntas Evgenideion Hospital, Unit of Endocrinology, Diabetes and Metabolism, University of Athens, Athens, Greece Marwan El Ghoch Department of Nutrition and Dietetics, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon Francesco Ferraù Department of Human Pathology of Adulthood and Childhood, University of Messina, Sicily, Italy Endocrine Unit, “G. Martino” University Hospital of Messina, Sicily, Italy Alessandra D. Fisher Andrology, Women’s Endocrinology and Gender Incongruence Unit, Careggi University Hospital, Florence, Italy Carlo Foresta Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy Evelyn Frias-Toral Clinical Research Associate Professor for Palliative Care Residency from Universidad Católica Santiago de Guayaquil, Av. Pdte. Carlos Julio Arosemena Tola, Guayaquil, Ecuador

Contributors

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Giacomo Galdiero Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Eloisa Garcia-Velasquez Clinical Nutrition Service, San Francisco Clinic Hospital, Guayaquil, Ecuador Francesco Garifalos Dipartimento di Sanità Pubblica, Università Federico II di Napoli, Naples, Italy Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Daniele Gianfrilli Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy Giuseppe Giuffrida Department of Human Pathology of Adulthood and Childhood, University of Messina, Sicily, Italy Endocrine Unit, “G. Martino” University Hospital of Messina, Sicily, Italy M. Grammatiki Division of Endocrinology and Metabolism – Diabetes Center, 1st Department of Internal Medicine, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Sriram Gubbi Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA Fady Hannah-Shmouni Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA Valeria Hasenmajer Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy Dragan Hrnčić Institute of Medical Physiology “Richard Burian”, Belgrade University Faculty of Medicine, Belgrade, Serbia Andrea M. Isidori Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy Eleni A. Kandaraki Department of Endocrinology and Diabetes, Hygeia Hospital, Athens, Greece

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Contributors

Christian A. Koch The University of Tennessee Health Science Center, Memphis, TN, USA Fox Chase Cancer Center, Philadelphia, PA, USA K. Kotsa Division of Endocrinology and Metabolism – Diabetes Center, 1st Department of Internal Medicine, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Andrea Lenzi Laboratory of Seminology – Sperm Bank “Loredana Gandini”, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy Francesco Lombardo Laboratory of Seminology – Sperm Bank “Loredana Gandini”, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy George Mastorakos Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieion Hospital, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece Ioanna Mavroeidi Endocrine Unit, 2nd Propaedeutic Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece Davide Menafra Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Andrzej Milewicz Faculty of Natural Sciences and Technology, Karkonosze College in Jelenia Góra, Jelenia Góra, Poland Dušan Mladenović Institute of Pathophysiology “Ljubodrag Buba Mihailovic”, Belgrade University Faculty of Medicine, Belgrade, Serbia Giovanna Muscogiuri Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia e Andrologia, Università Federico II di Napoli, Naples, Italy Centro italiano per la cura e il benessere del paziente con obesità (C.I.B.O) Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy Health Education and Sustainable Development, Federico II University, Naples, Italy Aleksandra Olsson DetoxED LLC, Gdańsk, Poland Carlos Ordoñez ESPOL Polytechnic University, Escuela Superior Politécnica del Litoral, ESPOL, Lifescience Faculty, Guayaquil, Ecuador Francesco Pallotti Laboratory of Seminology – Sperm Bank “Loredana Gandini”, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

Contributors

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Donatella Paoli Laboratory of Seminology – Sperm Bank “Loredana Gandini”, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy Maria Papagianni 3rd Department of Pediatrics, Aristotle University of Thessaloniki, School of Medicine, “Hippokrateion” General Hospital of Thessaloniki, Thessaloniki, Greece Olga Papalou Department of Endocrinology and Diabetes, Hygeia Hospital, Athens, Greece Marianna Pelloni Laboratory of Seminology – Sperm Bank “Loredana Gandini”, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy Melpomeni Peppa Endocrine Unit, 2nd Propaedeutic Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece Mariangela Piscopo Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Claudia Pivonello Dipartimento di Sanità Pubblica, Università Federico II di Napoli, Naples, Italy Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Rosario Pivonello Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Health Education and Sustainable Development, Federico II University, Naples, Italy Dominik Rachoń Department of Clinical and Experimental Endocrinology, Medical University of Gdańsk, Gdańsk, Poland Marta Ragonese Department of Human Pathology of Adulthood and Childhood, University of Messina, Sicily, Italy Endocrine Unit, “G. Martino” University Hospital of Messina, Sicily, Italy Aleksandra Rasic-Markovic Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Aleksandra Zofia Rutkowska Division of Community Nursing and Health Promotion; Institute of Nursing and Midwifery, Medical University of Gdańsk, Gdańsk, Poland DetoxED LLC, Gdańsk, Poland

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Contributors

Jacek Rutkowski Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland Anastasia-Konstantina Sakali Department of Endocrinology and Metabolic Diseases, Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece Francesca Sciarra Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy Sona Scsukova Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic Ariadni Spyroglou Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zurich, Switzerland Olivera Stanojlović Institute of Medical Physiology “Richard Burian”, Belgrade University Faculty of Medicine, Belgrade, Serbia Nikola Šutulović Institute of medical physiology “Richard Burian”, Belgrade University Faculty of medicine, Belgrade, Serbia Lorenzo Tucci Endocrinology and Diabetes Prevention and Care Unit, Department of Medical and Surgical Sciences, S. Orsola Policlinic, Alma Mater Studiorum University of Bologna, Bologna, Italy Mary Anna Venneri Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy Nunzia Verde Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Danijela Vojnović-Milutinović Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia Rachel Wurth Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA

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Environmental Endocrinology Basic Concepts Sriram Gubbi, Rachel Wurth, Fady Hannah-Shmouni, and Christian A. Koch

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Concept of an Endocrine Disruptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Environmental Factors and the Endocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine Physiology and Environmental Endocrine-Disrupting Chemicals . . . . . . . . . . . . . . . . . . . Hypothalamus and Pituitary Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adrenal Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reproductive Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bone Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine Pancreas, Adipose Tissue, and Cardiovascular Physiology . . . . . . . . . . . . . . . . . . . . . . Mechanisms of Environment-Mediated Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Challenges and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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S. Gubbi (*) Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA e-mail: [email protected] R. Wurth · F. Hannah-Shmouni Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA C. A. Koch (*) The University of Tennessee Health Science Center, Memphis, TN, USA Fox Chase Cancer Center, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2023 R. Pivonello, E. Diamanti-Kandarakis (eds.), Environmental Endocrinology and Endocrine Disruptors, Endocrinology, https://doi.org/10.1007/978-3-030-39044-0_1

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Abstract

The endocrine system comprises a complex array of intercommunicating pathways across several organ systems that modulate each other’s structure and function through production of hormones. Several natural and man-made factors occurring in the environment are known to adversely affect the normal functioning of the endocrine system. These factors are known as endocrine disruptors (EDs). Physical factors such as climate, temperature, photoperiod, radiation, and nutrition and chemical factors such as pH, water salinity, and endocrinedisrupting chemicals (EDCs) are known to affect endocrine function across several species. Currently, extensive data is available on the adverse effects of EDCs on the endocrine system, and novel data on mechanisms of endocrine disruption continue to rapidly accumulate in the literature. Nonetheless, environmental endocrinology is still a relatively young and upcoming branch of endocrinology and metabolism. This chapter introduces the basic concepts in environmental endocrinology and provides a synopsis on the various EDs and EDCs that affect the endocrine system and the various challenges and future directions in managing environmental endocrine disruption. Keywords

Endocrine disruptor · Climate · Estrogen · Bisphenol A · Phthalates · Breast cancer · Cancer · Thyroid

Introduction The endocrine system is a vital organ system that is necessary for sustenance of life in living organisms. Our body comprises of several endocrine glands, including the pituitary, thyroid, parathyroids, adrenals, gonads, endocrine pancreas, neuronal ganglia, and adipose tissue. Endocrine glands produce hormones belonging to a myriad of biochemical classes and with varied functions, and these hormones interact with several molecular pathways through intricate mechanisms. Table 1 lists the various endocrine glands in humans and the hormones secreted by each endocrine gland. Any living organism is vulnerable to several internal and external factors that predispose to or cause disease. Examples of internal factors include age, sex, and genetic makeup of an organism. External factors include diet, physical activity, socioeconomic status, and environment surrounding the organism. This chapter introduces environmental endocrinology and the various environmental factors that can disrupt the endocrine system in multicellular organisms. The importance of this topic and field is underscored by the fact that on January 14, 2020, the European Parliament passed a resolution in response to the European Union’s “Green Deal” (Endocrine-News 2020). This plan comprises an investment of more than 1 trillion Euro dollars to promote environmental initiatives. Among these are the plans to close gaps in the legislation of chemicals including endocrine-disrupting

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Table 1 List of endocrine organs in the body and their hormonal products Hypothalamus Growth hormone-releasing hormone (GHRH) Thyrotropin-releasing hormone (TRH) Gonadotropin-releasing hormone (GnRH) Corticotropin-releasing hormone (CRH) Dopamine Oxytocin Arginine vasopressin (AVP/antidiuretic hormone, ADH) Somatostatin Neuropeptide Y Vasoactive intestinal polypeptide (VIP) Galanin Pituitary gland Growth hormone (GH) Thyrotropin/thyroid-stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Proopiomelanocortin (POMC) Melanocyte-stimulating hormones (alpha- and beta-MSH) Endorphins Enkephalins Prolactin Oxytocin (produced in the hypothalamus and stored in the posterior pituitary gland) AVP (produced in the hypothalamus and stored in the posterior pituitary gland) Pineal gland Melatonin Thyroid gland Thyroxine (T4) Triiodothyronine (T3) Calcitonin Parathyroid gland Parathyroid hormone Thymus Thymulin Thymopoietin Heart Atrial natriuretic peptide (ANP/atrial natriuretic factor) Brain natriuretic peptide (BNP/B-type natriuretic peptide) C-type natriuretic peptide (CNP) Kidney Erythropoietin Renin 1,25-Dihydroxycholecalciferol (vitamin D) Adrenal gland (cortex) Aldosterone Corticosterone 11-Deoxycorticosterone Progesterone (continued)

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Table 1 (continued) Pregnenolone Cortisol 11-Deoxycortisol 17-Hydroxyprogesterone 17-Hydroxypregnenolone Dehydroepiandrosterone Dehydroepiandrosterone sulfate Androstenedione Testosterone Estradiol Adrenal gland (medulla) Norepinephrine Epinephrine Autonomic nervous system ganglia Norepinephrine Dopamine Calcitonin gene-related peptide (CGRP) Pancreas Glucagon Insulin Pancreatic polypeptide Somatostatin Amylin Gastrointestinal tract and liver Insulin-like growth factor-1 (IGF-1/somatomedin-c) Incretins (glucagon-like peptide-1, glucagon-like peptide-2, gastric inhibitory peptide) Secretin Gastrin Cholecystokinin VIP Serotonin (5-hydroxytryptamine) Pituitary adenylate cyclase-activating peptide Angiotensinogen Motilin Neurotensin Galanin Neuropeptide Y Peptide YY Tachykinins (substance P, neurokinin A, neurokinin B) Testicles Testosterone Dihydrotestosterone Androstenedione Inhibin A and B Anti-Mullerian hormone (AMH) Ovaries Estradiol Estriol Estrone (continued)

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Table 1 (continued) Progesterone Inhibin A and B AMH Activin Follistatin Placenta Beta human chorionic gonadotropin (Beta-HCG) Estriol Human placental lactogen IGF-1 Insulin-like growth factor-2 (IGF-2) Adipose tissue Leptin Adiponectin Ghrelin Neuropeptide Y Resistin Omentin Visfatin Apelin Skeleton Osteocalcin Fibroblast growth factor 23 (FGF23) Skin Cholecalciferol (Vitamin D3) Parathyroid hormone-related peptide (PTHrP) Note: Several of the above hormones are produced in multiple organ systems in the body. There are various other hormones whose functions are as of yet unknown and are not listed above

chemicals (EDCs) in order to substitute hazardous chemicals with safer alternatives. EDCs can be identified in consumer products, food containers, personal care products, pesticides, furniture, and other sources and can contribute to health issues such as diabetes mellitus, obesity, neurodevelopmental disorders, reproductive problems, cancer, and others (La Merrill et al. 2019; Soto and Sonnenschein 2010; Koch 2017; Cannavò et al. 2010; Lewis et al. 2017; Mangano 2009).

The Concept of an Endocrine Disruptor The United States Environmental Protection Agency defined an endocrine disruptor (ED) in 1991 as an exogenous agent that interferes with the synthesis, secretion, transport, metabolism, binding action, or elimination of natural hormones in the body that are responsible for homeostasis, reproduction, and/or behavior (Crisp et al. n.d.). A vast majority of studies on endocrine disruption has been conducted on a particular class of EDs, the endocrine-disrupting chemicals (EDCs). As per the 2009 Endocrine Society Statement, an EDC is defined as a compound that is either a

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naturally or a synthetically prepared, which through inappropriate environmental or developmental exposure can alter the hormonal physiology and homeostatic mechanisms that enable a living organism to interact with its environment (DiamantiKandarakis et al. 2009). Based on the EDC-1 scientific statement, the following six general rules/mechanisms can be applied to most EDs and EDCs (DiamantiKandarakis et al. 2009): I. Age: The age of exposure to an ED can determine the type of damage caused to an organism, and the observed disruptions can be markedly different with fetal/ embryonic exposure versus exposure during adulthood. II. Latency: With most EDs, there is a latency or a lag period between exposure and manifestation of disease. This latency period can vary based on the type of ED, dosage, route of exposure, target endocrine gland, and duration of exposure. III. Combination of EDs: Often, environmental exposure to one form of ED is likely to be combined with an exposure to another ED or a mixture of different EDs, and the effects of some combinations of EDCs can be synergistic or additive. IV. Dose of exposure: EDs/EDCs can cause endocrine abnormalities even at the most minimum doses of exposure, when exposed at a crucial time point in development of an organism. V. Dose-response dynamics: As observed with innate hormones and other signaling molecules, interactions between EDCs and their target response can generate atypical dose-response curves, such as U-shaped or inverted U-shaped curves (Vandenberg 2014). VI. Transmission to offspring: An ED/EDC can only affect an exposed organism but can also cause adverse effects in its offspring, many of which are likely mediated through epigenetic mechanisms (Anway et al. 2005). In addition, there is another rule that could be applied to some EDs, which is the rule of sexual dimorphism in the effects of an ED. An ED/EDC can cause different effects based on the sex of the organism, therefore resulting in sex-specific genotypes and phenotypes of endocrine disruption (Vieau 2011).

Environmental Factors and the Endocrine System The environment interacts with a living organism through several physical and chemical factors. An inadvertent exposure to any of these factors can potentially lead to endocrine disruption. Each form of ED is described below, and a list of EDs is provided in Table 2. Figure 1 provides a synopsis of the various endocrine disorders associated with physical and chemical EDs. I. Physical Factors: Some of the physical factors that can disrupt the endocrine system include climate, radiation, photoperiod, temperature, and nutrition. These factors are described below along with their effects on the endocrine system. (a) Climate: Climate is a result of the complex interplay among various physical and chemical factors, such as temperature, pH of the oceans or water bodies,

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Table 2 Classification of environmental endocrine disruptors Physical factors Climate Temperature Photoperiod Nutrition Radiation Ultraviolet radiation (UV-A and UV-B) X-rays Gamma rays Alpha particles Beta particles Chemical factors pH Water salinity Endocrine-disrupting chemicals (EDCs) Naturally occurring EDCs: Phytoestrogens and Isoflavones (daidzein, genistein, coumestrol) Goitrogens (flavonoids, goitrins, thiocyanates, perchlorates) Natural oils (lavender oil, tea tree oil) Synthetic EDCs: Pharmaceuticals (diethylstilbestrol, DES) Plastics (bisphenol A, BPA) Industrial solvents and lubricants (polychlorinated biphenyls, PCBs’ polybrominated biphenyls, PBBs; dioxins) Plasticizers (phthalates) Herbicides (Atrazine) Pesticides (dichlorodiphenyltrichloroethane, DDT; chlorpyrifos) Fungicides (vinclozolin) Stabilizers (organotins) Inorganic anions (perchlorates) Heavy metals (arsenic, lead, mercury, iron, manganese, cadmium, copper, zinc, nickel) UV sunscreens (camphor derivatives, cinnamates) Radioactive isotopes (iodine, cesium, strontium, radon)

water salinity, photoperiod, and radiation. Climate change is, without a doubt, one of the greatest threats to the stability of biodiversity and ecological niches, and its impact on socioeconomic and geographic attributes of human life cannot be overlooked. Climate change is predicted to cause higher frequencies of hot temperatures and lower frequencies of cold temperatures as per the Intergovernmental Panel on Climate Change (Morley and Lewis 2014). Mass die-offs, especially of birds and bats, have been increasingly reported (Boyles et al. 2011). In the recent past, El-Nino–Southern Oscillation events have had adverse influences on corals, oysters, crop plants, and humans by altering marine and terrestrial pathogens, and the continuing global climate fluctuations have morphed the marine and terrestrial biodiversity landscape (Harvell et al. 2002). Endothermic animals, which need to maintain a constant internal body temperature for optimal metabolic function, face a crucial challenge due to

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HYPOTHALAMIC-PITUITARY-PINEAL SYSTEM: • Disruption in hormonal synthesis and secretion. • Altered circadian rhythm. • • • •

PARATHYROID-SKELETAL SYSTEM: Abnormal ossification. Abnormal osteodifferentiation. Osteofibrosis. Risk for osteosarcoma.

CARDIOVASCULAR SYSTEM: • Ischemic heart disease. • Peripheral vascular disease. • Hypertension.

Hypothalamus Pituitary gland

Parathyroid gland

Bone ADRENAL PHYSIOLOGY: Cardiovascular system • Altered adrenal size, gene expression profile, and cortisol metabolism. Adrenal gland MALE REPRODUCTIVE PHYSIOLOGY: Kidney • Hypogonadism. • Cryptorchidism. • Testicular dysgenesis and risk for testicular cancer. Prostate gland • Oligozoospermia. • Prostatic hyperplasia. Testis • Hypospadias. • Early or delayed puberty.

Pineal gland

THYROID PHYSIOLOGY: • Impaired iodide transport. • Thyroid gland hypertrophy. • Altered thyroxine metabolism and protein binding.

ADIPOSE TISSUE PHYSIOLOGY: • Altered lipogenesis and lipolysis, and energy balance. Thyroid gland • Hyperphagia, reduced leptin and adiponectin levels. ENDOCRINE PANCREAS PHYSIOLOGY: • Reduced insulin sensitivity. • Insulitis. • Impaired glucose-mediated insulin secretion. Adipose tissue • Alpha and beta cell dysfunction. Pancreas FEMALE REPRODUCTIVE PHYSIOLOGY: • Hypogonadism and infertility. Uterus • Altered uterine and vaginal weights. Ovary • Vaginal adenocarcinoma. Vagina • Uterine leiomyomas. • Altered mammary development. • Risk for breast cancer. • Early or delayed puberty. Mammary gland

Fig. 1 Effects of environmental endocrine disruptors on the endocrine system

the necessity of complex thermoregulatory mechanisms. Several endocrine changes occur when an endothermic animal adapts to hot temperatures. Neuroendocrine mechanisms reduce food intake and metabolism in hot environment. This leads to reduced thyroid activity and reduced testosterone production, and the cortisol production initially increases and then decreases upon prolonged heat exposure (Morley and Lewis 2014). On the contrary, cold temperatures cause elevations in adrenal steroidal hormones and increase the activity in pituitary and thyroid glands. Prolonged cold exposure can cause thyroid and adrenal gland hypertrophy (Morley and Lewis 2014). Experiments on quails, finch, and other bird species have demonstrated that thermal adaptation varies across species of endotherms (Boyles et al. 2011). Facultative hyperthermia also results in different incubatory and bellysoaking behaviors among different avian species (Boyles et al. 2011). Among mammals living in hot subtropical deserts, the thermoregulation depends on a combination of surrounding temperature and circadian cycles (Boyles et al. 2011). In general, migratory or nomadic animals tend to possess narrow temperature tolerance, while sedentary or non-migratory animals tend to better tolerate wider fluctuations in temperature (Boyles et al. 2011). Therefore, climate change can likely have a significant impact on the survival of migratory species. In addition, climate change and thermal fluctuations can also change parasite biology and parasite establishment, development, growth, and fecundity within their endothermic hosts (Morley and Lewis 2014). The concentrations of the posterior pituitary hormone arginine vasopressin (AVP) in the body are influenced by water intake, food, heat, and seasonal changes to maintain adequate serum osmolality. Interestingly, high altitude and the subsequent hypoxic environment have been reported to alter plasma AVP levels. This is believed to occur in response to the diuresis and natriuresis resulting from inhibition of renal tubular sodium reabsorption

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under hypoxic conditions. Of subjects exposed to high altitude for 2 weeks, males had significantly decreased plasma AVP, a finding corroborated by previous studies. Additionally, both males and females had a statistically significant increase in urine output (Haditsch et al. 2015). The interdependent relationship of AVP signaling to both the internal and external environment makes this hormone of particular interest in the context of the current dynamic climate. Raising global temperatures also can lead to the generation of reactive oxygen species (ROS) which can disrupt mitochondrial membranes leading to impaired ATP production and aerobic respiration, which could be a major mechanism in causing endocrine disruption in endotherms such as birds and mammals. Climate change can act synergistically with EDCs in creating endocrine disruption. There is growing concern for Artic wildlife to inadequately adapt to changing climate due to damage inflicted by EDCs, especially on the thyroid, sex steroid, and glucocorticoid hormonal pathways (Jenssen 2006). In humans, knowledge of the impact of climate change on obesity and various endocrine systems is constantly evolving (Swinburn et al. 2019; Turner et al. 2016). Other EDs such as radiation, photoperiod, temperature, pH, water salinity, and EDCs can cause endocrine disruption through interlaced mechanisms. (b) Radiation: Radiation exposure can occur in different ways, and the effects depend on the duration, dose, and the type of radiation (Koch 2017; Lewis et al. 2017; Mangano 2009; Al-Zoughool and Krewski 2009; UNSCEAR 2008; Greenberg et al. 2007). Large nuclear accidents such as the ones in Chernobyl and Fukushima have resulted in massive amounts of radioactive spillage into the environment. However, more often, radiation exposure in humans is occupation-related, such as those working in nuclear plants or those handling radiopharmaceuticals. The severity of radiation-induced damage can range from inconspicuous to lethal. Among the endocrine glands, the thyroid, pituitary, and gonads are more frequently affected by radiation. Salt caverns have been used for a long time to store various hydrocarbon products and to dispose oil field wastes (https://www.evs.anl.gov/downloads/Veil-etal-1998-Salt-Cavern-Risk-Assessment.pdf). The Tatum Salt Dome in Lamar County, Mississippi, was the site of nuclear weapons testing in the 1960s, and around the year 2000, the government built a water pipeline to transport drinking water from far away from the test site to residents near the Tatum Salt Dome (http://mshistorynow.mdah.state.ms.us/articles/293/nuclearblasts-in-mississippi) (Koch 2017). Other forms of radiation include ultraviolet (UV) radiation, the main source being the Sun and X-rays, which are commonly used in diagnostic radiology; gamma radiation, which is a byproduct of nuclear explosions, lightning, and radioactive decay; and alpha and beta particles, which are products of nuclear decay (Niazi and Niazi 2011; Song et al. 2020). Ionizing radiation (which comprises of higher frequency, UV radiation, X-rays, and gamma rays) causes a variety of endocrine disorders and malignancies. Their

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effects upon chronic exposure have been well studied in crustaceans, some of which include reduced molting patterns, reduced reproduction, lower body mass, and reduced offspring fitness (Song et al. 2020). The Chernobyl nuclear accident in 1986 resulted in the release of large quantities of radioactive iodine [mainly I-131, a beta and gamma emitter, and some amount of I-129, I-132, and other radioisotopes such as cesium (Cs)137, a gamma emitter, and strontium (Sr)-90, a beta emitter] over a period of several days after the event (Song et al. 2020). The radiation exposure occurred in the form of contaminated food and air in the Ukraine and several neighboring countries (Niazi and Niazi 2011). Since the radiation accident, there has been a substantial rise in the occurrence of thyroid cancer, multinodular goiter, and autoimmune thyroid disease in the area (Niazi and Niazi 2011; Eheman et al. 2003). Several other endocrinopathies have also been identified, including congenital diabetes, reduced adrenocortical and sympathetic activities, altered serum thyroid hormone levels, low progesterone levels, and higher gonadotropin, prolactin, and renin levels (Niazi and Niazi 2011). Furthermore, increased incidence of congenital anomalies, intellectual disabilities, thyroid and non-thyroidal neoplasia, cardiovascular disease, and immune-related disorders were observed in children born soon after the radiation accident (Niazi and Niazi 2011). The Fukushima nuclear accident led to the release of Cs-137 and I-131 radioisotopes into the environment (Song et al. 2020). Pituitary adenomas have been reported after head and neck radiation therapy. Hypopituitarism is another adverse effect of external radiation treatment, and individuals who receive more than 20 Gy to the hypothalamus-pituitary axis are at risk for panhypopituitarism, with the earliest damage occurring in the hypothalamus (Littley et al. 1990). Those patients who undergo pituitary ablation can sustain direct damage to the pituitary cells (Littley et al. 1990). The effects of radiation could also cause delayed endocrine sequelae. In children, radiation exposure could cause short height due to GH deficiency, or potentiate premature puberty (Littley et al. 1990). Other effects of cranial radiation include hyperprolactinemia and hypogonadotropic hypogonadism (Niazi and Niazi 2011). Spinal and abdominopelvic radiation can affect the gonads, causing primary hypogonadism, oligozoospermia/azoospermia, follicular growth arrest, and decreased oocytes, and in children, there can be failure to attain puberty (Niazi and Niazi 2011). Several thyroid disorders, including thyroiditis, Graves’ disease, thyroid adenomas, and thyroid carcinoma are reported with the history of external radiation (Koch 2016, 2017; Niazi and Niazi 2011). Similarly, the odds of developing primary hyperparathyroidism in women were shown to be higher among those with any history of radiation (Beard et al. 1989). The radioactive noble gas, radon, has also been associated with exposure-related solid and hematologic malignancies (Al-Zoughool and Krewski 2009). UV radiation has been shown to play a role in maintenance homeostasis through complex mechanisms involving the hypothalamus-pituitary-adrenal (HPA) axis and immune system regulation (Slominski et al. 2018). However,

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UV radiation also possesses deleterious effects on the endocrine system. UV-B radiation interacts with EDCs and has been thought to be responsible for the decline in the survival of several amphibian species likely due to disruption of metamorphosis (Crump 2001). UV-B and octylphenol in combination can affect body weight and timing of hindlimb emergence in leopard frogs (Rana pipiens) and alter hypothalamic gene expression, leading to disruption in growth (Crump et al. 2002). Low-dose gamma ray exposure to the crustacean Daphnia magna results in the disruption of several molecular endocrine pathways such as oocyte apoptosis pathway, lipid peroxidation–ATP depletion pathway, DNA hypermethylation, and calcium influx– endocrine disruption pathway (Song et al. 2020). Exposure to ionizing radiation can also lead to transgenerational effects, mainly driven by epigenetic modifications. Studies have shown that the epigenetic changes in the offspring can be a result of radiation-induced damage to the gametes, and the risk of transgenerational effects is higher if the father or both parents are affected (Burgio et al. 2018; Koturbash et al. 2006). Paternal exposure to X-rays can lead to germline DNA methylation changes and altered global miRNA expression (Burgio et al. 2018). (c) Photoperiod: The term photoperiod refers to the length of daylight exposure. Hormonal production can vary with photoperiod and in turn result in altered endocrine function, and several studies have been conducted on various invertebrates and vertebrates, including mammals (especially rodents and ruminants). Photoperiod and the associated diurnal cycles have complex neuroendocrine mechanisms that modulate endocrine function. Model organisms for photoperiod study, such as Japanese quail and Siberian hamster, which follow seasonal patterns of endocrine function, have provided more insight into photoperiod-responsive endocrine changes (Nakayama and Yoshimura 2018). Melatonin, a hormone produced by the pineal glands, is involved in maintaining the day: night cycle and its duration of secretion positively correlate with the duration of darkness. In addition, studies on avian photoperiod signal transduction pathway have shown that the pars tuberalis of the anterior pituitary gland appears to play a key role in photoperiod modulation, and this structure also seems to be affected by melatonin secretion. Longer photoperiods stimulate the secretion of thyroid stimulating hormone (TSH) from the pars tuberalis, which leads to increased local thyroid hormone concentration in the hypothalamus, which in turn leads to activation of hypothalamus-pituitary-gonadal (HPG) axis, leading to gonadal growth (Nakayama and Yoshimura 2018). Similar mechanisms (pars tuberalis-driven TSH secretion) have been demonstrated to affect mammalian seasonal reproduction through studies on TSH receptor-null mice (Nakayama and Yoshimura 2018). Reduced photoperiod can reduce gonadal function in Japanese killifish (Oryzias latipes) (Urasaki 1972). Longer photoperiods result in increased plasma insulin-like growth factor-1 (IGF-1) concentrations and precede growth spurt in reindeer (Suttie et al. 1991). Photoperiods also potentially

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influence the action of ghrelin on the hypothalamus-pituitary axis in seasonal ruminants such as sheep, with longer photoperiods stimulating higher food intake and increased growth hormone (GH) release as compared to shorter photoperiods (Harrison et al. 2008). In seasonal breeders such as rodents, pre-ovulatory luteinizing hormone (LH) surges occur at fixed time points within the light-dark cycle; alterations in the ratio of light to dark hours dysregulate the amplitude and onset of the LH surge (van der Beek 1996). Maternal programming is the phenomenon of long-lasting effects on the phenotype of an offspring exerted through the maternal intrauterine environment. One such prototypical mechanism is the maternal photoperiod programming, where there is an establishment of a sense of calendar time prior to birth (de Miera et al. 2017). The interaction between melatonin and pars tuberalis seems to play a role in this phenomenon. For example, in rodents, the reproductive development occurs rapidly in spring-born animals, but this development does not happen until the following year in autumn-born animals (de Miera et al. 2017). Changes in photoperiod also affect plasma prolactin concentrations in fetal lambs. Higher concentrations of plasma prolactin were seen in fetal lambs with mothers exposed to increased duration of artificial light during winter months in late pregnancy, and the prolactin levels significantly dropped with intravenous melatonin infusion for 14 h duration to simulate winter months (Bassett et al. 1989). The circadian clock has potential influences on other endocrine functions, including beta cell activity and glucocorticoid rhythmicity. Shift work in humans, which flips the day-night cycle, results in antiphasic secretion of cortisol to its usual day-night secretory pattern. Moreover, misaligned day-night patterns in humans can reduce insulin sensitivity and sub-optimal insulin levels for elevations in plasma glucose (Perelis et al. 2016). Photoperiod interacts with other physical factors such as nutrition. Nutrient excess can disrupt the circadian clock, and studies on ob/ob leptin-deficient mice and Zucker obese rats have shown that these animals have altered circadian and sleep patterns, thus demonstrating a possible link between altered circadian rhythm and dysregulated metabolism (Perelis et al. 2016). Photoperiod also acts as a modifier of the effects of EDCs. Exposure to longer photoperiods and higher temperatures significantly increased estradiol or nonylphenol-mediated estrogen-responsive gene transcription levels in adult male Zebrafish (Jin et al. 2009). This evidence demonstrates that photoperiod is a potential ED, and therapeutic strategies targeting photoperiod and circadian rhythm could play a role in treating metabolic and reproductive endocrine disorders. (d) Temperature: Effects of temperature are largely controlled by the regional climate as well as the local weather. Exposure to elevated temperatures to 30  C results in a variety of changes in the secretion of pituitary hormones in lactating sows (Barb et al. 1991). Plasma testosterone transiently falls and later recovers in Hereford bulls exposed to high ambient temperatures of 35.5  C (Rhynes and Ewing 1973). As with other physical factors, temperature can either potentiate or diminish the effects of other physical EDs. This

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makes sense from an environmental standpoint. For example, physical factors tend to change together with changing seasons. With longer photoperiods during the summer, the ambient temperature tends to be higher, and the vice versa holds true for the winter months. These changes play an important influence on the reproductive behavior of several organisms. In juvenile Atlantic salmon, an increase in ambient temperature with an artificially longer photoperiod during winter months resulted in increased plasma GH, IGF-1, and thyroxine (T4) levels and increased gill Na + K+ ATPase activity, but the same changes failed to occur with increasing the photoperiod alone without raising ambient temperature (McCormick et al. 2000). Similarly, different temperature and nutrition states in various combinations can result in differential plasma profiles of GH, IGF-1, and T4 levels in Coho salmon (Oncorhynchus kisutch) (Larsen et al. 2001). Elevated ambient temperature during winter months resulted in increased melatonin and decreased corticosterone concentrations in red-sided garter snakes (Thamnophis sirtalis parietalis), and males maintained at elevated temperatures of 10  C (instead of a lower 5  C) demonstrated delayed courtship behavior following emergence (Lutterschmidt and Mason 2009). Temperature can also modulate the properties of EDCs, either alone or in conjunction with other physical and chemical factors such as photoperiod, pH, or water salinity. For instance, in adult male Zebrafish, E2 and nonylphenol-mediated estrogen-responsive gene transcription significantly increased at higher temperatures (Jin et al. 2009). Human studies on this topic are few, but the effects of altered temperatures are known to cause endocrine disruption in humans. Local increases in temperature (e.g., varicocele), or even transient hyperthermia through warm baths, can impair testicular function and spermatogenesis in men, while testicular cooling can restore sperm production (Hassanin et al. 2018; Rao et al. 2015). A study conducted on healthy, fasting adult women showed the cold temperatures were associated with increased diastolic blood pressures, decreased salivary amylase, and increased blood glucose concentrations (Okada and Kakehashi 2014). Moreover, humans also have small amounts of brown adipose tissue (BAT) whose quantity and metabolic activity changes with ambient temperature. BAT in humans is a relatively novel endocrine tissue, and has been shown to be involved in glucose and lipid metabolism and varied BAT activities have been associated with different endocrine and non-endocrine neoplasia (Xiang et al. 2018; Abdul Sater et al. 2020). Effects of temperature on human endocrine function are certainly worth exploring further (Turner et al. 2016; Retnakaran et al. 2018; Maushart et al. 2019). However, a much bigger concern is the effects of changing global temperatures and their potential catastrophic impact on altering endocrine functions of flora and fauna on a global scale. Temperature increase along with eutrophication in water bodies can increase metabolic demand in aquatic life and accelerated metabolic rates, thus resulting in hypoxic zones in the aquatic environment and further production of CO2

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(Nikinmaa 2013). Elevated temperatures (to 30  C), along with decreased pH, and decreased water salinity delay growth in Pacific oysters (Crassostrea gigas). Variations in temperature have shown to cause differential effects in the body growth and gonadal size in tropical sea urchins (Tripneustes gratilla), and warming ocean temperatures increase the susceptibility to disease and increase mortality among several species of sea urchins (Dworjanyn and Byrne 2018). (e) Nutrition: Imbalance in nutrition has been a well-documented cause of endocrine disruption not only in an organism’s life but also in its progeny. Malnutrition (either scarce or excess food intake) is known to cause impairment in glucose and adipose tissue homeostasis and hypogonadism. Malnutrition-induced endocrine disruption could be a result of a combination of factors, such as abnormal body composition, excess physical workload due to abnormal body habitus, and placental dysfunction, and mitochondrial abnormalities, leading to adverse fetal outcomes (Barouki et al. 2012). The untoward effects of nutritional imbalance can be passed on to the subsequent generations. Rat dams fed with low protein diet had low beta cell mass from low beta cell proliferation in the fetuses, along with decreased insulin secretion from the islets (Reusens et al. 2011). In addition, mitochondrial dysfunction and lack of glucose-mediated insulin secretion in pancreatic islets have been noted in a 3-month-old offspring of malnourished (both diet-restricted and high-fat diet fed) Wistar rats (Reusens et al. 2011). Such transgenerational effects of malnutrition have been witnessed several times in human history. The great Dutch famine in 1944–1945 is one such example, where the offspring of women who became pregnant during the famine were more likely to develop metabolic syndrome as opposed to offspring of women who became pregnant before or after the famine (Barouki et al. 2012). These offspring were found to have several epigenetic variations in the genes involved in growth and metabolism. Similar effects on metabolism have been found in the offspring of women exposed to nutritional imbalance at the time of gestation during the Chinese famine in 1959–1961 and Nigerian civil war famine in 1968–1970 (Barouki et al. 2012). The past few decades have witnessed a shift in the nutritional balance towards overnutrition and the epidemic of obesity and diabetes mellitus, especially in the western countries, which has also resulted in similar metabolic abnormalities in the offspring. Maternal obesity and pregnancy weight gain above normal limits have been associated with obesity during neonatal and early adulthood periods (Barouki et al. 2012). II. Chemical factors: Although several physical factors can potentially have constant and even lasting influence on the endocrine functions of an organism, a tremendous amount of awareness has been raised on the chemical factors. Apart from general chemical properties such as pH and salinity, the major endocrinedisrupting factors in this category are the endocrine-disrupting chemicals (EDCs). The chemical factors are described as follows:

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(a) pH: Water bodies harbor most of the life on the planet, with estimates of ~80% of life on Earth thriving in the oceans. Change in the pH of water bodies, no doubt, will create a substantial impact on aquatic and terrestrial life, global carbon cycle, and, in turn, the climate. A major effect of changes in pH is the acidification of the ocean. The devastating consequences of ocean acidification have been evident even from prehistoric times and have been postulated to have contributed to mass extinctions, especially the infamous late-Cretaceous mass extinction from the Chicxulub meteor impact that wiped out a substantial amount of life on Earth, including the non-avian dinosaurs and several marine invertebrate and vertebrate species (Henehan et al. 2019). Climate change and ocean acidification often go hand-in-hand in causing major or even catastrophic effects on biodiversity. This is because of the propensity of increasing CO2 levels in the atmosphere to cause a shift in the CO2-HCO3 equilibrium towards the acidic direction (Nikinmaa 2013). Changes in pH can also affect the dissociation status of EDCs, many of which happen to be weak acids/bases (Nikinmaa 2013). In addition, the concentrations of various metal ions can be affected by ocean acidification, which in turn can result in endocrine disruption (Nikinmaa 2013). Another major effect of pH changes and ocean acidification is its impact on water oxygenation levels. Deficiency or excess in water oxygenation can give rise to ROS which can exert toxic effects on the body and on the endocrine system (Nikinmaa 2013). Low pH-mediated decrease in calcium carbonate mineral saturation can impair adequate tissue calcification and growth (Dworjanyn and Byrne 2018). Low pH and low temperatures have been shown to reduce the success of fertilization, embryonic development, and size of the larvae and increase abnormal larval morphology in Sydney rock oyster (Saccostrea glomerate) and C. gigas (Parker et al. 2010). Similarly, low pH and acidification has also shown to reduce gonadal and body growth in T. gratilla (Dworjanyn and Byrne 2018). Although data on the effects of pH on vertebrate animals and humans is sparse, future studies can potentially shed more light on this topic. (b) Water salinity: The term salinity refers to the amount of dissolved salts in a water body. Most of the present knowledge on endocrine disruption from water salinity changes is based on research conducted on aquatic organisms. Salinity is an important physiological factor for aquatic organisms as these creatures would have adopted certain osmoregulatory mechanisms based on the salinity of their environment (Bosker et al. 2017). The effects of various EDCs vary based on the salinity of the water body. Heavy metals and polycyclic aromatic hydrocarbons have differential toxicity profiles in fishes exposed to freshwater versus saline water (Bosker et al. 2017). Reduction in water salinity has been shown to cause several changes in the neuroendocrine system, including changes in the concentrations in peptide hormones, biogenic amines, and enzymes and second messengers of G-protein pathways in whiteleg shrimp (Litopenaeus vannamei) (Zhao et al. 2016). Egg production in mummichog fishes (Fundulus heteroclitus) declines on exposure to

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5 alpha dihydrotestosterone at high salinity levels, while egg production in low saline levels declines regardless of hormonal exposure (Glinka et al. 2015). Exposure to environmental concentration of the herbicide, diuron, to estuarine fish Menidia beryllina resulted in increased T4 levels at lower salinity and lower T4 levels at higher salinity and increased gene expression of deiodinases 1 and 3 with higher salinity even at different temperatures, thus suggesting a modulatory role on the effects of diuron on deiodinase pathway activation (Moreira et al. 2018). Acid rains are caused due to oxides of sulfur, nitrogen, and ozone, which predominantly originate from the combustion of fossil fuel (Singh and Agrawal 2007). Acid rains can lower the pH of water bodies, and this has resulted in a drop in populations of amphibians, mollusks, and phytoplankton (Singh and Agrawal 2007). Similarly, on terrestrial landscapes, acid rains have adversely affected the environment. Apart from altering the growth and physiology of trees and crop plants, acid rains can indirectly affect human health through liberation of toxic metals such as cadmium, lead, tin, mercury, aluminum, iron, and manganese (Singh and Agrawal 2007). These metals could seep into groundwater, which is consumed by humans, that could potentially lead to various endocrine abnormalities. The effect of acid rain on human health is an important area for further research. (c) Endocrine-Disrupting Chemicals: Numerous forms of EDCs of varied molecular structures have been identified over the past century. Thus far, two scientific statements on EDCs have been released by the Endocrine Society. The first scientific statement, referred to as “EDC-1,” was formulated in 2008–2009 (Diamanti-Kandarakis et al. 2009). It was a pioneering effort in creating awareness about the potential adverse effects of EDCs among the medical fraternity. EDC-1 was then followed by “EDC-2” which was drafted in 2014–2015 (Gore et al. 2015). A special journal issue dedicated to this topic has been published in Reviews in Endocrine and Metabolic Disorders (Koch and Diamanti-Kandarakis 2015). Most EDCs are small-molecule compounds that are heterogeneous in their structures and typically bear a molecular mass of B > A) (Cannavò et al. 2010). These findings also highlight the potential influence of EDCs on the differences observed in acromegaly epidemiology across different geographical areas, as recently demonstrated in a meta-analysis of global epidemiological studies carried on by our workgroup. Herein, we reported, globally, a pooled prevalence of 5.9 (95% CI: 4.4–7.9) per 100,000 persons and a pooled incidence rate (IR) of 0.38 (95% CI: 0.32–0.44) per 100,000 person-years (Crisafulli et al. 2021). Of note, a study by another workgroup from our university analyzed the effects of cadmium in adolescents living in the same industrial area (Interdonato et al. 2015). Researchers recruited 111 male subjects aged 12–14 years, evaluating pubertal development by Tanner stage, and measuring testicular volume by ultrasonography, 24-h urinary cadmium concentration, and FSH and LH serum levels. Data were compared with those gathered in two control areas (a rural and an urban center, respectively). Urinary cadmium levels were significantly higher than the reference threshold of 0.5 μg/L, a burden maybe increased by the volcanic origin of the area. Besides, case patients presented with a delayed pubertal maturation and a lower testicular volume than age-matched controls. Testosterone levels were inversely correlated with cadmium urinary levels, while FSH levels significantly higher than controls probably due to a direct damage to Leydig cells. However, since cadmium is characterized by a slow renal excretion, a prolonged exposure can also alter the blood–brain barrier permeability, a concomitant HPG axis disruption at pituitary level cannot be excluded (Interdonato et al. 2015). An interesting experience comes from an observational study regarding domestic animals. In fact, Dirtu et al. investigated the contamination from organohalogenated compounds (OHCs), namely, organochlorine pesticides, PCBs, and polybrominated diphenyl ethers (PBDEs), together with their hydroxylated (HO–) metabolites, in a

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cohort of domestic cats. The animals were affected by type 2 diabetes mellitus only, or acromegaly-induced diabetes mellitus, and were compared to a healthy control group. The authors found an increased plasma concentration of OHCs in acromegalic cats, with a significant difference in the PCBs/HO-PCBs ratio suggesting a lower capacity to metabolize persistent OHCs (like PCBs) by this group. Since PCBs may act as xenoestrogens, these data confirm a possible link of pituitary tumorigenesis with estrogen pathways. Besides, considering that BDE-47/BDE-99 ratios in cats were similar to those in house dust, these animals could represent a good model of human exposure to chemicals present in indoor dust (Dirtu et al. 2013). On this basis, we evaluated the role of the pollution exposure and the genetic variants of AHR and AIP in acromegaly patients. Several AHR gene polymorphisms have been described, mostly in the exon 10, with some of them associated with an altered induction of CYP1A1 and CYP1A2 activity in response to specific ligands (Harper et al. 2002). In one of our studies published in 2014, we screened a population of acromegalic patients searching for AHR gene variants. Among 70 studied subjects with sporadic GH-secreting pituitary tumors (43 F, 27 M, median age 59 years), in 18/70 (25.7%) we found the AHR rs2066853 variant. It consists of a G > A substitution, causing the replacement of an arginine residue with a lysin in the transactivating domain. Its occurrence was positively correlated to significantly higher IGF-1 ULN (upper limit of normal) levels at diagnosis (mean 2.93  2.29 in carriers versus 2.29  0.86) and more frequent cavernous sinus invasion. Moreover, acromegalic patients harboring thers2066853 polymorphism resulted in a higher risk of developing other neoplasms like differentiated thyroid cancer, bladder cancer, and lymphohematopoietic neoplasms (Cannavo et al. 2014). Besides, in a following multicentric study, we demonstrated that acromegaly was more severe and pituitary tumors were bigger, and SSa were less effective in patients living in polluted areas (classified at high risk for health by the Italian government because of environmental pollution) and harboring AHR and/or AIP gene variants (Cannavo et al. 2016). In the studied cohort, 23 out of 210 (10.9%) acromegaly patients lived in high-risk areas versus the remaining inhabitants of nonpolluted areas, the former showing no significant differences in features like age at diagnosis, sex distribution, mean serum GH and IGF-1 levels at presentation, prevalence of macroadenomas, and maximum diameter at diagnosis. However, among the 23 HR patients, AHR polymorphisms were found in 7 (30.4%) and AIP mutations in 2 (8.7%), respectively, and such individuals presented with higher IGF-1 levels and tumor diameter than the HR patients without genetic variants. Moreover, treatment with SSa normalized IGF-1 values only in one out of seven HR patients with variants, while GH levels were significantly lower in the same subgroup, thus suggesting an increased GH bioactivity. Overall, our study postulated a possible interaction between an altered AHR/AIP pathway in the presence of polymorphisms, and the effects of pollutants acting via non-AHR pathways (Cannavo et al. 2016). These data are in line with the aforementioned in vitro findings by Fortunati et al. (2017). More recently, we investigated the methylation of glutathione-S-transferaseP1 (GSTP1), a phase II enzyme implicated in xenobiotics metabolism and DNA protection, in GH-secreting pituitary adenomas, and its potential interaction with

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other known polymorphisms implicated in pituitary tumorigenesis. GSTP1 detoxifies reactive hydrophobic and electrophilic toxic intermediates by glutathione conjugation. Its epigenetically mediated silencing has a well-known role in cancer susceptibility, mainly in the context of prostate gland. We evaluated 77 AIP wildtype acromegalic patients (50 F, mean age at diagnosis 47.5  12.5 years), referred to our unit along a 15-year interval. In 71 of them, clinical and biochemical response after a 6-month course of somatostatin analogs (SSa) was assessed. Analyzing the entire cohort of patients, 33.8% of them presented with GSTP1 gene promoter hypermethylation, although without statistically significant differences in features like age at diagnosis, gender prevalence, tumor volume, or residence in highpolluted areas. Conversely, the presence of hypermethylation was associated with a higher prevalence of type 2 diabetes mellitus, colonic polyps, and an increased resistance to treatment with SSa. Moreover, 17 subjects carried the AHR rs2066853 variant, while 6 patients who harbored both GSTP1 methylation and AHR rs2066853 variant were all resistant to SSa therapy (Ferraù et al. 2019). Finally, AHR polymorphisms can be a bridge between EDCs’ tumorigenic potential and their transgenerational effects. Eskenazi et al. published several papers on the role of TCDD on fertility among the women involved in the Seveso disaster (Italy, 1976), in the context of the so-called Seveso Women Health Studies (SWHS). The last update of this study investigated fertility issues in combination with the patients’ genetic profiles (Eskenazi et al. 2021). The authors analyzed the data of 981 women enrolled among the Seveso population, involved in a chemical disaster in Italy in 1976 and thus exposed to high doses of TCDD. As mentioned before, TCDD is a lipophilic compound that bioaccumulates in the environment and a halflife of 7–9 years. Of the studied subjects, 873 became pregnant in the years after the accident, with 617 (62.9%) having at least one pregnancy, while 442 women underwent gene analysis in search of polymorphisms involved in the EDCs detoxification pathways. Moreover, a second-generation study comprehending the daughters was carried on, from a cohort of 677 children (341 F, 336 M). In the main cohort, TCDD concentrations were the highest in younger women, and 1976 (log10) TCDD concentrations was significantly associated with lower fecundability or longer time to pregnancy (TTP). In fact, SWHS women had a median time to conceive of 3 months, while 18% of them took more than 12 months. The same association between TCDD concentrations and low fecundability was observed, although not in a significant statistical fashion, among the daughters in the second-generation study. Indeed, the researchers identified five SNPs in AHRR directly associated with TTP and ten SNPs related to detoxification mechanisms (AHR: rs2066853, rs6968865; AHRR: rs10044468, rs11746079, rs17562461, rs2015774; CYP1A1: rs4646903; CYP1B1: rs1056836, rs162549, rs163080) demonstrated to interact with the initial TCDD concentration on TTP (P < 0.2) (Eskenazi et al. 2021). These data, together with what reported by Cauwenbergh et al. about the male factor, open new perspectives in the public/individual health initiatives for prevention. For example, we can find several diet supplements (i.e., antioxidants) that could also improve sperm health by preventing or reducing epigenetic damages. Even gut microbiota has been hypothesized to be altered by EDCs since gut flora is one of the first-line

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barriers to xenobiotics, also influencing their metabolism. These perturbations, often involving epigenome, observed in second generations of rats, could be the target of novel therapies (Van Cauwenbergh et al. 2020).

Conclusion In conclusion, environmental factors and xenobiotics can exert several effects on pituitary gland, leading to multiple consequences ranging from hormone dysfunction to tumorigenesis. EDCs’ influence on hormonal synthesis, secretion, and action is a well-known issue, although not all the pathophysiological mechanisms are still clarified. Moreover, the potential body deposition/accumulation of each type of EDC, the different timing of exposure, and the so-called “cocktail effect” should be kept into account in the evaluation of such broad range of effects, observed at multiple levels of the hypothalamus–pituitary axes. The AHR detoxification pathway and the noncanonical AHR-mediated pathways, with their numerous intracellular interactions, acting as a potential bridge between metabolic responses to toxic insults and cellular biology alterations, have a significant role in pituitary pathophysiology that deserves further studies to be better understood and treated with tailored therapies. Acknowledgments This chapter has been supported by the following grants: grant of the Ministry of Health (Progetto Ordinario Ricerca Finalizzata RF-2013-02356201) of the Italian government; grant (Progetto Rilevante di Interesse Nazionale, PRIN 2017): identification of new biomarkers and clinical determinants for management improvement of patients with pituitary tumor-related syndromes (code: PRIN 2017S55RXB) of the Italian government; and Industrial PhD Course 2017 (EU P.O.N. – Progetto Operativo Nazionale 2014–2020, code: DOT1314588).

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Environmental Endocrinology and the Hypothalamus-Pituitary-Thyroid Axis Leonidas H. Duntas

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HPT Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HPT Function and the Classes of EDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Industrial Chemicals and the HPT Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organotin Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organochlorines and Organophosphate Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phthalates and Plasticizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heavy Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cosmetics and Sunscreen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Food and Isoflavones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

The hypothalamus represents a potential target for a wide spectrum of endocrinedisrupting chemicals (EDCs). Their effects can be exerted at a lower dose which may not be predicted at higher doses, there being a nonlinear relationship (nonmonotonic dose-response) between dose and effect. Among the various categories of EDCs that may disrupt thyroid function, some are more analytically discussed. Polychlorinated biphenyls (PCBs), which are halogenated organochlorines, show variable biodegradation depending on various congeners which may interfere at the different levels of thyroid hormone (TH) production, transportation, and metabolism; they may also display agonist or antagonist action by binding to TH receptor and affecting TH signaling. Pesticides, which are associated with low T4 and T3 levels, appear to be involved in the development of L. H. Duntas (*) Evgenideion Hospital, Unit of Endocrinology, Diabetes and Metabolism, University of Athens, Athens, Greece e-mail: [email protected] © Springer Nature Switzerland AG 2023 R. Pivonello, E. Diamanti-Kandarakis (eds.), Environmental Endocrinology and Endocrine Disruptors, Endocrinology, https://doi.org/10.1007/978-3-030-39044-0_3

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autoimmune thyroiditis. Plasticizers, like bisphenol A (BPA), widely used in consumer products, may perturb thyroid function altering the hypothalamicpituitary thyroid axis when the fetus is exposed to these compounds prenatally. Heavy metals, even at low concentrations, can interfere with thyroid function by decreasing iodine uptake and accelerating thyroid parenchymal transformation, and, depending on duration of exposure, they may ultimately induce hypothyroidism. As stated by the WHO in 2010, “Humans are actively squandering and destroying nature’s wealth and abundance” (Gristle: From Factory Farms to Food Safety (Thinking Twice About the Meat We Eat) – Moby & Miyun Park (editors) – March 2010), thus what is needed is an entire reevaluation of our relationship with nature – and this obviously includes drastic reduction of the present-day tsunami of EDCs in our world. Keywords

BPA · Endocrine disruptors · PCBs · Thyroid · Thyroid hormones · TRH · TSH

Introduction Some manmade chemicals are found in the most remote places in the environment but also in our bodies. Chemicals are everywhere. European Commission, Jan. 2020

Endocrine-disrupting chemicals (EDCs) may be either natural or, far more usually today, manmade molecules, variably distributed in the environment, which, on entering the organism via food ingestion, air, water, and the skin, may alter hormone transport, receptor binding, metabolism, and action and thereby disrupt the endocrine system in humans and in wildlife (Diamanti-Kandarakis et al. 2009). Although good experimental and epidemiological evidence exists on the vulnerability of the endocrine system to EDs, methods are as yet lacking to quantify the effects of these molecules on the environment in order to predict their impact on populations and ecosystems (Gore et al. 2015). Pregnant women and children are the most susceptible groups, while the transport of EDCs to the fetus via the placenta can cause altered fetal and postnatal development and predispose to other diseases, including obesity, type 2 diabetes mellitus, and attention deficit later in life. Among the most widespread of EDCs are industrial chemicals and pesticides: These leach into the soil and groundwater, thereby entering and bioaccumulating in the food chain and eventually impacting human health and well-being. A few of the numerous consumer products containing EDCs or else packaged in containers that may leach EDCs are plastic bottles, toys, household chemicals, protective coatings of food cans, cosmetics, lotions, fabrics treated with flame retardants, processed foodstuffs, and medical equipment. Recently, the European Commission undertook to implement a new “chemicals strategy for sustainability” by summer 2020, this being one component of the European Green Deal, an overarching environmental program announced in

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December, 2019 (EU Green Deal promises new chemicals strategy for toxic-free environment 2019). The program aims to fast-track the establishment of a toxic-free environment in the EU. It comes on the back of revelations that the risks of toxic contamination to both multiple environments and wildlife – for instance, numerous pollutants can now be found in polar ice and mountain glaciers, in seals and in whales – and to humans exceed all prior estimations. Needless to say, whatever affects the environment sooner or later also affects human and animal life. Concerning the impact on humans, among other health effects, today’s steadily increasing rates of cognitive deficits in children, behavioral abnormalities among the young, and cognitive impairments among the elderly, the latter often leading to Alzheimer’s disease and other progressive brain disorders, have been linked to the rise in low-level exposures to multiple chemicals. More specifically, the past two decades have seen ever-increasing reports on the adverse effects of EDCs on the endocrine system, that crucial system that regulates all biological processes in the body. This has resulted in the accumulation of strong translational evidence that EDCs are involved in such serious health conditions as diabetes and obesity, hormone-sensitive cancers (uterine, ovarian, and breast cancer in females, and increased risk of prostate cancer in males), and thyroid dysfunction, as well as disruption of female and male reproduction systems and of neurodevelopment and neuroendocrine systems, although the effects are variable depending on dose and duration of exposure (Gore et al. 2015). The aim of this chapter is to review the effects of EDCs on the hypothalamicpituitary-thyroid (HPT) axis, although the involvement of EDCs in the development of thyroid cancer is not herein dealt with. There is good evidence from numerous experimental studies that the HPT is affected by a number of EDCs, therefore several recent articles will be discussed, particularly of the last 5–7 years. Other excellent reviews summarizing the developments in this field since 2000 – with emphasis on experimental studies of high quality as regard methodology and on the impacts of these ubiquitously found chemicals on human health – have also been included.

HPT Axis The HPT axis is part of the neuroendocrine system responsible for the regulation of metabolism by a tight interaction among stimuli from the hypothalamus, pituitary, and, peripherally, the thyroid (Lechan and Toni 2016; Santisteban and Costagliola 2021), and also responds to stress, for example, fasting or infection in order to reduce the energy expenditure during the adverse stimulus and preserve homeostasis (Mariotti and Beck-Peccoz 2016; Persani and Beck-Peccoz 2021). The thyrotropin-releasing hormone (TRH) released by the hypothalamus stimulates the anterior pituitary to produce the thyroid-stimulating hormone (TSH). Upon binding to its pituitary G-protein-coupled receptor, TRH activates the phosphoinositide-specific phospholipase C (PLC) signaling cascade. PLC hydrolyzes phosphatidylinositol 4,5-P(PIP) into inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers mobilize intracellular calcium

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stores and activate protein kinase C, leading to downstream transcription of TSH. TRH also directly stimulates lactotrophic cells in the anterior pituitary to produce prolactin (Mariotti and Beck-Peccoz 2016). TSH is released into the blood and binds to the TSH G-protein-coupled receptor on the basolateral surface of the thyroid follicular cell. The TSH receptor activation leads to the activation of adenylyl cyclase and increased intracellular levels of cAMP, resulting in the activation of protein kinase A (PKA) and activation of downstream processes required for the production of the main thyroid hormones, thyroxine or tetraiodothyronine (T4), and triiodothyronine (T3) (Mariotti and BeckPeccoz 2016). The production of thyroid hormones is a process made up of different phases. Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine; it is a precursor protein stored in the lumen of follicles, produced in the rough endoplasmic reticulum. Golgi apparatus packs TG into the vesicles, and TG is transported and released into follicular lumen by exocytosis. The subsequent phase includes the iodide uptake. PKA phosphorylation increases the activity of the sodium/iodide symporter located on the basolateral surface, a transporter deputed to the uptake of iodide from the circulation into the thyrocytes. Iodide then diffuses from the basolateral to the apical surface of thyrocytes, where it is released into the colloid through the pendrin transporter. Thereafter, TG undergoes the process of iodination mediated by the enzyme thyroid peroxidase (TPO), activated by phosphorylation by PKA. TPO has three different functions: oxidation, organification, and coupling. TPO uses hydrogen peroxide generated by the NADPH oxidase enzyme located on the apical surface to oxidize iodide to iodine (Mariotti and Beck-Peccoz 2016). The organification process consists in the incorporation of iodine in tyrosine residues of TG, by producing monoiodotyrosine (MIT), which is characterized by a single tyrosine residue coupled with iodine, and diiodotyrosine (DIT), which is characterized by two tyrosine residues coupled with iodine. During the last reaction catalyzed by TPO, the coupling reaction, TPO combines iodinated tyrosine residues to produce T3, deriving from the coupling of MIT and DIT molecules, and T4, deriving from the coupling of two DIT molecules. Thyroid hormones are stored in the follicular lumen as bound to TG and are released by thyrocytes into fenestrated capillary network in different steps: (1) thyrocytes uptake iodinated TG via endocytosis; (2) lysosome fuses with the endosome containing iodinated TG; and (3) proteolytic enzymes in the endo-lysosome cleave TG into MIT, DIT, T3, and T4. T3 (20%) and T4 (80%) are released into the fenestrated capillaries via MCT8 transporter (Mariotti and BeckPeccoz 2016). Deiodinase enzymes remove iodine molecules from DIT and MIT. Iodine can be recycled and redistributed to an intracellular pool (Mariotti and BeckPeccoz 2016). Deiodinases also convert T4 to T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I (DIO1) and II (DIO2) deiodinases are located in liver, kidney, muscle, and thyroid gland; type III (DIO3) deiodinases are located in the central nervous system and placenta. DIO1 and DIO2 convert T4 to T3 and DIO3 converts T4 into rT3 (Mariotti et al. 2021). Thyroid hormones are lipophilic and circulate bound to transport proteins. Only a fraction (approximately 0.2%) of the thyroid hormones (free T4 – FT4) is unbound

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and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin. TBG transports the majority (two-thirds) of T4, and TTR transports T4 and retinol. Once reached target site, T3 and T4 dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Thyroid hormone receptors are transcription factors that can bind both T3 and T4; nevertheless, they have a much higher affinity for T3. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and activate gene transcription by determining cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile (Mariotti et al. 2021). The regulation of HTP axis function is based on a typical feedback loop. T3 levels in the pituitary gland direct the secretion TSH, and an inverse relationship exists between thyroid hormone formation and iodide level in the thyroid. Subsequently, the rate of hormone production is not affected by rapidly changing levels of iodide, and the reservoir of thyroid hormone balances against quick changes in hormone synthesis. TSH has a circadian rhythm with the highest peak between 02:00 and 04: 00 h and the lowest peak between 16:00 and 20:00 h (Mariotti and Beck-Peccoz 2016). This timed secretion is finely regulated by both thyroid hormones and TRH (Mariotti and Beck-Peccoz 2016). Moreover, pituitary TSH is able to inhibit TRH secretion at the hypothalamic level (short feedback) and to block TRH stimulation of TSH secretion at the pituitary level (ultra-short feedback) (Prummel et al. 2004).

HPT Function and the Classes of EDCs TRH, the discovery of which in 1969 initiated the era of neuroendocrinology, plays a critical role in mediating the HPT response to EDCs as its neurons control the synthesis and release of TSH which, in turn, stimulates the synthesis and secretion of thyroid hormone (Kim et al. 2017). The axons containing TRH terminate on hypothalamic tanycytes, highly differentiated glial cells, which, due to local DIO2 and TRH-degrading ectoenzyme activity, regularly reset the levels of TRH (Toft et al. 1974). Recently, it was discovered that TRH receptor 1 stimulation increases the size of tanycyte of the median eminence via Gaq/11 proteins, resulting in enhanced activity of TRH-degrading ectoenzyme, leading to decreased release of TRH to the pituitary (Toft et al. 1976). Therefore, tanycytes are emerging as the central transponder of HPT responses to various stimuli, such as energy balance, stress, and nutritional factors, this possibly elucidating why the HPT axis is particularly susceptible to insults (Toft et al. 1974). Thyroid hormones are essential for normal brain development, thus thyroid hormones insufficiency during pregnancy is associated with abnormal neurodevelopment in the neonate. While iodine deficiency remains the most common etiology of thyroid hormones deficiency in pregnant women, exposure to endocrine contaminants is increasingly being revealed as an additional cause (Vagenakis et al. 1975). Numerous studies have clearly shown that both maternal, fetal, and perinatal exposures to EDCs adversely impact such fetal brain processes as neurogenesis, neural differentiation, and neural connectivity. EDCs interfere with

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Fig. 1 Classes of endocrinedisruptive chemicals which affect the hypothalamicpituitary thyroid axis at different levels

thyroid function at different levels of the hypothalamic-pituitary system, as well as with the thyroid and thyroid hormones production, transfer, and metabolism. Though EDCs mainly interact with the effects of lipid- or protein-derived hormones, they also interact with protein hormone synthesis and signaling (Kaplan et al. 1982). Furthermore, perinatal exposure to EDCs modulates hypothalamic setpoints by interfering with different nuclear receptor signaling (Kaptein et al. 1980). Based on the fact that a large number of EDCs have long been known to have the ability to either mimic or interfere with hormones, in the 1990s, scientific observations suggested that these chemicals can impact both the human and the animal organism even at low doses, this giving rise to the “low-dose hypothesis.” In her important 2012 study, L. N. Vandenberg stated that, crucially, these adverse effects can often not be predicted based on their effects observed at far higher doses, thereby reintroducing the above hypothesis as well as the concept of nonmonotonic doseresponse curves, these being defined as a nonlinear relationship between dose and effect (Boelen et al. 1993). The classes of EDCs potentially affecting HPT are presented in Fig. 1.

Industrial Chemicals and the HPT Axis Industrial chemicals are regarded as essential in our modern-day world as they contribute in many ways to developing and preserving a high standard of living, playing as they do important roles in such areas as food production and health care. However, the huge volumes of these chemicals now found in both outdoor and indoor environments everywhere cannot but have, as noted above, highly negative

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impacts not only on the environments themselves but also, inevitably, on the health and lives of both animals and humans. Industrial chemicals are classified into three main categories: (1) halogenated organochlorines including polychlorinated biphenyls (PCBs); polybrominated biphenyls ethers (PBBs); dioxins; (2) perfluoroalkyl substances (PFASs); perfluoro octane sulfonate (PFOS); perfluorooctanoic acid (PFOA); and (3) organochlorines pesticides (CPs) such as Arachlor, Dicamba, Fipronil, Lindane, dichlorodiphenyltrichloroethane (DDT) and organophosphate pesticides (OPPs) (Surks and Sievert 1995). PCBs, polychlorinated dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) are persistent organic pollutants (POPs) which exhibit toxic effects that are mainly mediated through the aryl hydrocarbon receptor (AhR). PCBs are lipophilic POPs. Though produced only up until the 1980s, many products and materials containing these chemicals are still present worldwide today (e.g., plastics and paints). The biodegradation and endocrine-disruptive activity of these compounds are related to specific congeners, the composition and concentration of which in the environment are usually different from those of the original substances (Sherman et al. 1999). PCBs are thought to interfere in the various steps of thyroid hormones production, transportation, and metabolism, while some may bind to the TH receptor and thus exert an agonist or antagonist action that affects thyroid hormones signaling (Gow et al. 1985). PCBs and PPBs are metabolized in hydroxylated metabolites, which bind more easily than the original chemicals to thyroid transporter TTR, while they also displace thyroxine and disrupt thyroid hormones metabolism (Emerson et al. 1973). Experimental studies using FRTL-5 cells have shown that high concentrations of PCB118 congener inhibit cell viability and natrium iodine symporter and decrease mRNA levels. The congener may induce thyroid cell dysfunction in a concentration- and time-dependent manner through the Akt/FoxO3a/NIS signaling pathway (Bigos et al. 1978). Several studies, some very recent, are presented in this chapter demonstrating apparent associations of PCBs with thyroid dysfunction though to date without sufficient evidence of causality. However, other studies did not find any association. Serum concentrations of 35 PCBs were measured in 765 adults, living in the vicinity of a former PCB factory in Anniston, Alabama, as part of a health survey, which also collected demographic data, questionnaire information, and measurements of thyroid hormones, TSH, and autoantibodies against thyroglobulin (TgAb] or TPO (TPOAb) (Bacci et al. 1982). Though the PCBs were manufactured between 1929 and 1971, traces were found of these compounds in the participants’ blood samples collected three to seven decades later. It was found that the participants had two- to threefold higher PCB concentrations than those of individuals of similar age and racial groups of the general population. Linear regression revealed inverse associations between total T3 and PCBs particularly for two pesticides (hexachlorobenzene and pp’-DDE) and two individual congeners (PCBs 74 and 105). However, logistic regression analysis did not confirm this for T3 and found no association with any other thyroid bioindicator, suggesting that there is no clinical effect of these PCBs on thyroid function (Bacci et al. 1982).

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In line with this, another analysis of a cross-sectional population-based study of 816 adults from Brescia, Italy, showed that the serum levels of PCB functional groups were positively associated with age and negatively with female gender, education, smoking habits, and BMI. However, by a multivariate analysis the serum levels of PCBs were not associated with serum levels of thyroid hormones, TSH, glycemia, or with the presence of endocrine diseases, diabetes, and hypertension (Brent et al. 1986). PCB exposure has been associated with depressive symptoms and correlated with lower dopamine and T4. It is well known that T4, which is essential for DA synthesis, binds to TTR and is thereby transported into the brain. PCBs can displace T4 by binding to TTR itself, thus passing into the brain and, by disturbing dopamine synthesis, inducing depressive symptoms. A multicenter international study recruiting 116 participants (91.6% men) who had taken part in three annual examinations of the HELPcB health surveillance program investigated interaction of PCBs with FT4 and its associations with the HVA and depressive symptoms (Refetoff et al. 1996). Interestingly, an association was observed for lower chlorinated PCBs (LCPBCs), dioxin-like PCBs (DLPCBs), and OH-PCBs with depressive symptoms. These results indicate for the first time that a physiological process involving the thyroid and the dopamine system induces depressive symptoms after PCB exposure. In a cross-sectional analysis of 715 participants in the Michigan PBBs Registry, higher PBB levels were associated with higher serum free T3 (FT3) (FT3; p ¼ 0.002), lower FT4 ( p ¼ 0.01), and higher FT3:FT4 ratio ( p ¼ 0.0001), while higher PCB levels were associated with higher FT4 ( p ¼ 0.0002) and higher FT3: FT4 ratio ( p ¼ 0.002). An association was demonstrated between PBB and thyroid hormones which depended on age at exposure. Specifically, participants exposed before the age of 16 (N ¼ 446) exhibited higher FT3, lower FT4, and higher FT3: FT4 ratio ( p ¼ 0.0001) which was directly linked to higher PBB exposure. Meanwhile, no significant associations were noted among individuals exposed after 16 years of age (Abramowicz et al. 1997). A systematic analysis that examined the relationship between “standardized biological concentration-thyroid parameters” reviewed 19 studies, through the application of adequate methodological criteria, in both pregnant women and newborns (Ahlbom et al. 1997). The biological concentrations were expressed in total PCB equivalent per kg of lipids in maternal plasma. A significant difference was observed between PCB exposure and total T3 levels, but no associations were noted between PCB exposure and TSH and FT4 levels. In contrast, some studies with high, preselected criteria have clearly demonstrated associations of PCBs with thyroid hormones. The Hokkaido study, a prospective cohort investigation, analyzed the effects of dioxins and PCBs in maternal blood of 386 mothers and 410 infants (Xie et al. 1997). Fifteen dioxins and 70 PCBs were collected between 23 and 41 weeks of gestation and measured by high-resolution gas chromatography and high-resolution mass spectrometry. FT4 and TSH levels were dosed from an early gestational stage (median 10 weeks), and from infants between 4 and 7 days of age, respectively. Three PCB congeners had significant positive

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association(s) with maternal thyroid hormones while nonortho PCBs were positively associated with maternal FT4, suggesting that perinatal exposure to background levels of dioxin-like compounds (DLCs) increases neonatal FT4, especially in boys (Xie et al. 1997). On the other hand, epidemiological reports on the relationships between DLCs/PCBs and human thyroid homeostasis are inconsistent. None of the five studies on DLC effects on thyroid hormones levels of pregnant women reported significant associations for TSH or FT4. The fact that only FT4 and not TSH was observed to be impacted in this study suggests that the effect of dioxin toxicity on thyroid homeostasis involves mechanisms similar to those underlying resistance to thyroid hormones, where the mutant thyroid hormone receptor beta gene is identified in the majority of cases (Xie et al. 1997; Joseph-Bravo et al. 2015). A 2015 study conducted in China demonstrated that levels of in utero exposure to PCBs and dioxins may affect serum concentrations of growth hormone, thyroid hormones, TBG, and insulin growth factor binding protein-3 (IGFBP-3) in 8-yearold children (Joseph-Bravo et al. 2016). High levels of in utero exposure to PCDD/ F + PCB (polychlorinated dibenzo-p-dioxins, dibenzofurans) levels were significantly associated with increased serum concentrations of growth hormone, T3, T4, and TBG, suggesting that the level of exposure in utero to PCB and dioxins may determine the serum concentrations of thyroid hormones and the other parameters. While several congeners of PCDDs, PCDFs, and PCBs have dioxin-like toxicity, non-dioxin-like PCBs are hypothesized to have different mechanisms and different toxic potentials. In a Danish study, concentrations of PBDEs, PCBs, PCDD/Fs, organotin chemicals (OTCs), OCPs, T4, T3, and rT3 were measured in 58 placenta samples. Several POPs were significantly associated with thyroid hormones. It is noteworthy that T4 was negatively associated with PBDE and positively with 1,234,678-HpCDF; T3 was positively associated with 2378-TeCDF and 12,378PeCDF; and rT3 was positively associated with PCB 81, 12,378-PeCDF, and 234,678-HxCDF, and negatively with tributyltin, OTC, and methoxychlor (MüllerFielitz et al. 2017). These findings imply that prenatal exposure to POPs, with the effects possibly mediated by thyroid hormones levels in placenta, may negatively impact childhood growth and development. An experimental study with pregnant albino rats treated with two different doses of PCB 126 demonstrated placental changes on gestation day 20, the studied tissues showing degeneration, hemorrhage, hyperemia, and apoptosis in the labyrinth layer of the placenta and spiral arteries (Ghassabian and Trasande 2018). The two administrations of PCB 126 were seen to raise serum TSH levels while lowering FT4 and FT3 concentrations, leading to maternofetal hypothyroidism. While bearing in mind that PCB action is thought to be dependent on its congeners as well as on the methodology applied to quantify it, there are nevertheless strong indications that PCBs and PBDEs may affect pregnancy in relation to the extent and duration of perinatal exposure and also to the levels of placental thyroid hormones. Perfluorododecanoic acid (PFDoA), an artificial perfluorochemical that has been extensively utilized in industry and widely distributed in ambient media, was reported to strongly affect thyroid hormones homeostasis (Wuttke et al. 2010). A

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study shows that zebrafish embryos/larvae that were exposed to various concentrations of PFDoA (0, 0.24, 1.2, 6 mg/L) for 96 h postfertilization (hpf) lead to reduced thyroid hormones contents in the zebrafish larvae and, as a consequence, to growth restriction (Wuttke et al. 2010). In an analysis of the transcriptional level of genes within the HPT axis, gene expression levels of TRH and corticotrophin-releasing hormone (CRH) were upregulated upon exposure to 6 mg/L of PFDoA, while DIO2 was upregulated in the 1.2 mg/L PFDoA group. Thus, the potential mechanisms of PFDoA disruption of thyroid function could occur at several levels in the processes of synthesis, regulation, and action of thyroid hormones. Moreover, PFDoA could also decrease the levels and gene expression of sodium/iodide symporter and TTR in a concentration-dependent manner following exposure (Wuttke et al. 2010).

Organotin Compounds Studies examining organotin compounds, often found in antifouling paints on ships, have shown that these EDCs exert obesogenic and thyroid-disruptive activity, though the mechanisms have not been completely clarified (Decherf et al. 2010). Tributyltin (TBT) belongs to the class of organotins characterized by the presence of one or more tin-carbon bonds. Human exposure to organotins occurs mainly through fish and shellfish consumption, since TBT enters the food chain after leaching into the marine environment (Vandenberg et al. 2012; Duntas and Stathatos 2016). The disruptive effects are exerted at different levels of the HPT axis, thus affecting TRH, TSH, thyroid hormones, DIOs activity, and thyroid hormone receptors (TRs). This may be supported by animal studies in which, for example, it was demonstrated that exposure to TBT in pregnant rats altered the transcription of TRH gene promoter: This modified nuclear receptor signaling, which, in turn, modulated hypothalamic set points that control metabolic responses (Kaptein et al. 1980). Organotins also impact the morphopathology of the thyroid, thus increasing collagen deposition, which in turn induces thyroid dysfunction. In corroboration of the latter, exposure of male rats to TBT for 15 days (daily dose of 1000 ng TBT/kg BW) resulted in changes of thyroid morphology and serum T4 levels and higher activity and expression of dual oxidase (DUOX), an enzyme that is crucial for the production of hydrogen peroxide and for thyroid hormone synthesis. Since H2O2 is a reactive oxygen species, overproduction, particularly in cases of selenium deficiency, could cause an imbalance of redox homeostasis, thus predisposing to thyroid disease (Xiang et al. 2020; Brucker-Davis et al. 2016).

Organochlorines and Organophosphate Pesticides Chronic environmental exposure to pesticides is hypothesized to constitute a considerable risk factor for thyroid diseases. A large population-based, case-control study was carried out in Spain among 79,431 individuals diagnosed with goiter, thyrotoxicosis, hypothyroidism, and thyroiditis and 1,484,257 controls matched for age, sex, and area of residence, the latter categorized as being of high or low

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pesticide use (Grimm et al. 2013). It was found that prevalence rates and risk of developing thyroid diseases were considerably higher in regions with greater pesticide use, a 49% higher risk being registered for hypothyroidism, 45% for thyrotoxicosis, 20% for thyroiditis, and 5% for goiter. The results of this study clearly point to an association between increased environmental exposure to pesticides, as a consequence of ever-increasing agricultural exploitation, and thyroid diseases. It is particularly noteworthy that a greater risk of autoimmune thyroiditis of about 20% was found for the population living in areas of high versus low pesticide use. These results are among the very few that have incontrovertibly linked exposure to pesticides with autoimmune thyroid disease (AITD). It is well-established fact that while genetic predisposition contributes to around 60–70% of the pathogenesis of AITD, the remaining 40–30% is caused by environmental factors, such as mineral and vitamin deficits, stress, and pregnancy, the latter capable of triggering AITD by activation of the innate immune system (Yang et al. 2015). Therefore, pesticides can be now added to the environmental factors that are implicated in the development of AITD. In a study in an agricultural population in Brazil, 122 adults were sampled in the low and high pesticide season: During the latter period, dithiocarbamate use was associated with decreased serum TSH levels, pyrethroid with low T4, and use of the herbicide paraquat with low FT3 concentrations (Benson et al. 2018). Lifetime use was also associated with low T4 and T3 levels, suggesting that both short- and longterm exposure to pesticides is likely to induce hypothyroidism. While it has been reported that recent and cumulative exposure to pesticides may induce thyroid dysfunction, a study carried out in Thailand comparing 195 conventional and 222 organic farmers suggested that exposure to pesticides, depending on the amount applied, could lead to metabolic and thyroid diseases by altering the HPT axis (Zani et al. 2019). Thus, paraquat (the most widely used herbicide together with glyphosate) as well as atrazine increased TSH and FT3, while acetochlor increased FT4, glyphosate T4, and the more recent pesticides, alachlor, propanil, and butachlor, increased the levels of both FT4 and T3 (Zani et al. 2019). It is hence clear that pesticides exert different effects on the HPT axis by increasing or decreasing T4 production in accordance with the types used and the respective response of TSH. The use of neocotinoid imidaclopid and mancozed (dithiocarbamate) may disrupt seasonally breeding wild birds. Imidaclopir exposure decreases both T4 and TSH, indicating a nonfunctioning negative feedback mechanism (Gaum et al. 2019). Interestingly, the decrease of T4 and TSH was more prominent in the breeding than in the prebreeding phase, pointing to a nonthyroidal source of T3 generation compensating for T4 decrease.

Phthalates and Plasticizers Bisphenol A (BPA) is an organic synthetic compound, which, in its carbonate form, is commonly found in polycarbonate plastics. BPA is a xenoestrogen, exhibiting estrogen-mimicking, hormone-like properties and which has been more frequently

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detected in infertile women, thus leading to the hypothesis of a possible involvement of BPA in natural conception and fecundity (Curtis et al. 2019; El Majidi et al. 2014). In animal studies, though neonatal exposure to BPA did not modify TSH levels in female rats, it increased TSH in adult rats in the estrous cycle; T4 increased at low and at high concentrations of BPA and T3 did not change (El Majidi et al. 2014). The above results therefore indicate that neonatal exposure to BPA alters the HPT axis in adult rats, possibly affecting both the pituitary and the thyroid. Neonatal exposure to BPA induces polycystic ovary-like syndrome (PCOS) in adulthood. In a crosssectional study, 71 PCOS and 100 healthy women were investigated (Baba et al. 2018). BPA levels were found significantly higher in the whole PCOS group compared with the controls (1.05  0.56 vs. 0.72  0.37 ng/ml, P < 0.001), while PCOS women, both lean and overweight, had higher BPA levels compared to the corresponding control groups. Multiple regression analysis showed that BPA is correlated with the presence of PCOS as well as with insulin resistance (Bigos et al. 1978). In a case-control study conducted in China including 1416 women aged 18 years or older (705 cases and 711 controls), an inverse association of BPA urinary concentration with thyroid volume and the risk for multiple nodules was observed (Refetoff and Dumitrescu 2007). The study population was stratified into positive and negative thyroid autoantibody groups and it was noted that higher urinary BPA concentration was linked to increased risk of thyroid nodules (TNs) only in the positive thyroid autoantibody group and irrespective of iodine status (Refetoff and Dumitrescu 2007). The fact that the association was near linear suggests that BPA exposure is coupled to elevated TN risk in autoimmune patients. The HOME Study was a prospective cohort of 380 pregnant women from Cincinnati. It explored whether maternal urinary BPA concentrations during pregnancy were linked to thyroid hormones in maternal or cord serum and whether an infant’s sex at birth or maternal iodine status altered these associations (Su et al. 2015). There was no association between mean maternal urinary BPA and cord TSH in the newborns; however, in girls, though not in boys, a tenfold increase in mean BPA was associated with lower cord TSH (Su et al. 2015). The inverse BPA-TSH relationship observed among girls was seen to be greater in iodine-deficient versus sufficient mothers (Su et al. 2015). It is therefore clear enough that prenatal BPA exposure can reduce TSH in newborn girls, particularly when exposure takes place later in gestation. Thus, the latter studies point to the importance of the early stages of life for the potential impact of plasticizers on thyroid status.

Heavy Metals Cadmium (Cd) and mercury (Hg), two nonbiodegradable metals with a high degree of toxicity which tend to bioaccumulate in different organs, have adverse effects on the thyroid gland. Both have been identified as disruptors of thyroid function. In a study conducted in Rome, Italy, with the aim of evaluating whether exposure to low concentrations of Cd have an impact on thyroid hormone levels, investigated

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workers exposed to urban pollutants (Li et al. 2018). The study included a sample of 277 individuals (184 males and 93 females): A negative correlation between urinary Cd and FT4 and FT3 levels and a positive direct correlation between urinary Cd and TSH levels was found, suggesting that low concentrations of Cd, as those in urban air, have a decreasing effect on TH but that chronic exposure may result in hypothyroidism. In an experimental study in rabbits investigating the effects of coadministration of Cd and Hg on the parameters of oxidative stress and thyroid function, Cd (1.5 mg/ kg) and Hg chloride (1.2 mg/kg) were orally administered, with or without vitamin C, to eight treatment groups. The results showed a significant decline ( p < 0.05) in mean T3 and T4 hemoglobin concentration, while TSH (0.23  0.01 nmol/l) and triglyceride (4.42  0.18 nmol/l) were significantly ( p < 0.05) increased. It is noteworthy that treatment with vitamin C reduced the effects of Cd and Hg, but did not restore initial TSH values, which were similar to those of controls (Ahmed et al. 2018). In another study, female Wistar rats on a low-iodine diet and methimazole treatment received ad libitum drinking water supplemented with boron (B), Cd, and molybdenum (Mo) at concentrations corresponding to those detected in the urine samples of residents of the volcanic area around Catania (Zhang et al. 2018). Histological examination revealed a significant increase of malignant using any hormone therapy, in whom logistic regression was adjusted for demographic factors, menopausal status, nutrient intake, and urine iodine, and a strong association was found between Hg and TgAB transformation in thyroid follicular cells of rats treated with B, Cd, and Mo compared with those of the control group. These abnormalities were associated with decreased iodine content in the thyroid, possibly indicating that slightly increased environmental concentration of contaminants such B, Cd, and Mo can precipitate features of malignant transformation in the thyroid gland of hypothyroid rats. In the 2007–2008 National Health and Nutrition Examination Survey (NHANES), women were found to be at increased risk for autoimmune thyroiditis. Meanwhile, associations between positive thyroid autoantibodies and total blood Hg were studied using multiple logistic regression (de Oliveira et al. 2019). Women with the lowest mercury levels (0.40 μg/L) versus women with mercury >1.81 μg/L (upper quintile) showed lower odds for TgAB positivity. Another analysis included 1587 adults participating in the 2007–2008 NHANES, with no history of thyroid disease or use of thyroid medications, and with data on metals in blood (lead, [Pb], Cd, and Hg) and urine (Pb, Cd, Hg, barium, cobalt, cesium, molybdenum, antimony, thallium, tungsten, and uranium), and serum thyroid hormones (Santos-Silva et al. 2018). Multivariate linear regression was used to determine the association between thyroid hormones levels and metals in either urine (creatinine adjusted) or blood and the models were adjusted for various demographic and biochemical cofounders. Few participants (10 microM, the interference having started at >0.1 microM (Duntas 2008). The above study underlined that consumption of large amounts of soya may impact thyroid function by potently competing for T4 binding to TTR in serum and CSF and altering free thyroid hormone concentrations, resulting in altered tissue availability and metabolism. The association between soya food intake and serum TSH concentration in North American churchgoers of the Seventh-day Adventist denomination was investigated in the Adventist Health Study-2 (Santos et al. 2019). Soya protein and soya isoflavone intakes and their relationships to TSH concentrations measured at the end of a 6-month period were analyzed by logistic regression analyses. The participants were 548 men and 295 women who were not taking any thyroid medication. Of note, in multivariate models adjusted for age, ethnicity, and urinary iodine, soya isoflavone intakes were associated with high TSH in women but not in men. Given that soya isoflavones can influence the feedback regulation and peripheral thyroid hormones networks, thus causing endocrine disruption in the pituitarythyroid axis, this should be considered by both physicians and the public, particularly as concerns children and during pregnancy.

Conclusions EDCs are, in their majority today, chemical substances which, ever-increasingly occurring in multiple environments, are able to disrupt different levels of the HPT axis, including most notably the synthesis, metabolism, and biological effects of thyroid hormones. Given the importance of the thyroid gland for homeostasis and regulation of the basal metabolic rate, a better understanding of the mechanisms underlying the numerous adverse effects of EDCs on thyroid function is crucial. EDCs also play a role in the development of the metabolic syndrome and of obesity. Thyroid dysfunction is associated with changes in body weight and composition, with overweight or obesity frequently being symptoms of hypothyroidism. While hypothyroidism is thought to trigger obesity, in turn, the functional effects of obesity on the thyroid, namely, an increase in TSH levels and in the activity of deiodinases, constitute an adaptive process to increase energy expenditure. Therefore, EDC effects on both thyroid function and weight gain may be mainly mediated by decreasing thyroid activity. In fact, most classes of EDCs exert either an inhibiting effect directly on the thyroid gland or on the transport and metabolism of thyroid hormones, or by decreasing TSH. These effects are usually not dose dependent, as already noted in the case of low concentrations of heavy metals that affect thyroid hormones. Duration of exposure and particularly age at which exposure occurs, as with PCBs, are of importance. EDCs certainly do not affect only the thyroid but all endocrine organs, therefore their actions are multilevel and multidimensional: By disrupting one organ, they are

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likely to create dysfunctions at multiple levels, given the cyclicity of the endocrine system in its maintenance of homeostasis and health. In light of all the above, it is more than evident that production of EDCs must be radically reduced. Indeed, for the healing of our planet, reduction of numerous human activities is urgently needed so that we may at last adopt a relationship with our planet that is one of cooperation instead of antagonism. Has our experience with the COVID-19 crisis sounded an alarm concerning this issue? It is to be hoped so.

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Environmental Impact on the Hypothalamus–Pituitary–Adrenal Axis Krystallenia I. Alexandraki, Ariadni Spyroglou, Lorenzo Tucci, and Guido Di Dalmazi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Part 1: The Mechanisms of Adaptation of the HPA Axis Under Environmental Stimuli . . . . . The Stress System: Components and Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stress System Physiological Stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stress System Pathological Stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Part 2: Environmental Endocrine Disruptors and the HPA Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Plasticizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Flame Retardants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Air Particulate Matter Pollution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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All authors contributed equally. K. I. Alexandraki Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece e-mail: [email protected] A. Spyroglou Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zurich, Switzerland e-mail: [email protected] L. Tucci · G. Di Dalmazi (*) Endocrinology and Diabetes Prevention and Care Unit, Department of Medical and Surgical Sciences, S. Orsola Policlinic, Alma Mater Studiorum University of Bologna, Bologna, Italy e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2023 R. Pivonello, E. Diamanti-Kandarakis (eds.), Environmental Endocrinology and Endocrine Disruptors, Endocrinology, https://doi.org/10.1007/978-3-030-39044-0_4

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Abstract

Endocrine-disrupting chemicals (EDC) are exogenous compounds interfering with the actions of hormones at several steps. They are part of our environment and come in contact with humans frequently, through different routes. EDCs have shown deleterious effects on the endocrine system, mainly on the thyroid gland and steroid hormones, in the context of female and male reproduction. The hypothalamic–pituitary–adrenal (HPA) axis plays a pivotal role in the regulation of homeostasis, through regulation of adaptation to stress at multiple levels. Alterations of the HPA axis lead to severe metabolic and cardiovascular diseases, making this complex system a central player for human health. The HPA axis is a potential preferential target for disruption due to the chemical properties of EDCs and the specific features of the adrenal glands. Nonetheless, the consequences of EDCs exposure on the HPA axis have been underinvestigated to date in humans. The first part of this chapter provides an extensive summary of the mechanisms of HPA axis adaptation to environmental stimuli. The second part describes the current evidence on the deleterious effects of the main EDCs on the HPA axis. Keywords

HPA axis · Disruptors · Adrenal · Steroid · Stress · Environment

Introduction Endocrine-disrupting chemicals (EDC) are exogenous chemicals, or mixture of chemicals, that can interfere with any aspect of hormone action (Gore et al. 2015). These compounds have become part of our environment since the era of the chemical revolution during the mid-50s when they have been employed in several industrial processes. The widespread diffusion of these compounds has facilitated the human contact with EDC through consumer goods and air pollutants. The deleterious effects of EDC on the endocrine system have been identified decades ago, when the first evidence has come to the attention of the public authorities (Gore et al. 2015). Since then, the scientific community has put their focus on the disrupting effects of EDC on thyroid gland and steroid hormones in the context of female and male reproduction, which are now well-known. Even though this is a fast-growing area of research with high public interest, the endocrine effects of EDC on the hypothalamic–pituitary–adrenal (HPA) axis have been underinvestigated to now. Indeed, the adrenal gland is particularly susceptible to EDC damaging actions on steroidogenesis due to some specific features. Among them, the high vascularization may favor the contact with chemicals through blood supply and the lipophilic nature, together with the high capability of uptake, might facilitate the uptake of lipophilic compounds. Additionally, the susceptibility to EDC may rely on the high content of unsaturated fatty acids of adrenal cell membranes, which are sensitive to lipid peroxidation, the presence of several targets for

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disruption, like the enzymes of the multistep process of steroidogenesis, and the production of free radicals as a result of steroidogenesis (Harvey 2016). Despite their highly disrupting potential on the adrenal gland, which is a fundamental endocrine organ for life through the maintenance of homeostasis in several biological processes, the impact of EDC has been poorly studied in humans. Indeed, many difficulties may arise when assessing the effects of environmental compounds on the HPA axis because such a system is highly dynamic due to the mechanisms of adaptation that occur to maintain homeostasis. Additionally, a comprehensive study of the HPA axis requires simultaneous measurement of several compounds (i.e., ACTH and cortisol, or renin and aldosterone, when assessing the glucocorticoid and mineralocorticoid secretion, respectively, and androgen precursors when investigating defects of the steroidogenic enzymes), which should be interpreted in the light of the extreme variability of the steroid secretion according to stressful condition and interindividual differences. Finally, when performed with immunoassays, the measurement of hormones and peptides of the HPA axis may be inaccurate in several cases. Therefore, most of the evidence on the disrupting potential of environmental compounds on adrenal gland relies on studies investigating the consequences of EDC exposure on adrenal weight, adrenal histopathological characteristics, hormonal levels in animal models, and, mostly, steroid secretion in in vitro experiments on H295R adrenocortical cell lines. Given the complexity of the HPA axis in adaptation under several external stimuli, the first part of the chapter summarizes the tangled mechanisms of adaptation of the HPA axis under several environmental stimuli and includes a description of the components of the stress system and their properties. The second part of the chapter is focused on the alterations of the HPA axis caused by specific EDC.

Part 1: The Mechanisms of Adaptation of the HPA Axis Under Environmental Stimuli The Stress System: Components and Properties Components of the Stress System Homeostasis is the steady state of internal physicochemical conditions in the organism. Physical and physiological stressors stimulate the stress response altering the homeostasis; adaption is required to counteract these stimuli. The two main pathways that regulate this response are the HPA axis secreting glucocorticoids and the sympathetic adrenomedullary axis secreting epinephrine and norepinephrine. The cross-talk between these two systems enables complex behavioral responses (Godoy et al. 2018). Physical stressors (systemic inflammation, blood loss, hypoxia, fluid and electrolyte balance, hypoglycemia) give a signal to visceral afferents of the vagus nerve and sympathetic nervous system that end up stimulating ascending brainstem noradrenergic neurons in the locus coeruleus and the nucleus of the solitary tract. The locus

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coeruleus is the center of the arousal and autonomic nervous systems, which consist of the adrenomedullary and the systemic sympathetic system components. Activation of this system drives to release of norepinephrine from an extremely dense network throughout the brain leading to enhanced arousal and increased anxiety (Godoy et al. 2018; Chrousos and Gold 1992). These noradrenergic and adrenergic cell groups preferentially innervate the corticotropin-releasing hormone (CRH)producing subdivision of the paraventricular nucleus (PVN) of the hypothalamus. The PVN receives also signals from numerous neuropeptides including angiotensin II, glucagon-like peptide 1, α-melanocyte-stimulating hormone (α-MSH), and neuropeptide Y that serve to modify the overall impact of the neurotransmitters. Involvement of the prelimbic area in the prefrontal cortex is sometimes also observed in the physical stress response. Alternatively, in response to psychological stressors another pathway, the transsynaptic pathway, is activated leading to hypothalamic stimulation. This pathway involves descending information from limbic structures, including the ventral hippocampus, infralimbic and prelimbic cortices, and amygdala. These latter structures project indirectly to the PVN of the hypothalamus via the stria terminalis and other hypothalamic nuclei. It is now believed that the hypothalamic CRH and brainstem norepinephrine centers of the stress system mutually innervate each other and interact (Herman et al. 2016). Hypothalamic inhibition occurs through negative feedback through binding of glucocorticoids to the receptors located in the PVN. This results in the synthesis of endocannabinoids, which finally reduce driving to CRH neurons. Additionally, GABAergic projections from other hypothalamic nuclei limit the CRH expression from the PVN. Transsynaptic inhibition of the HPA axis occurs through the hippocampus and prefrontal cortex, which express glucocorticoid and mineralocorticoid receptors in high abundance and send projections to GABAergic PVN-projecting neurons. Maintenance of the basal HPA activity and of the circadian rhythm is achieved by binding of glucocorticoids to the mineralocorticoid receptor of the PVN (De Kloet et al. 1998). The hypothalamic cells of the PVN send axon projections to the median eminence so that peptide products can be released in the capillaries of the portal blood system and transported to the anterior pituitary. When stimulated, hypothalamic cells release hormones into the portal blood, mostly represented by CRH and arginine vasopressin (AVP). CRH, which does not cross the blood–brain barrier, binds to CRH receptors of the anterior pituitary leading to the release of adrenocorticotropic hormone (ACTH) from the corticotrope cells. ACTH in turn binds to the MC2 receptor of the adrenal gland and stimulates the secretion of cortisol. Although additional factors, such as gonadal steroids and cytokines, can also directly or indirectly modulate glucocorticoid secretion, the HPA axis is the main pathway stimulating glucocorticoid release in response to a stressor. Peripheral secretion of CRH by postganglionic sympathetic neurons, peripheral immune cells, and other cell types present in inflammatory sites (immune CRH) has also been described and is taking part in the immune response by degranulation of mast cells and induction of inflammatory reaction. Rapid glucocorticoid feedback contributes to the termination

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Fig. 1 Simplified depiction of the main circuits activated upon different stressors. NE, norepinephrine; E, epinephrine; CRH, corticotropin-releasing hormone; iCRH, immune CRH; PVN, paraventricular nuclei; AVP, arginine vasopressin; ACTH, adrenocorticotrophic hormone

of the stress response (Chrousos 2009). A simplified depiction of the main circuits activated upon different stressors is shown in Fig. 1.

Equilibrium of the Stress System Walter Bradford Cannon was the first to describe the coordination of body systems by the brain in order to achieve stability of the internal environment of the organism and named this procedure “homeostasis” or “eustasis.” Stress occurs when homeostasis is threatened. The newer concept of “allostasis” or “different homeostasis” accepts that the goal levels of various internal variables might themselves change and describes the adaptive processes of the body to restore optimal conditions upon stressors. Frequent stress, failure to adapt to repeated stress, inability to eliminate allostatic responses when the stressor is removed, and inadequate allostatic response lead to “allostatic load,” or “cacostasis” or “dyshomeostasis,” which can accelerate disease processes (Goldstein and McEwen 2002; Chrousos 2009). Cannon was also the first to introduce the “fight or flight response,” a physiological reaction that occurs acutely in response to a perceived threat. Such a response is designed to prepare animals for fighting or fleeing upon attack. Within this notion, harmful environmental or internal stimuli perturbating homeostasis stimulate

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simultaneously the sympathetic nervous system and the adrenal medulla, termed “sympathoadrenal activation.” Epinephrine and norepinephrine stimulate several responses with suppression of the visceral activity and activation of arousal, increase of heart rate, respiratory gas exchange, muscle blood flow, and glucose production from glycogen, among several others (Goldstein 2010). A similar concept, termed “general adaptation syndrome,” was proposed by Hans Selye as a response to stressors. This three-step approach includes an initial “alarm reaction,” analogous to the “fight or flight response,” an adaptation phase with resistance to the stressor and eventually a stage of exhaustion of the organism. Selye attributed “diseases of adaptation” to specific effects of the evocative stressors, still upon exclusion of specific responses, nonspecific stress effects were present. Chrousos and Gold modified this principle suggesting a threshold above which any stressor induces a stress syndrome (Chrousos and Gold 1992).

Intensity and Duration of Stress The two major steroids of the HPA axis, released in response to a stressor, are the glucocorticoids cortisol and corticosterone. These exert their effects mainly by altering the transcription rates of several genes in order to increase blood glucose, alter behavior, modulate the immune system, and block growth and reproduction. Stressor intensity is an important effector of the overall HPA axis response: high intensity and long duration challenges typically cause prolonged responses, whereas shorter responses are typically observed following exposure to psychological stressor. The glucocorticoid response is recruited to meet this perceived need. Whereas acute rises in glucocorticoids following stressors are part of a homeostatic mechanism and potentially serve to avoid chronic stress, prolonged glucocorticoid stimulation can lead to pathological metabolic, immunological, and behavioral alterations (Herman et al. 2016). In response to prolonged stress the secretion of hypothalamic CRH and pituitary ACTH increase. However, upon continued exposure to CRH a desensitization of the pituitary corticotroph cells occurs, with subsequent reduction of the ACTH release. In parallel, hypothalamic AVP expression, which is low at baseline, increases significantly upon chronic stress. AVP acts synergistically with CRH on the pituitary to potentiate ACTH release to novel stressors upon repeated activation of the HPA axis, despite concomitant CRH desensitization. Repeated or prolonged exposure to stress causes a dysregulation of the HPA axis and an increase of the glucocorticoid burden. The adrenal glands become frequently enlarged and are more responsive to ACTH. Unlike this, repeated exposure to stress can result in habituation of the HPA axis with decreased cortisol response. In such a case, the PVN undergoes selective activation upon the same repeated or several different (i.e., a homotypic or a heterotypic) stressors. But even homotypic stressors, which are “severe,” might not cause habituation. Exposure to a previous stressor facilitates the glucocorticoid response to a subsequent stressor, in both habituation and nonhabituation versions of chronic stress. The mechanism underlying facilitation includes the PVN and its blockade impairs facilitation, suggesting its involvement in memory (Myers et al. 2012).

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Table 1 A simplified presentation of physiological and pathophysiological stress system stimuli Physiological stimuli Circadian rhythm Gender Aging Prenatal stress Early-life stress Maternal care Diet Temperature

Pathological stimuli Immune response Somatic stressors Neuropsychological factors Hypothalamus–pituitary–adrenal dysregulation Stress-induced adrenal conditions

Stress System Physiological Stimuli A schematic presentation of the pathophysiological stress system stimuli is summarized in Table 1.

Circadian Rhythm HPA axis activity undergoes circadian oscillations with diurnal changes in pulsatile CRH, ACTH, and corticosterone/cortisol secretion, with peak levels occurring before awakening. Not only the size of the pulses varies within a 24 h period but also the sensitivity of the corticotroph cells to the glucocorticoid feedback presents diurnal variation. The magnitude of the HPA oscillations is controlled by the lightactivated central clock through synapses of the suprachiasmatic and PVN of the hypothalamus and through direct alteration of the sensitivity of the adrenal zona fasciculata to ACTH (Lightman and Conway-Campbell 2010). On the molecular level, an interplay between the clock genes Per1, Per2, Per3, Cry1, Cry2, and the CLOCK/BMAL1 heterodimer has been identified to dominate these oscillations. On the other hand, HPA axis also affects the circadian rhythm since glucocorticoids exert an effect on the expression levels of several clock genes (Minnetti et al. 2020). By changing the expression of these genes in response to stressors, glucocorticoids transiently abolish the peripheral clock system to ensure homeostasis. Typical examples of dissociation between the diurnal rhythm and the HPA axis are rotating shift workers, and subjects who are exposed to frequent jet lag due to traveling over time zones. These individuals present a blunted decrease of late evening cortisol levels, are prone to development of metabolic syndrome, and have an increased risk for myocardial infarction and stroke, infections, and mood disorders, which are all possible results of a continuous activation of the HPA axis. Not only the uncoupling of the clock and the HPA axis but also both objective and subjective disturbances in sleep quality potentiate the stress reactivity of the HPA axis. On the other hand, normal variations in sleep duration do not seem to influence cortisol stress responsiveness, whereas excessive daytime sleepiness is associated with a blunting of the cortisol response (Nicolaides et al. 2015).

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Gender A sexual dimorphism is present in several physiological responses. Gender difference in both magnitude and duration of the stress responses are defined by male and female sex hormones. In general, testosterone inhibits stress reactivity, whilst estradiol appears to enhance HPA axis responses. Still, the role of sex steroids in HPA regulation remains controversial. In childhood, girls tend to more variable diurnal rhythms, higher cortisol-awakening response, and more pronounced cortisol response to social stress tests. Circulating cortisol levels change during the menstrual cycle, with low levels associated with high estrogen states (Hamidovic et al. 2020). Under physiological conditions, women in the follicular phase present a greater salivary cortisol response than during the luteal phase. Estrogens lead to a downregulation of the 11β-hydroxysteroid dehydrogenase (11β-HSD), and, in parallel, to an upregulation of the cortisol binding globulin (CBG) levels. Still, the magnitude of CBG alterations due to estradiol changes within menstrual cycles remains unclear. Furthermore, estradiol was shown to disrupt glucocorticoid receptor (GR)-mediated negative feedback on the HPA axis and to interfere with GR expression and binding in the pituitary gland (Hamidovic et al. 2020; Heck and Handa 2019). In peri- and postmenopausal women, reduced sensitivity of the hypothalamus and pituitary to cortisol and ACTH leads to increased cortisol levels and increased sympathoadrenal responsiveness. Similarly, older women tend to have larger cortisol responses to stimuli. Androgens enhance GR-mediated negative-feedback in the pituitary gland but modulate GR expression in a tissue-specific manner. Testosterone administration decreases cortisol responses to acute stressors (Heck and Handa 2019). Interestingly, healthy male subjects display greater HPA axis responses to a psychological stressor than females (Goel et al. 2014). Under gonadal suppression, men still present increased stimulated ACTH and cortisol levels, suggesting that these sex-related differences are independent of the known characteristic differences in reproductive steroids (Roca et al. 2005). Aging Aging affects the HPA axis at different levels due to a neural cell degeneration and increased gliosis of the hypothalamus and the limbic system, which affects the circadian clock. The impaired sensitivity to steroid feedback and, in part, the hyperreactivity of the HPA axis in elderly are attributed to these degenerative changes. In several studies, the circadian rhythmicity is maintained in older adults, but a reduced amplitude of the diurnal rhythm is observed. This flattened cortisol slope is mainly due to a relative increase of cortisol levels in the evening and during night-time. Cortisol output seems to increase with advancing age, potentially beginning with the cortisol-awakening response. Additionally, an impaired HPA sensitivity to steroid feedback has been detected in elderly people. Older individuals may present a reduced number of GRs both in the brain and in the periphery, rendering these tissues more resistant to glucocorticoids, or an increased 11β-HSD activity due to the rather low levels of sex steroids (Gaffey et al. 2016). Upon insulin hypoglycemia test, cortisol responses in the elderly are much more pronounced than in young

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subjects. Similarly, pharmacological challenges with dexamethasone or CRH induce higher cortisol responses with aging. Conversely, the ACTH response to stress seems reduced in older adults. Gender differences are also observed within the population of older adults, with men exhibiting a flatter slope and greater cortisolawakening response with aging, and women presenting higher overall cortisol levels and responding with enhanced cortisol output upon dexamethasone suppression test or CRH stimulation test. Estradiol treatment in older women blunts the cortisol response in comparable levels to untreated premenopausal women, suggesting a reproductive hormonal effect on cortisol output (Herman et al. 2016). DHEAS levels, in response to ACTH stimulation, significantly decrease during age. The reduction in DHEAS levels with the preservation of plasma cortisol underlines a dissociation of the adrenocortical secretory pattern and accentuate frailty. An inverse relationship between plasma DHEAS levels and age-related conditions, including cardiovascular and metabolic diseases, has been documented; however, the pharmacological substitution of DHEAS in these populations has not been substantiated yet (Arlt 2004).

Prenatal Stress Manipulations of the early environment can affect the developing nervous system, shaping individual differences in physiological, neuroendocrine, and behavioral responses to environmental factors. Early-life stress exposure (prenatal or early postnatal) may affect several developmental pathways that predispose to adulthood disease. The adaptive changes of developing organisms in response to environmental stimuli are called early-life programming. Early-life stress programs HPA axis activity and can cause permanent changes in physiology, structure, and metabolism (Maniam et al. 2014). In several studies, prenatal stress in terms of maternal exposure to natural disasters or maternal depression affects the stress responses of the children in various ways, either by both increased baseline and stimulated cortisol levels or by increased ACTH responses to stressors and commonly by a flattened cortisol circadian rhythm. Preterm birth with low birth weight act also as stressors and studies show that very preterm newborns tend to present relatively insufficient adrenocortical response to stress, whereas later in life display features of increased glucocorticoid action, such as central obesity, insulin resistance, increased blood pressure, short stature, and behavioral problems, due to defects in the pituitary responsiveness to exogenous corticotropin-releasing hormone, impaired 11β-hydroxylase activity, and imbalance between cortisol and inactive cortisone (Heim and Binder 2012). Early-Life Stress The first five years of life are considered a critically vulnerable period, where the presence of stress causes epigenetic imprinting, which follows the child for the rest of his life. This stress hyporesponsive period is supposed to be necessary for the brain development after birth. During this period, the physiological response to mild stress with increase in glucocorticoids does not occur. The consistency of maternal

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care significantly affects the neurobiology and behavior of the child by improving the cardiac rhythm, sleep pattern and growth hormone secretion, and suppressing the HPA axis, thus predisposing the future susceptibility to stress later in life (Curley and Champagne 2016). According to the match/mismatch theory, early-life stress prepares an organism for similar experiences in the future. Conversely, mismatching experiences result in increased predisposition to pathological conditions, suggesting that early-life stress can be either useful or harmful, depending on the environmental background (Van Bodegom et al. 2017). An overactive HPA axis puts the organism at a continuous catabolic state due to increased glucocorticoids, which could damage hippocampal neurons among other factors. Thus, glucocorticoid concentration correlates with neuronal density in the hippocampus across the life span. Specifically, glucocorticoid-induced neuronal catabolism produces vulnerability to metabolic disturbances. On the other hand, insufficient glucocorticoid response under intense stress does not sufficiently prepare the individual to meet a life-threatening challenge. Hence, a low cortisol response to stress predicts increased susceptibility to development of post-traumatic stress disorder (Van Bodegom et al. 2017). Popular postnatal stressors such as maternal separation for varying time, maternal deprivation or the limited nesting model, dysregulate HPA axis through stimulation of hypothalamic peptides [Neuropeptide Y (NPY), Agouti-related protein (AgRP), Pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexins] and through activation of hypothalamic inflammation via tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1B. It is suggested that these stimuli affect the expression of enzymes activating glucocorticoids (such as 11β-HSD) and lead to increased exposure of peripheral tissues to the glucocorticoid action. Such a glucocorticoid excess results in metabolic derangements, causing hyperinsulinemia and insulin resistance. Postnatal stress has been found to strongly correlate with adulthood obesity, type 2 diabetes mellitus, and increased inflammation, identified by increased baseline CRP levels (Maniam et al. 2014). Victims of childhood abuse present a sensitization of the HPA axis with increased ACTH concentrations in response to stressors. Chronic hypersensitization leads to downregulation of the CRH receptors of the anterior pituitary and thus to depressive and anxiety symptoms. On the other hand, subjects who were submitted to early social deprivation, such as children raised in orphanages, seem to present an HPA hypo-reactivity with reduced morning cortisol levels and less steep cortisol slope (Van Bodegom et al. 2017).

Maternal Care Pregnancy and lactation are physiological states in which HPA axis responsiveness to stressors is altered. In early pregnancy, salivary cortisol levels are typically lower than in late pregnancy. Lower glucocorticoid secretion in this period is associated with a facilitation of the implantation of the fetus. Additionally, the amplitude of the diurnal rhythm becomes greater as cortisol levels increase during pregnancy (Lightman et al. 2001). During late pregnancy, a pronounced increase in cortisol levels is observed, even though assessment of the maternal HPA axis cannot be

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performed accurately due to the production of CRH and other HPA axis regulatory peptides by the placenta. Still, an HPA hyporesponsiveness to a wide range of stressors due to reduced CRH activation in the parvocellular PVN is indicated by low ACTH. In parallel, in line with the progressive increase in free cortisol levels, up to 1.6-fold in the third trimester, a progressive CBG increase up to 2–three-fold during the second and third trimester can be observed throughout gestation (Jung et al. 2011). During delivery, an increase of HPA axis hormones is observed in response to the stressor. However, whether this effect reflects only maternal hormone secretion or placental/fetal mechanisms remains unclear. Lactation represents another physiological state of HPA axis alteration, mainly originating from the suckling of the offspring. Acutely, suckling rapidly increases ACTH and corticosterone secretion. Furthermore, breastfeeding women display a state of HPA hyporesponsiveness to stressors. Suckling-related factors, including the activation of the brain oxytocin and prolactin systems, contribute to the reduced HPA axis response to stress. HPA response to stress in breastfeeding women is also affected by the nature of stressors. Lactating women present reduced HPA axis responses upon physical exercise or cold stressor, but not upon a social stressor, unless breastfeeding occurs shortly before (Heinrichs et al. 2001). Furthermore, multiparous but not primiparous breastfeeding women show reduced cortisol responses to emotional stressors (Hasiec and Misztal 2018).

Diet The activity of the HPA axis is modulated by factors involved in weight regulation. Numerous neuropeptides, neurotransmitters, cytokines, and adipokines, such as AgRP, CART, ghrelin, adiponectin, NPY, atrial natriuretic peptide (ANP), melanocortin, leptin, orexin, serotonin, and IL-6, contribute to the HPA axis regulation (Bornstein et al. 2006). Alterations of the HPA axis responsiveness have been attributed to both extremes of food intake, that is, caloric restriction/fasting and obesity. Elevated plasma cortisol levels have been reported in several studies following caloric restriction. The stimulatory effect of caloric restriction on the HPA axis becomes significant only with fasting and not with low and very low caloric intake (Nakamura et al. 2016). Similarly, diet showed no effect on salivary cortisol levels. In the same context, in anorexia nervosa, a significant increase in mean fasting, 120 min post-meal, in urinary-free cortisol, morning salivary cortisol, and late-night salivary cortisol is observed in comparison to healthy controls. Furthermore, an insufficient cortisol suppression upon dexamethasone test is observed during starvation. This HPA hyperreactivity could be a leptin-mediated effect. Under normal conditions, leptin suppresses the HPA axis. During prolonged fasting, hypoleptinemia stimulates the HPA axis and increases cortisol in order to increase appetite (Giovambattista et al. 2000). The effects of overweight and obesity on the HPA axis appear to be more controversial. On the molecular level, an increased 11β-HSD activity is observed in the adipose tissue of obese subjects, leading to increased tissue glucocorticoid levels. Furthermore, GR levels and activity but also some gene polymorphisms

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appear to correlate with obesity and type 2 diabetes/metabolic syndrome (Akalestou et al. 2020). Overweight and obese children present a maintained diurnal rhythm of cortisol secretion with reduced early morning and late-night cortisol levels in comparison to normal-weight adolescents. Adult subjects with obesity display a blunted adrenal response of cortisol release. In some studies, body mass index (BMI) and waist circumference negatively correlate with awakening cortisol and positively correlate with the early decline slope. Unlike this, studies discerning between central and peripheral obesity show a positive correlation between BMI and cortisolawakening response in men with visceral obesity. Daily cortisol output assessed either by 24-h UFC, or multiple days of diurnal blood or salivary cortisol sampling presents also inconsistent results, with some studies documenting hypercortisolism and others normal cortisol levels or even hypocortisolism. When comparing generalized obesity and abdominal obesity, it appears that abdominal obesity is the better predictor of pronounced acute cortisol reactivity upon stress stimuli (Incollingo Rodriguez et al. 2015). Obese women class I appear to display low cortisol levels, lower than lean women, but as obesity becomes more severe, cortisol levels gradually increase. Apparently, extreme under- or overweight both activate the HPA axis in a perceived condition of chronic stress to the organism (Schorr et al. 2015). In normal subjects, an increase of serum cortisol levels is documented upon a meal consumption. Unlike hypoglycemia, which stimulates central CRH production and thereby cortisol secretion, postprandial cortisol increases seem to be direct effects of macronutrients on the adrenal and extra-adrenal cortisol production and on the 11β-HSD activity (Stimson et al. 2014). The composition of food intake also causes alterations on the HPA axis, but the effects of various macronutrients on the HPA axis are not yet conclusive. A high carbohydrate meal significantly increases cortisol concentrations in visceral obese subjects as opposed to a high-protein or high-fat meal. In normal weighted subjects, the protein as well as the fat meal caused a significant decrease in cortisol concentrations when compared to the carbohydrate meal and showed no difference from the baseline (Martens et al. 2010). In another study, high-fat diet consumption blunted the HPA axis response to acute stress in a gender-dependent manner.

Physical Activity Physical activity is a physiological regulator of the HPA axis. In the acute setting, low-intensity exercise does not result in significant increases, whereas moderate- and high-intensity exercise leads to a significant stimulation of the HPA axis, with increased ACTH and cortisol levels and a fast recovery to the basal levels. The cortisol response to exercise depends on the nutrition status as overweight/obese subjects present a more pronounced cortisol response during acute physical exercise. Sustained physical conditioning in highly trained athletes is associated with a decreased HPA response to exercise. On the other hand, highly trained athletes exhibit a chronic mild hypercortisolism at baseline, possibly an adaptive mechanism to chronic exercise. Cortisol-awakening response does not present any difference upon single exercise session but increases in the first days upon repeated physical exercise. Upon prolonged training, though, the cortisol-awakening levels do not

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present uniform trends as both increases and decreases have been documented, possibly depending on the intensity of routine exercise or the individual’s fitness levels. Additionally, repeated physical activity facilitates a protective role against stressors with trained subjects showing reduced cortisol response to stressful stimuli (Mastorakos et al. 2005).

Temperature Thermal stressors such as low and high ambient temperature induce a neuroendocrine response including an activation of the HPA axis. Under heat exposure, several nuclei in the brain stem such as catecholaminergic nuclei or the limbic system are stimulated. These in turn stimulate hypothalamic centers, which secrete both CRH and AVP. They both act synergistically to stimulate the ACTH release. Acute exposures to extreme weather conditions (cold or warm temperatures but also precipitation) show strong support for eliciting glucocorticoid responses, whereas prolonged exposures >24 hours present mixed results concerning the HPA activation (De Bruijn and Romero 2018). Heat acclimatization has been investigated under several different conditions. During exercise, heat acclimatization attenuates plasma cortisol responses. Heat exposure in chronic alcoholics and cocaine addicts induces lower ACTH and cortisol increments than in normal subjects. Additionally, significant seasonal variations in overnight urinary glucocorticoid (decreased in June) and catecholamine (increased in June) concentrations and in saliva cortisol response to awakening have been observed. Exercise during cold exposure leads to significantly higher cortisol values than under room temperature (Brazaitis et al. 2015).

Stress System Pathological Stimuli Immune Response The immune system and the HPA axis present a bidirectional feedback. Soluble cytokines originating from the immune system can have important effects on the HPA axis. Infection caused by viruses, bacteria, fungi, or parasites, tissue damage, and inappropriate responses to autoantigens all activate the immune system to release cytokines responsible for the innate immune response [IL-1, IL-6, TNF-α, and interferon (INF)-α/β]. Later, adaptive immunity is mediated through IL-2 and INF-γ. Cytokines released for both the innate and adaptive immune response exert a stimulatory effect on the HPA axis, resulting in the release of adrenal glucocorticoids. These in turn give a negative feedback to the immune cells to suppress further secretion of cytokines. Additionally, they alter immune responses shifting from cellular to humoral immune responses (Chrousos 1995, 2000). Cytokine receptors are located not only at the hypothalamic level, but also in the pituitary and the adrenal glands. During an immune response, released cytokines can stimulate the HPA axis at all three levels. At the brain level, cytokines may stimulate visceral afferents that project to the brainstem, activating the release of norepinephrine in the PVN, passively cross to the brain at areas where the blood–brain barrier is not intact and directly activate CRH nerves or neurons that project to the

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hypothalamus, act on endothelial brain cells to secrete central cytokines acting in paracrine manner or actively cross the blood–brain barrier via transport. Furthermore, cytokines stimulate AVP secretion, which synergistically with CRH stimulates ACTH release (Watkins et al. 1995). This mechanism is predominantly observed in chronic inflammation processes such as in rheumatoid arthritis, where although CRH levels are relatively decreased, AVP and ACTH levels are increased and, thus, an increased HPA response to further stressors is documented. At the pituitary level, cytokines can directly stimulate POMC transcription and ACTH release and also increase sensitization of the corticotrophs to CRH. A direct action of cytokines on the adrenal gland has also been described. Here, catecholamines from the medulla are able to influence steroidogenesis in the adrenal cortex. As in the hypothalamus and the pituitary, local cytokine production in the adrenal gland has also been documented (Chrousos 2000).

Somatic Stressors Somatic pain, trauma, blood loss, tissue injury, hypotension, and further physical stressors (e.g., hypoglycemia) all require successful adaptation to ensure survival. A representative example including several somatic stressors is surgical stress, which activates cortical centers of the brain and the spinal and baroreceptor reflexes that stimulate pulsatile CRH secretion from the hypothalamus. CRH triggers the pulsatile release of ACTH from the pituitary gland, which, in turn, induces the continuous release of glucocorticoids from the adrenal cortex (Calogero et al. 1992). Simultaneously, surgical stress activates the sympathetic system to release catecholamines. The postoperative cortisol circadian rhythm is altered in these patients, whereas a biphasic HPA activation is also observed during the recovery. Furthermore, surgical stress can result in long-term cortisol secretion in the absence of a corresponding increase in ACTH, which is accompanied by marked elevations in circulating cytokines, thus, through induction of the immune response (Herman et al. 2016). Neuropsychological Factors Psychosocial stressors have also significant impact on the HPA axis. Interestingly stressors such as public speaking and mental arithmetic in front of an audience induce acutely an increase in cortisol, ACTH, epinephrine, and norepinephrine, whereas upon repeated exposure, two different patterns, one with habituation and less significant cortisol and ACTH increases and one without habituation, where upon prolonged stimulation a more pronounced cortisol and ACTH increase could be observed, suggesting individual differences in the habituation process. Social isolation and loneliness lead to an increase in morning cortisol and flatter diurnal rhythm, indicative of HPA axis alteration. Fear conditioning and stress share common neuronal circuits. Fear induces glucocorticoid secretion, and the control of fear during extinction is also sensitive to these stress–response mediators. More specifically, glucocorticoid administration facilitates fear extinction memory in a genderdependent manner and extinction recall of conditioned fear acquired after stress depends on estrogen status in women (Stockhorst and Antov 2015).

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HPA Dysregulation The HPA axis dysregulation and prolonged exposure to elevated glucocorticoids attenuate the ability of neurons to adequately respond, increasing the risk for injury by other toxic phenomena. HPA axis hyperactivity is observed in the following diseases: Cushing syndrome, chronic stress, melancholic depression, anorexia nervosa, obsessive-compulsive disorder, panic disorder, chronic alcoholism, alcohol and narcotic withdrawal, diabetes mellitus, metabolic syndrome with central obesity, hyperthyroidism, and pregnancy. Inversely, decreased HPA activity is observed in adrenal insufficiency, atypical depression, chronic fatigue syndrome, fibromyalgia, nicotine withdrawal, following cessation of glucocorticoid therapy or cure of Cushing syndrome, following chronic stress, postpartum, in adult post-traumatic stress disorder, hypothyroidism, asthma, eczema, and rheumatoid arthritis (Chrousos 2009). Somatic consequences of HPA hyperactivity are hyperinsulinemia, low growth hormone, hypogonadism, osteoporosis, sarcopenia with visceral obesity, dyslipidemia, hypertension, insulin resistance, or even type 2 diabetes. Behavioral changes include anxiety, anorexia or hyperphagia, depression, and cognitive dysfunction. Anxiety disorder, depression, post-traumatic stress disorder, and epilepsy all share pathogenetic mechanisms including stress dysfunction. Patients with major depression often have increased levels of cortisol in plasma and urine, increased cortisol response upon ACTH stimulation, blunted ACTH response but normal cortisol response upon CRH stimulation and present with hyperplasia of the pituitary and adrenal glands (Gold et al. 1988). In addition, one of the most common findings in major depression is the reduction of hippocampal volume by 10–15%. Chronic treatment with corticosterone not only induces depressive-like symptoms but also leads to a hypertrophy of the amygdala and, thus, to increased anxiogenic behavioral responses. Inversely, patients with post-traumatic stress disorder display low baseline cortisol levels. These patients also present an enhanced glucocorticoid receptor sensitivity and increased negative feedback at the CRH level. Factors such as war, violence, sexual abuse, disasters, and many others are believed to be associated with the development of post-traumatic stress disorder, leading individuals to present physiological and behavioral alterations including nightmares, hypervigilance, flashbacks of the trauma, and sleep disturbances. Interestingly, despite the trauma severity, other factors such as socioeconomic status, psychiatric history, substance abuse, genetics, and epigenetics play an important role in the development of the disease. In patients with epilepsy, stress usually represents one of the major seizure precipitants, and in adults, a positive correlation between stress and frequency of epileptic seizures has been reported (Frucht et al. 2000). Stress-Induced Adrenal Conditions Aging or senescence results changes in the cortisol secretion pattern by the zona fasciculata of the adrenal cortex. In stress-induced senescence, the hypothesis is that DNA is damaged from free radicals, or replication, in the presence of internal or external stressors via mutations in the repair enzymes as a result of the dysfunction and further aging. The stress theory of aging, also known as hormonal theory,

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supports the theory that the cumulative effects of stress and stressful environments disrupt physiological cellular function, cause cellular damage, which eventually is expressed in system dysfunction and aging. The available data imply that decreased responsiveness and integration of the various components of the stress response can contribute to both aging and age-related diseases (Yiallouris et al. 2019). On top of that, cortisol concentrations increase throughout aging, as opposed to most hormones, whose levels diminish. Upon chronic stress, prolonged exposure to high glucocorticoid levels could lead to decreased glucocorticoid receptor sensitivity in the brain, and, subsequently, to reduced negative feedback. This causes a vicious cycle and more pronounced cortisol levels. Alternatively, older individuals may display fewer glucocorticoid receptors inhibiting negative feedback. The term “adrenal fatigue” used by doctors, healthcare providers, and the general media usually describes a condition caused by chronic exposure to stressful situations. Despite this, the available data in the literature do not substantiate it as a medical condition (Cadegiani and Kater 2016).

Part 2: Environmental Endocrine Disruptors and the HPA Axis The main effects of environmental EDCs on HPA axis and steroidogenic enzymes are summarized in Table 2.

Plasticizers Plasticizers are a heterogenous group of molecules widely used in numerous and different types of industries for intermediate and consumer goods. Thanks to their great versatility, these molecules are mainly employed as additive in many production processes, especially plastics, giving them flexibility, resistance, transparency, durability, workability, and a volume-expanding effect. An estimated 90% of plasticizers are used for polyvinyl chloride (PVC), even though they can be found in stucco, fuel propellants, firefighting foams, hydraulic fluids, pesticides, medical devices, preservatives, and cosmetics. The large number of applications listed previously make plasticizers one of the most diffused compounds among the general population, urban and natural environments. Today, many plasticizers are known to exert several harmful effects on many endocrine organs, including the adrenal gland. Interestingly, the disrupting potential of plasticizers may affect the HPA axis at multiple levels (Fig. 2).

Phthalates Phthalate acid esters, commonly known as phthalates, are the most representative class of plasticizers. Discovered in the 1920s, they became fundamental plastic additives due to the capability of improving flexibility and workability of the materials. The compound di(2-ethylhexyl) phthalate (DEHP) is among the most used plasticizers in polymer products (51% of total phthalates). Phthalates can be

Econazole Miconazole Lindane Glyphosate Dimethoate Carbachol Ethanol Arsenic Anisomycin

Patulin

Cadmium

Aminoglutethimide

Dichlorodiphenyltrichloroethane (DDT)

Tris(2-butoxyethyl) phosphate (TBOEP)

Arsenate (sodium arsenate)

Phthalates (DEHP) Perfluorooctanesulfonic acid (PFOS)

#b #b #b #b #b #b "a "b "b

#a

Steroid Acute regulatory (StAR) protein

#b

#a

#b

#a

#b #b

#a

#b

3CYP11B1 Hydroxysteroid (CYP11β/ CYP19 dehydrogenase 17β-Hydroxysteroid CYP11A1 (aromatase) CYP21 18) (CYPscc) CYP17 Δ 4,5 isomerase dehydrogenase a # #a #b "b #b #a "b

(continued)

CYP11B2 (aldosterone synthase) Other Epigenetic modificationsa "b Downregulation of glucocorticoid receptor (GR)a and CRH expressiona Upregulation of GRa and CRH expressiona Downregulation of GRa, mineralocorticoid receptora, CRH receptora, POMC receptora Upregulation of β-catenin/ Wnt pathwaya and downregulation of nuclear transcription activitya Downregulation of ACTH signal pathwaya Downregulation of ACTH signal pathwaya Upregulation of nuclear transcription activityb

Table 2 Summary of the main effects of several EDCs on HPA axis and steroidogenic enzymes: (a) in vivo studies; (b) in vitro studies

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Bromocriptine Bisphenol A (BPA) Aniline and aniline derivatives Biochanin A Chrysin Daidzein Formononetin Genistein 6-Hydroxyflavone 7-Hydroxyflavone, chrysin, apigenin, hydroxyflavanone, naringenin, rotenone, synthetic flavonoids (flavonoids) Quercetin PCB 101 PCB 110 PCB 126 PCB 149 Ketoconazole Brominated diphenyl ethers (BDE), OH-BDE, CH3O-BDE Pioglitazone (Thiazolidinediones) Cyanoketone Trilostane Polycyclic aromatic hydrocarbons (PAHs)/

Table 2 (continued)

#b

Steroid Acute regulatory (StAR) protein #a "a #b

#b

#b

#b #b

#b

#b

#b #a #a #b #b

"b "b

" "b

" "b "b "b #b b

#b

"b #b "b

b

#b #b #b #b

#b #b #b #b

" "b "b "b b

#b

"b "b "b "b "b "b

#b

"b

"b

"b "b "b "b

3CYP11B2 CYP11B1 Hydroxysteroid (aldosterone (CYP11β/ CYP19 dehydrogenase 17β-Hydroxysteroid CYP11A1 Other (aromatase) synthase) CYP21 18) (CYPscc) CYP17 Δ 4,5 isomerase dehydrogenase #a "a #a #b #b "b #b #b

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a ¼ in vivo studies b ¼ in vitro studies " ¼ up regulated # ¼ down regulated

polybrominated biphenyl ether (PBE) Metyrapone Mitotane/MeSO2-DDE Etomidate Efonidipine/mibefradil Epoxiconazole/flurprimidol/ ancymidol Octyl methoxycinnamate/ acetyl tributyl citrate Diindolylmethanes Simazine, propazine (triazinesatrazine derivatives) Di-, tributyl, and phenyltin chlorides Vinclozolin Fenarimol Fadrozole Perfluorooctanoic acid (PFOA) Guanabenz-related amidino hydrazones

#b

#b

#b

#b

#b

"b #b #b #b

#b

#b

#b

"b

"b "b "b

#b #b

#b

#a #b #b #b #b

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Fig. 2 Visualization of the main endocrine-disrupting chemicals on the adrenal gland

found in medical tubes, coatings, toys, food wrapping, cosmetics, personal care products, and even employment as emulsifiers have been reported in food industry. The manufacturers in the European Union (EU) produced 46% of plasticizers in the world, whereas the consumption of DEHP was 37% (476.000 tpa) (https://echa. europa.eu/documents/10162/e614617d-58e7-42d9-b7fb-d7bab8f26feb). DEHP was listed among substances subject to authorization by the European Community (EC) in 2009 (https://echa.europa.eu/documents/10162/6f89a308-c467-4836-ae1e9c6163a9ae10) and recognized as having endocrine-disrupting properties affecting human health in 2017 (Article 57(f) of Regulation (EC) No 1907/2006), among other compounds (https://echa.europa.eu/documents/10162/88c20879-606b-03a6-11e49edb90e7e615). Phthalates can spread in the environment because they do not chemically bind to plastics, making human contact very easy through ingestion, inhalation, or skin contact. These circumstances have led to the finding of phthalates in human fluids, including urines in pregnant women living in houses with PVC flooring (Gore et al. 2015). Exposure to phthalates has been associated to alterations in steroidogenesis. Diethyl phthalate (DEP), benzyl butyl phthalate (BBzP), and diisobutyl phthalate (DiBP) were able to downregulate 17β-hydroxy-steroido-dehydrogenase (17β-HSD) and steroidogenic acute regulatory protein (StAR), upregulate CYP19A, and reduce testosterone levels. In addition, the human-derived metabolites of DEP, BBzP, and DiBP [monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate

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(MiBP), respectively] showed similar effects on StAR and CYP19A, and downregulated 3β-hydroxy-steroido-dehydrogenase type 2 (3β-HSD2). Several recent studies showed that a DEHP “first hit,” as an in utero exposure, may increase the susceptibility of the endocrine system after a “second hit,” intended as a later life contact. In male offspring rats exposed to DEHP in utero, aldosterone levels were reduced in adult life, whereas glucocorticoid secretion resulted not affected. Additionally, the potassium channel Kcnk5 was downregulated after exposure to both first and second hit of DEHP, leading to the hypothesis that early phthalates exposure may predispose to endocrine disease later in life, with selective disrupting activity confined to adrenal gland (Martinez-Arguelles and Papadopoulos 2015). Limited studies in human cohorts have investigated the consequences of prenatal phthalate exposure, finding a potential link with reduced levels of androgen precursors like dehydroepiandrosterone (DHEA), DHEA-sulfate, and androstenedione in girls at pubertal age. More recent data have identified an inverse association between mono(2-ethylhexyl) phthalate (MEHP), after prenatal exposure, and glucocorticoid levels in infants (Araki et al. 2017). Taken together, those studies have raised attention to the potentially deleterious effects of phthalates on adrenal steroidogenesis later in life and have proposed a hypothetical role of the phthalate prenatal exposure.

Bisphenol A Bisphenol A (BPA) is a synthetic compound belonging to diphenylmethane derivatives, used in common plastic goods, as additive for bottle, compact discs, DVD, water tubes, thermal paper, and internal coating for food and beverage containers. BPA is used in the manufacture of thermal paper. BPA has been largely studied starting from 1936, when its xenoestrogen properties were discovered. Several studies have shown a link between BPA exposure and diabetes, obesity, metabolic syndrome, polycystic ovary syndrome, infertility, premature ovarian failure, and increased risk of breast and prostate cancer. Those studies have led the EC to classify BPA as a substance of very high concern, according to the criteria established in Article 57(c) of the REACH Regulation (https:// op.europa.eu/en/publication-detail/-/publication/c3811f31-079d-4d13-966c83a25b2fc08c/language-en), in 2016, as a toxic agent for reproduction (https://op. europa.eu/en/publication-detail/-/publication/5de69f73-4e3f-11e6-89bd01aa75ed71a1/language-en), and, in 2017, as a compound subject to authorization, according to the Article 59(1) of the REACH Regulation. Recently, in 2019, the General Court of the EU confirmed the inclusion of BPA as a substance of very high concern due to the toxic effects on reproduction (https://curia.europa.eu/jcms/upload/ docs/application/pdf/2019-07/cp190092en.pdf). The EU has banned the use of BPA in infant feeding bottles since 2011 and in the production of thermal paper from January 2020 (https://eur-lex.europa.eu/legal-content/EN/TXT/?uri¼CELEX:32016R2235). Due to the wide use of BPA and the strict regulations concerning the utilization of this compound, European paper manufacturers have started to use bisphenol S (BPS) instead of BPA. However, the Risk Assessment Committee of the European Chemical Agency has recently expressed concerns about the potential toxic effects of BPS, which may be similar to BPA (https://echa.europa.eu/-/bpa-being-replaced-by-bps-in-thermal-

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paper-echa-survey-finds). Since 2018, the maximum amount of BPA allowed in toys for children up to 3 years old and toys that can be put in children’s mouths has been severely restricted (0.04 mg/L). Prenatal exposure to BPA was able to induce the activity of StAR and CYP11A, without altering ACTH concentrations. BPA has been associated with increased adrenal glands weight in several studies (Medwid et al. 2016) due to stimulation of proliferation linked to the activation of the sonic hedgehog signaling pathway through the estrogen receptor, a well-known BPA target. BPA has been studied as a potential functional adrenal cortical disruptor. In silico models have shown that BPA can alter the HPA axis by binding to the glucocorticoid receptor. Data from animal studies showed that exposure to BPA was able to impair the stress response at a central level, leading to increased ACTH and CRH production and reduction of expression of glucocorticoid receptor in several regions involved in stress response (Caudle 2016). Nonetheless, the data on BPA as a disrupting agent on HPA axis derive from studies providing contrasting results due to the different exposure schemes of BPA (in utero or lactational) and the different methods of assessment of HPA axis response upon BPA stimulation (basal and stressful conditions). Recent data from cohort studies have investigated for the first time the effects of BPA exposure on adrenal steroidogenesis and cortisol secretion in humans. Increasing urinary BPA levels have been associated with reduced cortisol levels and a flatter diurnal cortisol slope. Additionally, infants born from BPA-exposed mothers showed sex-specific differences in cortisol levels and HPA axis reactivity upon stress at 3 months of age, with increased baseline cortisol levels and reduced cortisol reactivity in females, as opposed to infant males, who showed an opposite pattern (Giesbrecht et al. 2017). Studies in peripubertal boys have confirmed that increasing levels of BPA in urine were negatively associated with cortisol levels (Mustieles et al. 2018). Taken together, the data coming from human cohorts are consistent with potential endocrine-disrupting properties of BPA on the adrenal gland, with differential alterations of the steroidogenesis according to sex, since in utero up to prepubertal age.

Polychlorinated Biphenyls (PCBs) PCBs are organochlorine chemicals characterized by two benzene rings with a chlorine atom each in a variable position. Since the 1930s, they have been extensively employed as plasticizer in electric cables, coolants fluids, pesticides, flame retardants, lubricants, and carbonless copy paper due to their chemical stability and heat resistance. After the discovery of their toxic effects on human health, employment and production of organochlorines have decreased drastically during the last 50 years, until severe restrictions have been applied to PCBs’ use and marketing by the EC in 1985 (https://ec.europa.eu/environment/waste/pcbs/index.htm). PCBs can store in body fat and are reported to have also disrupting effects on thyroid gland, adipose tissue, and gonads by showing antiandrogenic effects in animal studies. Moreover, they are considered probable human carcinogens. Studies in humans confirmed that PCBs were able to alter menstrual cycle rhythmicity and impair fertility. As an adrenocortical disruptor, many studies were carried out on animal

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offspring (mice or goats) after in utero exposure of PCBs, showing either reduced or increased basal corticosterone, sometimes with differences according to sex. In H295R cell lines, PCBs 101, 110, and 126 have been associated with an increased mRNA expression of several steroidogenesis enzymes, like 3βHSD, CYP19, CYP21, CYP11B1, and CYP11B2, and to a reduced mRNA expression of StAR and CYP17 (Xu et al. 2006). However, the wide range of different types of PCBs makes the comparison among different experimental setting extremely difficult.

Flame Retardants Flame retardants are groups of molecules widely used as an additive in a huge number of industrial products, typically for plastics, fabrics, mattresses, and clothing, to prevent or slow fire ignition. Their massive employment through the years has led to an inevitable and constant exposure for human. Flame retardants are highly lipophilic, accumulating in body tissues, and have shown synergic interactions among different molecules (Gore et al. 2015). The main classes of flame retardants are organophosphates and organohalogens, which include organochlorines and organobromines. Organophosphates derive from the addition of three radicals to a phosphoric acid through esterification. It is a versatile chemical class and can be employed as a flame retardant, insecticide, and herbicide. Organophosphates are known to exert a toxic effect on nervous system, but they have other harmful effects, like increased body weight, risk of miscarriage, and prostate cancer in humans. Recent studies showed that exposure to tris-(2-butoxyethyl)-phosphate (TBOEP), a common flame retardant, was able to exert central deleterious effects by downregulation of POMC gene and upregulation of glucocorticoid and mineralocorticoid receptors in the brain. Additionally, a decreased expression of CYP11A and CYP17 genes has been reported in adrenal gland tissues. Therefore, TBOEP may lead to reduced pituitary ACTH synthesis and lowered adrenal CYP11A and CYP17 production, with consequent adaption exerted through upregulation of glucocorticoid and mineralocorticoid receptors. Additionally, organophosphates are reported to impair ACTH- and cAMP-induced steroidogenesis, but not the pregnenolone-derived steroid production, leading to the hypothesis that they may act after cAMP production and before pregnenolone synthesis. In vitro evidence supported this concept showing that exposure to dimethoate, an organophosphate derivative, led to a reduced expression of StARgene. Organobromines are organic molecules characterized by a carbon bound to a bromine. Brominated flame retardants are well-known EDCs, which have been associated with alterations of thyroid-releasing hormone expression and uterine cancer [tetrabromobisphenol A (TBBPA)], alterations of spermatogenesis and testicular abnormalities, like cryptorchidism and reduced testicular weights [polybrominated diphenyl ether (PBDE)] in humans. Organobromines and brominated flame retardants are reported to be present in breast milk and in the atmosphere due to the waste incineration and disposal.

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Data from in vitro experiments showed that exposure to PBDE, TBBPA, and their hydroxylated and methoxylated metabolites led to an inhibition of CYP17 in H295R adrenocortical cell lines (Canton et al. 2006). Additional studies showed that increasing concentrations of several bromophenols and brominated biphenyls, mimicking the concentrations found in the atmosphere, were able to alter the gene expression of almost all steroidogenic enzymes, including CYP11B2, CYP17, CYP19, CYP21, 3βHSD2, 17βHSD, and StAR. 3βHSD2 expression stood out as the most upregulated enzyme by exposure to each chemical (Ding et al. 2007).

Pesticides Historically, human civilization had always tried to fight or control pests with several compounds intended as pesticides. In the modern era, many substances and techniques have changed, and different chemical classes have taken place in this category, like organohalogens, organophosphates, and imidazole derivatives. Pesticides are currently employed as herbicides, insecticide, fungicides, avicide, molluscicide, germicides, and animal/insect repellents. These products are worldwide distributed and used from the single farmer and citizen to the industrial and agriculture mass production to ensure food safety. Several harmful effects of pesticides have been demonstrated in humans, with specific consequences on the autonomous nervous system. Many pesticides are also adrenocortical disruptors. In this niche of literature, most studies focus on insecticide, herbicide, and fungicide (Fig. 3). Several types of pesticides have shown downregulation of CYP19 gene expression, encoding for aromatase, the enzyme involved in aromatization of androgens into estrogens (Sanderson et al. 2002). Insecticides Many classes of compounds belong to insecticides, including also PCBs and organophasphates, which have been described above. Triazophos is an organophosphate pesticide, used as a broad-spectrum insecticide. This compound was banned in EC and several other countries because of its high toxicity and long half-life (https:// echa.europa.eu/substance-information/-/substanceinfo/100.041.791). Nonetheless, there is still a risk of human contact through food, after the detection of triazophos in fruits, vegetables, and rice in China. According to recent studies, chronic exposure to triazophos has been linked to downregulation of HPA axis, characterized by reduction of ACTH e corticosterone in animal models (Gore et al. 2015). Organochlorines are compounds largely used as insecticides because of the main property of disrupting several ion channels involved in neurotransmission, which are highly conserved among species. Due to the specific target of action, organochlorines are particularly dangerous for humans. A singular mention must be done for dichlorodiphenyltrichloroethane, an organochlorine known as DDT. In the past, it was advertised as a beneficial chemical for human health because its utilization was associated with a drastic decrease of malaria and typhoid fever. Nonetheless, DDT has shown evidence of being a highly lipophilic and cytotoxic chemical, with many noxious effects on human health. Therefore, after extensive use of DDT between the 1950s and the 1970s, it was banned worldwide more than 20 years ago, in 1983 by the

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Fig. 3 Schematization of principal endocrine disruptors, physiological and pathological stimuli acting on adrenal gland

Directive 83/131/EEC. Nowadays, this compound is employed as an intermediate in the closed production system of dicofol, a pesticide. Additionally, it is still used as an insecticide in several countries under specific conditions. DDT has been associated with several diseases, including metabolic alterations like type 2 diabetes, due to the DDT-induced damage to the pancreatic β-cells, and several types of tumors, such as breast, pancreatic, testicular, and endometrial cancer. Additionally, in human studies, DDT exposure has been linked to spontaneous miscarriage, alteration of spermatogenesis, and cryptorchidism in men. The first noxious effects of DDT on the adrenal glands were observed in the 1950s, when the first reports of an adrenolytic effect of this drug were shown in dogs. After confirmation by several subsequent studies, it became clear that exposure to DDT leads to severe alterations of the steroidogenesis, causing adrenal insufficiency. Indeed, 1,1-(dichlorodiphenyl)-2,2-dichloroethane (o,p’-DDD), known as mitotane, was synthesized from DDT, and is currently used as antineoplastic drug for adjuvant treatment of adrenocortical carcinoma and management of severe hypercortisolism. Although there is awareness about its toxicity, it is still indicated for the treatment of adrenocortical carcinoma in the absence of alternative pharmacological options. Mitotane has a multitude of effects on the cell, including antiproliferative effects, damage to the mitochondrial structure, disruption of mitochondrial function, alteration of steroidogenesis, and induction of apoptosis, among others. As regards steroidogenesis, decreases in cortisol, aldosterone, testosterone, and progesterone levels have been observed in H295R cells under mitotane treatment. Reduction of conversion rate of 11-deoxycortisol to cortisol and cortisone or corticosterone to aldosterone has been shown in human cohort studies. Gene expression analyses in H295R studies showed suppression of the activity of many steroidogenic enzymes, including HSD3β1,

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HSD3β2, CYP21A2, CYP11A1, CYP17A, StAR, CYP11A1, and CYP11B2 (Waszut et al. 2017). Apart from DDT, other organochlorines have shown endocrine-disrupting properties. A recent study highlighted higher concentration of several pesticides, including α-, β-, and γ-hexachlorocyclohexane, hexachlorobenzene and PCBs 28, 52, and 101 in tumor tissues of aldosterone-producing adenomas when compared to normal adrenal tissues (Fommei et al. 2017). This was the first study showing the potential relevance of pollutants in specific adrenal diseases, like primary aldosteronism, paving the way to further studies.

Herbicides This type of pesticides gathers many chemicals that also belong to insecticides. The effects of organophosphates on adrenal gland have been discussed in the Flame retardants paragraph. Glyphosate, an old organophosphate herbicide sold under the name “Roundup,” is among the most used herbicides worldwide for several decades. This compound is currently approved in the EC until December 2022 (https://ec. europa.eu/food/plant/pesticides/glyphosate_en). In December 2019, a group of companies, the Glyphosate Renewal Group, started the process of renewal of approval for use of glyphosate to the European Assessment Group on Glyphosate. Glyphosate has been shown to disrupt StAR mRNA expression, leading to inhibition of steroidogenesis in vitro. Animal studies confirmed the inhibition of the HPA axis upon exposure to glyphosate, through reduction of cAMP/PKA pathway downregulation reduced StAR phosphorylation and synthesis of corticosterone (Pandey and Rudraiah 2015), leading to concerns about the potential induction of adrenal insufficiency in humans. Atrazine, propazine, and simazine are herbicides derived from triazine, a compound similar to benzene, with three nitrogen-substituting carbons. All those compounds are currently banned in the EC (https://ec.europa.eu/food/plant/pesticides/ eu-pesticides-database/public/?event¼activesubstance.detail&language¼EN& selectedID¼972). Exposure to atrazine has been associated with a higher risk of prostate cancer, menstrual irregularities, and fetal growth retardation in humans. Conversely, the link between atrazine and risk of breast cancer has not been identified to date. In studies on animal models investigating the effects on the endocrine system, atrazine was linked to disrupted pulsatility of LH, increased expression of StAR, CYP11A1, 3β-HSD, and CYP19 in ovarian tissue. On HPA axis, exposure to atrazine and its derivative desisopropylatrazine has been associated with increased secretion of ACTH, corticosterone, and progesterone at the same extent as hormonal levels after a stressful event (Fraites et al. 2009). Similar effects on the HPA axis were obtained after exposure to paraquat, a methyl viologen largely used in the past in several countries as nonselective herbicide. After recognition of its toxic properties, which have been linked to neurological disorders, paraquat has been banned in the EC, in 2007 (https://ec.europa.eu/food/plant/pesticides/eupesticides-database/public/?event¼activesubstance.detail&language¼EN& selectedID¼1669), and is under restricted use in the United States. In animal models, paraquat exposure has been linked to activation of the HPA axis centrally, through

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upregulation of AVP and CRH, and increased oxidative stress and reactive oxygen species generation. Therefore, the exposure to several herbicides seems to lead to a central activation of the HPA axis as one of the main mechanisms of action (Yadawa et al. 2019).

Fungicides The fungicide class has always received consideration as endocrine disruptor because imidazole and derivatives belong to this group. Imidazole is part of a well-known class of steroidogenic disruptors that inhibits several CYP450 enzymes. Due to their specific properties on steroidogenic enzymes, some imidazole derivatives are being used as cortisol-lowering medications. Etomidate is an ultra-short-acting imidazole-derived hypnotic intravenous anesthetic. Studies on etomidate as an adrenal gland disruptor increased during the last 30 years, after the first evidence of a decreased survival in intensive care unit patients treated with etomidate, compared to patients treated with benzodiazepines. Subsequent studies showed that etomidate was able to induce a dose-dependent inhibition of the enzyme 11β-hydroxylase, the enzyme that converts 11-deoxycortisol to cortisol. Indeed, patients treated with etomidate had an increase in ACTH, 11-deoxycortisol and 17-hydroxyprogesterone associated with reduced cortisol and aldosterone levels, resulting in a transient inhibition of adrenal steroidogenesis. Due to the specific target of actions, etomidate has been proposed as a potential treatment of hypercortisolism and is being studied as a label for molecular imaging in primary aldosteronism (Harvey 2016). Ketoconazole is an antifungal drug used for skin mycotic infections. Oral administration is reserved for selected cases. During the last years, concerns on potential side effects of ketoconazole, mainly hepatotoxicity, by European and US regulatory agencies have strongly limited the utilization of this drug. The disrupting effects of ketoconazole on steroidogenesis are known since the 1980s, after reports of gynecomastia in men under treatment. As shown in several subsequent in vitro and in vivo studies, ketoconazole has deleterious effects on different steps of adrenal steroidogenesis by inhibiting CYP11A1, CYP11B1, CYP17, and CYP21 (Harvey 2016). Due to the specific mode of action, ketoconazole has been proposed and is still being used as an alternative treatment for management of hypercortisolism in Cushing syndrome (Harvey 2016). Other imidazole derivatives like prochloraz and imazalil, used in the EU but not approved in the United States, are used mostly in agriculture. Imazalil and prochloraz are known powerful inhibitors of aromatase expression, according to in vitro studies. Non-imidazole fungicide like fenarimol or vinclozolin, belonging to different chemical classes, has been the subject of several studies on fungicide noxious properties: fenarimol reduces CYP19 activity, while vinclozolin induces CYP19 mRNA expression. Even though several in vitro studies showed that those compounds had the capability of inhibiting CYP19 mRNA expression, no targeted studies have been performed to investigate the effects of fenarimol on adrenal gland (Sanderson et al. 2002).

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Air Particulate Matter Pollution Particulate matter (PM), or atmospheric aerosol particles with diameter less than or equal to 10 μm, is a combination of microscopic liquid or solid matter in the air, made by pollen, house and heavy dust, microorganisms, smog, tobacco smoke, metals, and other contaminants. It is classified by the diameter of its compounds: less than or equal to 2.5 μm, it is called PM2.5; greater than 2.5 μm but less than or equal to 10 μm, it is called PM10. PM is a well-known noxious and carcinogenic agent to humans, listed among group 1 carcinogens by the World Health Organization. Several studies on the endocrine-disrupting potential of PM have been carried out during the last 10 years, a very little time considering the awareness of its harmful actions and the global attention given to EDCs. Very recently, a few studies have shown that acute exposure to PM2.5 may have deleterious effects on the human HPA axis. Data from a longitudinal study and a randomized-controlled trial have consistently shown an increase in CRH, ACTH, and cortisol in the context of hyperactivation of the HPA axis (Niu et al. 2018; Li et al. 2017). Among carbonaceous and elemental compound, NO3 was found to have a higher association with CRH increase. Interestingly, overactivation of the HPA axis after PM2.5 exposure was linked to increased blood pressure and markers of oxidative stress and inflammation (Niu et al. 2018).

Other Compounds Several compounds and molecules naturally present in the environment and human diet are capable of disrupting the endocrine system, including the adrenocortical function or the entire HPA axis.

Licorice Licorice is a root used as food, spice, and medicinal for over 2500 years. It is widely distributed and used all over the world and is easy to find in any grocery store. Licorice has been used for the treatment of Addison’s disease before the discovery of fludrocortisone because of the ability to raise blood pressure. That characteristic is derived from a specific compound, the glycyrrhizic acid, which can raise blood pressure in two ways. The first is the block of 11HSD2, the enzyme-converting active cortisol to inactive cortisone, making cortisol available for mineralocorticoid receptor activation. Additionally, glycyrrhizic acid may act as a mineralocorticoid receptor agonist. From a clinical perspective, excessive licorice consumption leads to a reversible form of apparent mineralocorticoid excess syndrome, characterized by hypertension, hypokalemia, and a biochemical picture of pseudohyperaldosteronism (Sabbadin et al. 2019). Cadmium Cadmium is an elemental compound widely distributed in nature. It can be found also in iron and steel industries as a component of tobacco smoke and as a contaminant in soil. Therefore, human contact is frequent in several ways, including

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food and beverages, and breathing. Several studies evaluated the noxious properties of cadmium, including damage to the kidney, a preferential site of cadmium storage, lung and prostate cancer, and altered testosterone excretion. Recent studies in humans have identified a positive association between cadmium and urinary excretion of cortisol and mineralocorticoids in both sexes, while urinary testosterone was positively associated to cadmium only in men (Bochud et al. 2018).

Arsenic Arsenic is commonly found in the environment. The human contact is frequent through food and water ingestion, and air pollution. The toxic effects of arsenic are well-known, leading to a wide spectrum of diseases, ranging from cardiovascular to immunological disorders and cancer. Arsenic has also been recognized as an endocrine disruptor. Arsenic exposure may lead to alteration of the HPA axis through different mechanisms. One of the main mechanisms is related to the impairment of the intracellular signaling upon glucocorticoid receptor activation due to the formation of stable complexes with several downstream proteins (Sun et al. 2016). Additionally, arsenic has shown interfering actions on the HPA axis via altered stability of the glucocorticoid receptor–DNA-binding domains and DNA damage induced by oxidative stress. Additionally, studies in animal models have shown that perinatal exposure to arsenic derivatives, like sodium arsenate, has been associated with increased basal CRH and corticosterone, but lower stress-induced glucocorticoid secretion. Moreover, a decreased hippocampal 11β-HSD1 expression and altered hypothalamic distribution of glucocorticoid receptor have been identified in exposed animals (Goggin et al. 2012).

Conclusion The entangled net of interactions of the components of the HPA axis under different stimuli is still a subject of active investigation. Such a complex system plays a key role in the maintenance of homeostasis in acute and chronic stressful conditions. Disruption of the homeostatic processes regulated by the HPA axis may lead to chronic and severe diseases, leading to reduced life expectancy and impaired quality of life. In this context, several noxious stimuli have been identified as potential disruptors of the HPA axis, deriving from environmental compounds and human-derived chemicals. Considering that the specific properties of most of those compounds (lipophilicity, potential of bioaccumulation and bioamplification), on the one side, and the particular characteristics of the adrenal gland facilitating the chemical insult, it is clear that EDCs should be considered an emerging problem of high relevance for human health. Until now, the scientific community is still at the beginning of the discovery of the impact of the environmental disruptors on the adrenal gland, and their potential causative role in chronic diseases, mainly altered glucose metabolism and cardiovascular diseases, well-known consequences of HPA axis dysfunction. Therefore, targeted studies are urgently needed to understand the global impact of EDC on HPA axis.

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Environmental Impact on the Hypothalamus-Pituitary-Ovary Axis Olivera Stanojlovic´, Dragan Hrnčic´, Danijela Vojnovic´-Milutinovic´, Dušan Mladenovic´, and Nikola Šutulovic´

Contents EDCs and Development of Gonadal Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sleep Disorders, Behavioral Disturbances, and Steroids As Endocrine Disruptors Affecting Gonadal Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Direct Effects of Endocrine Disruptors on Hypothalamus and Pituitary . . . . . . . . . . . . . . . . . . . EDCs and the Effect on Ovary and Uterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects on the Ovarian Development and Postnatal Period Including Folliculogenesis and Endometrium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects of EDs on the Steroidogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EDs Actions on Puberty and Menstrual Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bisphenol A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Dysfunction of hypothalamic-pituitary-gonadal (HPG) axis can be caused by complex and multilevel interactions between altered sleep quality, behavioral O. Stanojlović (*) · D. Hrnčić · N. Šutulović Institute of Medical Physiology “Richard Burian”, Belgrade University Faculty of Medicine, Belgrade, Serbia e-mail: [email protected]; [email protected]; [email protected] D. Vojnović-Milutinović Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia e-mail: [email protected] D. Mladenović Institute of Pathophysiology “Ljubodrag Buba Mihailovic”, Belgrade University Faculty of Medicine, Belgrade, Serbia e-mail: [email protected] © Springer Nature Switzerland AG 2023 R. Pivonello, E. Diamanti-Kandarakis (eds.), Environmental Endocrinology and Endocrine Disruptors, Endocrinology, https://doi.org/10.1007/978-3-030-39044-0_5

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disturbances, and chemicals that interfere with normal functioning of the endocrine system, known as endocrine disruptors (EDs). Sleep deprivation disrupts circadian rhythm and via modulation of melatonin secretion and hypothalamic neural outputs inhibits gonadotropin-releasing hormone (GnRH) secretion and reduces the levels of gonadotropins and androgens. Although many evidence suggest that EDs may affect the function of HPG axis, the precise actions on EDs on reproductive health are still controversial. More studies have been performed in female than in male animals. Major mechanisms of deleterious action of EDs on HPG axis include stimulation or inhibition of nuclear hormone receptors via direct binding, alterations of steroid biosynthesis and degradation, and changes in neurotransmitter release and effects. Some EDs may also cause the apoptosis of GnRH neurons or induce epigenetic changes that can be transmitted to the offspring. In ovaries, EDs may inhibit key steroidogenic enzymes and estrogen synthesis or directly injure granulosa or theca cells. They can also have high affinity for estrogen, androgen, progesterone, or glucocorticoid receptors, and to stimulate or inhibit different signaling pathways in the cell. All of these changes may impair oocyte maturation, increase the frequency of anovulatory cycles, and ultimately lead to disturbed puberty onset, reduced female fecundity, and premature ovarian failure. This chapter summarizes the current knowledge on the effects of sleep disturbances and major EDs on reproductive function from prenatal to adult period. Keywords

Hypothalamic-pituitary-gonadal axis · Endocrine disruptors · Sleep disturbances · Steroidogenic enzymes · Puberty onset

EDCs and Development of Gonadal Axis Sleep Disorders, Behavioral Disturbances, and Steroids As Endocrine Disruptors Affecting Gonadal Axis The definition of disruptor in the wider biological context could be analyzed through the complex network of sleep quality, behavioral disturbances, and gonadal hormones. This enigma remains unclear from ancient times until now. The definition of hysteria (Greek “υστερία”) was first mentioned by Hippocrates (fourth century BC) explaining the disease in the hysterical girl’s marriage and pregnancy. More lately, the phenomenon of hysteria was described in the nineteenth century as a wide range of symptoms, like weakness, nervousness, excessive sexual desire, decreased libido, and obligatory insomnia. At the beginning of the twentieth century, Sigmund Freud closed the loop by discovering a close relationship between behavior and sexual dysfunctions (neurotic reactions) and sleeping disturbance (Holka-Pokorska et al. 2014). The homeostatic process of sleep considers dynamic and regulated set of physiological and behavioral states leading toward absence of consciousness, increased waking threshold, arousability, reduction of muscle tone, and other symptoms.

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Regulatory inputs, arising from the interaction between circadian processes and limbic and cognitive variables, modulate sleep duration and wakefulness. These regulatory actions include interactions between neural circuits of the hypothalamic circadian, the mesopontine ultradian (REM-NREM oscillators), and GABAergic neurons in the preoptic-anterior hypothalamic region. Therefore, sleep could be disrupted by the change of different endocrine somnogens and other substances including prostaglandin D, adenosine, cytokines, growth factors, DSIP, and others (Stanojlović et al. 2005). Sleep begins in non–rapid eye movement (NREM) and progresses through deeper NREM stages followed by later episodes of REM sleep. The circadian element of sleep has major influence on sleep state and is located in the suprachiasmatic nucleus (SCN) forming a key sleep pacemaker. These intrinsic circadian rhythms together with exogenous ones can be resynchronized by external disruptors including light, exercise, social cues of eating frequency, and by endogenous or endocrine ones, including rhythmic secretion of pineal melatonin during the dark (Waterhouse et al. 2012).

Homeostatic Role for the Hypothalamus–Pituitary–Gonadal Axis Pituitary-gonadal axis is an important part of the human endocrine system, and it is crucially involved in the regulation of metabolism, body composition, growth, reproduction, immunity, and psychological well-being, all controlled via negative feedback loops. Estrogens, androgens, and luteinizing hormone have protective cognitive function, and they modulate learning and memory and induce neuronal plasticity (Lee et al. 2019). Sleep Disorders As a Disruptor of the Secretory Activity of HPG Axis Complex feedback loops between sleep and sleep loss and their influence on the secretory activity of the pituitary-gonadal axes, and all hormones in both sexes also profoundly affect the quality of sleep. Mammalian reproductive system is driven by pulsatile release of small population GnRH hypothalamic neurons, which receive, as potent activator, kisspeptin neuron input, suggesting critical role for both the electrophysiological and reproductive activity. On the other hand, photoperiodic changes in kisspeptin levels were related to changes in the pattern of melatonin secretion and affect children’s sexual maturation together with puberty onset. Pineal gland and melatonin exert a neuroendocrine control of sleep, reproductive physiology, and human sexual maturation (Waterhouse et al. 2012; Parry et al. 2011). Melatonin has direct inhibitory function on the reproductive hypothalamic GnRH/ LH pulsatile secretion in humans leading toward amenorrhea in athletes, dysregulation of puberty, and even anorexia nervosa. It must be highlighted that melatonin plays an important role in seasonal fluctuations in the human reproductive function and in the fertilization and pregnancy rates, in the quality of the embryo and the number and quality of the oocyte or the spermatozoon, and more (Karatsoreos et al. 2011). First of all, transmission and processing of sensory information through sexually dimorphic neural networks are likely to be distinct in males and females. Sex differences and gonadal steroids influence sleep via androgen receptors in the master “circadian clock,” modulate photic activity, and thus suggest a link between

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reproductive endocrine and sleep pathologies. Both photic input from the environment and androgens as well as internal signals from the body reach the same population of circadian timing system and can alter the processing of photic cues by the SCN. Androgens affect both sleep duration and the quality of sleep (Liu et al. 2003). Complex feedback loops between sleep and sleep loss profoundly affect the secretory activity of the pituitary-gonadal axes and erectile tissue. Sleep deprivation (SD) presented as total or partial sleep loss, disrupted circadian rhythm, and accompanying abnormal hormonal secretion inhibits GnRH secretion, reduces the levels of LH, and subsequently decreases the levels of androgens. Restriction of sleep to 5 hours a night decreased testosterone level by 10–15%. Together with hormones disturbance, SD-induced changes of leptin and ghrelin concentrations, as well as aggravation of insulin resistance and obesity with consequent increase in type 2 diabetes, and changes in other metabolic pathways. Sleep fragmentation revealed by wake index may influence the preoptic area, which consequently leads to higher activity of gonadotropic cells and increase of GnRH (Mohammadi et al. 2019). Clinical studies have shown changes in sleep architecture, reduction of the total amount of sleep (both REM and NREM sleep duration) together with increased frequency of awakenings in men with aging, and at the same time decline in androgen levels (late onset hypogonadism) (Lee et al. 2019; Liu et al. 2003). Testosterone level is the most important endocrine marker related to sexual functioning, and it is positively related to sleep quality/sleep disorders. The rhythm of testosterone secretion is regulated by the SCN, acting directly via its receptor in the SCN. On the other side, sleep may modulate the pattern of gonadotropin secretion. Circulating levels of testosterone concentration are increased during the first period of REM, with the highest concentration observed at the beginning of the third period of REM sleep and a maximum around the time of awakening in the early-morning hours, and decrease to the lowest concentrations in the evening (Boafo et al. 2019). Insomnia as a sex-dimorphic feature is distinguished by short sleep duration, difficulties in initiating and maintaining sleep, or awakening early in the morning. The time of sleep onset is earlier in women from childhood to menopause by comparison with men, and this difference disappears after menopause. Insomnia like female-biased sleep disorder activates both sympathetic system and hypothalamus–pituitary–adrenal axis and elevates the risk of hypertension, diabetes, neurocognitive impairment, and mortality (Holka-Pokorska et al. 2014). Hormonal fluctuations resulting from the menstrual cycle and menopausal status, together with hormone therapy studies, indicate direct relationship between sex steroids and sleep quality. Estradiol may be acting to reduce VLPO neuronal activity and resulting in increasing arousal, facilitated courting behavior, and shortening periods in REM and NREM sleep (Hadjimarkou et al. 2008). Premenstrual syndrome several days prior to menses, together with premenstrual dysphoric disorder (experience of anger, irritability, and other mood symptoms), has been associated with sleep disturbance with awake after sleep onset and frequent night time awakenings in young healthy women. These sleep-related problems decreased alertness and produced poor performance at work. Secondary insomnia with difficulties in

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falling asleep, poor sleep efficiency at the onset of menstrual phase, especially affects stage 2 and REM sleep in women. The hormonal status in the luteal phase of the menstrual cycle reduces melatonin secretion, and this can explain sleep disturbances in premenstrual syndrome (Parry et al. 2011; Jehan et al. 2016).

Direct Effects of Endocrine Disruptors on Hypothalamus and Pituitary Hypothalamic neurons regulate the anterior pituitary gland via releasing/inhibiting hormones synthesized in these neurons, packaged into secretory vesicles, and released directly into the portal capillary system, i.e., corticotropin-releasing hormone (CRH); gonadotropin-releasing hormone (GnRH); growth hormone-releasing hormone (GHRH) and somatostatin; thyrotropin-releasing hormone (TRH); and dopamine (prolactin-inhibiting hormone). The pituitary in turn releases its corresponding hormones, i.e., LH and FSH in gonadal axis. Thus, effects of endocrine disruptors (EDs) on hypothalamus and pituitary are of pivotal significance, having in mind the wide variety of consecutive repercussions in different endocrine axis and target organs. Unsurprisingly, a trend of increased interest in EDs action related to hypothalamus and pituitary could be noted in recent literature, and newly discovered EDs are constantly added to the list, like triazophos. In the last decade, approach to these issues comprised in vitro and in vivo studies in different animal strains, as well as studies in human population (Yilmaz et al. 2019). Regardless of the class of EDs, their mechanisms of deleterious action could be related, but not limited, to a) stimulation or inhibition of nuclear hormone receptors via direct binding; b) alterations of steroid biosynthesis due to modulation of enzyme activities; c) changes in neurotransmitter release and effects; and d) alterations of hormone degradation. As summarized by Rattan et al. (2017), in the hypothalamus of female rodents, pesticides increase GnRH mRNA level, while polychlorinated biphenyls decrease GnRH levels and increase GnRH cell apoptosis. In pituitary, pesticides decrease LH release, suppress LH frequency, and increase FSH release, while diethylstilbestrol suppresses LH and FSH levels and decreases pituitary gland cavity. Recently, in addition to these mechanisms, Sena et al. (2017) have demonstrated involvement of kisspeptin/leptin signaling in mechanisms of tributyltin, a xenobiotic used as a biocide in antifouling paints, in female rats. According to this study, tributyltin led to increased irregular estrous cycles, and decreased LH levels, GnRH expression, and Kiss responsiveness, while a strong negative correlation was also observed between the serum and ovary levels with lower Kiss responsiveness and GnRH mRNA expression. On the other hand, organochlorine pesticides could act via binding to the aryl hydrocarbon receptor (AhR). This provokes the expression of CYP1 genes which consecutively metabolizes estradiol to hydroxylated derivatives. We have demonstrated that the brain effects of pesticides like lindane (gammahexachlorocyclohexane) could be mediated by nitric oxide-mediated signaling, increased oxidative stress, as well as increased acetylcholinesterase activity (Vucević et al. 2009).

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As for other EDs and their early developmental actions, exposure windows with highest propensity of deleterious effects in adulthood could be also identified for lindane exposure, i.e., early postnatal lindane exposure-affected neuronal networks in adult rats (Stanojlović et al. 2013). Also, Fernandez et al. (2018) have recently reported that neonatal exposure (from postnatal day 1 to 10) to bisphenol A (BPA) alters hypothalamic pituitary-thyroid axis in adult female rats in estrus, possibly with effects on the pituitary and thyroid in both in vivo and in vitro. Additionally, Kandaraki et al. (2011) reported elevated serum levels of bisphenol A in women with polycystic ovary syndrome (PCOS). Increasing number of reports documented that perinatal exposure to EDs is intensely harmful for higher brain functions, having in mind that they induce longlasting changes in sex hormone receptors function, neurotransmitter signaling, and related behaviors. Effects of EDs on brain sexual differentiation are revealed as alterations in reproductive development and may be harmful to fertility. It should be underlined that brain structures of developing fetus and neonates are the most vulnerable to endocrine disruption (Yilmaz et al. 2019).

EDCs and the Effect on Ovary and Uterus Effects on the Ovarian Development and Postnatal Period Including Folliculogenesis and Endometrium Female reproductive disorders are becoming more prevalent, while the overall fertility rates in women are constantly dropping. Human epidemiological studies suggest that exposure to EDs has numerous adverse health outcomes in females. EDs are known to target the ovary and cause reproductive health problems such as reduced female fecundity, premature ovarian failure, and abnormal sex steroid hormone levels (Zama and Uzumcu 2010). Any perturbations in follicle growth can cause inadequate oocyte development, frequent appearance of anovulatory cycles, and reduction of sex hormone synthesis. In turn, this can result in reduced fecundity. The primary functions of ovaries are steroidogenesis, folliculogenesis, ovulation, and initiation and maintenance of pregnancy. Major events during folliculogenesis are formation of primordial follicles and the recruitment of a primordial follicle into the pool of growing follicles that undergo cell proliferation and cytodifferentiation into preantral and antral follicle, which either ovulates or undergoes death by atresia. The initial, preantral phase of folliculogenesis is gonadotropin-independent and is regulated by growth factors through paracrine mechanisms and local concentrations of steroid hormones. The antral phase of folliculogenesis is regulated by FSH and LH as well as by growth factors.

Bisphenol A Bisphenol A (BPA) is an endocrine-disrupting chemical frequently used in the plastic industry for the production of polycarbonate plastics (suitable for

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transparency, heat resistance, and mechanical properties) and epoxy-resins, used for can coating. BPA is also present in toys, office products, and plastic eating utensils. BPA exposure has been associated with female fertility problems, polycystic ovary syndrome, and endometriosis (Caserta et al. 2014). Several human studies have analyzed the association between urinary BPA levels and early IVF outcomes and ovarian reserve. Environmental and Reproductive Health (EARTH) Study is one of the first studies on the BPA effects on female fecundity in women undergoing fertility treatments. EARTH Study found the association between high urinary BPA and decreased primordial follicle pool, antral follicular count (AFC) and number of normally fertilized oocytes. It has been shown that BPA disturbs the estrous cycle and steroidogenesis, reduces probability of implantation and fertility, and leads to premature ovarian failure (Wang et al. 2014). In contrast, Longitudinal Investigation of Fertility and the Environmental (LIFE) Study, and Maternal-Infant Research on Environmental Chemicals (MIREC) Study, found that BPA did not affect the fertility and embryonal implantation in women. BPA exerts ovotoxic effects in animal models and women. Experimental studies have shown that BPA inhibits growth of antral follicles by disruption of steroidogenesis and by interfering with aryl hydrocarbon receptor (AHR). In vitro and in vivo studies have shown that BPA induces follicle atresia by increasing proapoptotic factor BCL2-associated X protein (Bax), decreasing the antiapoptotic factor B cell lymphoma 2 (Bcl2), and by inducing caspase-3 (Lee et al. 2013). Gestational and neonatal BPA exposure impairs proper germ cell nest breakdown, leading to formation of multioocyte follicles, which may lead to ovulatory problems. Furthermore, BPA accelerates follicle transition by enhancing recruitment and growth of primordial and primary follicles which could lead to premature reproduction senescence. Numerous studies have shown the association between BPA exposure and decreased oocyte quality. These studies provide strong evidence that BPA exposure disrupts meiosis, increases methylation errors, which induce epigenetic changes, and alters gene expression in germ cells of mice (Mlynarčíková et al. 2009). The data on BPA exposure and uterine endometrium in women are limited and contradictory. Study by Cobellis et al. (2009) suggested that elevated serum BPA may be associated with the occurrence of endometriosis. Experimental studies on adult CD-1 and ICR mice are in agreement with findings of Cobellis (2009) and reported that prenatal exposure to BPA increased expression of Hoxa10 that mediates proliferation of stromal tissue. Furthermore, female Balb-c mice exposed prenatally and neonatally to BPA developed endometrial-like structures in adipose tissue surrounding genital tract. On the other hand, Hiroi et al. (2004) have shown unexpectedly that BPA serum concentrations in women with simple hyperplasia did not differ from women without hyperplasia, while women with complex endometrial hyperplasia had significantly lower BPA serum concentrations. These observations are consistent with findings from in vitro studies that showed decreased proliferation potential of BPA-treated human endometrial stromal fibroblast (ESF). In vitro studies on human ESF have found that BPA significantly decreases cell proliferation and upregulates Hoxa10 and osteopontin which are important for endometrial receptivity in vivo. Furthermore, BPA exposure impairs proliferation in the uterus

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by decreasing expression of uterine estrogen receptor α (ER α) as found in rodent in vivo studies (Mendoza-Rodríguez et al. 2011). All aforementioned data indicates that BPA has the potency to induce PCOS either by acting at the level of hypothalamic–pituitary unit, or affecting ovarian steroid hormone production and follicle maturation. Only limited number of studies have assessed the association between BPA exposure and PCOS. Kandaraki et al. (2011) showed an association between serum BPA levels and increased testosterone, androstenedione, and insulin resistance in PCOS. High-dose BPA exposure in rodents also leads to ovarian cysts, follicle degeneration, and an accumulation of large antral follicles (Cobellis et al. 2009). The effects of BPA on human and rodent ovary and uterus have been shown in Fig. 1.

Phthalates Phthalates are widely used to give flexibility and resilience to plastics. These chemicals are found in many products, used in everyday life, including detergents, soaps, adhesives, shampoos, lotions, etc. (Rashtian et al. 2019). There are many types of phthalates, but DEHP (di(2-ethylhexyl) phthalate), DIDP (diisodecyl phthalate), and DBP (dibutyl phthalate) are most commonly used. Human studies have found that phthalate exposure is associated with fertility problems, decreased ovarian reserve, and poorer IVF outcomes (Hauser et al. 2016). Higher urinary concentrations of DEHP and its metabolite MEP (monoethyl phthalate) were associated with decreased total and mature oocyte yield during IVF, and DIDP was associated with reduced fertilization rates in women undergoing IVF treatment (Hauser et al. 2016). In humans, there is a potential concern that phthalates can accelerate follicle loss and reproductive aging. Studies in mice have shown that exposure to DEHP in vivo accelerates primordial follicle recruitment, probably through overactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, decreases the number of primary and secondary follicles, and increases the number of atretic follicles (Ryan et al. 2010). DEHP effects are probably mediated by MEHP, and it is proven that MEHP in vitro can accelerate folliculogenesis and inhibit antral follicle growth. Exposure to DBP in vitro inhibits growth of antral follicles by disrupting the cell cycle, which leads to cell cycle arrest (Rashtian et al. 2019). Phthalates can induce multigenerational or transgenerational effects. Parental exposure to phthalates can induce adverse transgenerational effects on hormones and reproduction in mice in the third filial generation (F3). DEHP exposure induces multigenerational acceleration of follicle recruitment in F1 and F2 mice while DBP exposure decreases the number of corpora lutea. Multigenerational effects are due to fetal (F1) or fetal germ cells exposure (F2) to an endocrine disruptor. The suggested mechanism that underlies DEHP transgenerational effects in females involves DNA methylation of imprinted genes in the oocytes of F1 and F2 mice, or transgenerational effects through estrogen receptor 1. In addition, epigenetic modifications can occur due to chromatin modifications or noncoding RNA interactions (Hauser et al. 2016).

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Fig. 1 Effects of gestational, postnatal, and adult BPA exposure on human and rodent ovary and uterus. In in vivo studies, gestational and postnatal BPA exposure has been found to induce ovarian structural and functional changes, impairing proper germ cell nest breakdown, leading to formation of multioocyte follicles; accelerating follicle transition by enhancing recruitment and growth of primordial and primary follicles which could lead to premature reproduction senescence; and increasing epigenetic changes in mice germ cells. Moreover, gestational and postnatal BPA exposure has been found to induce uterine structural and functional changes, by increasing the proliferation of stromal tissue of uterine endometrium and by inducing the development of endometrial-like structures in adipose tissue surrounding genital tract. Effects on ovarian and uterine functions of adult exposure of BPA have been evaluated in in vitro and in vivo studies on humans and rodents. BPA inhibits antral follicle growth and disrupts steroidogenesis, decreasing estradiol production, partially interfering with AHR pathway. Moreover, BPA induces follicle atresia by increasing proapoptotic factor Bax, by decreasing the antiapoptotic factor Bcl2, and by inducing caspase-3. Human and rodent high serum BPA levels are associated with the occurrence of endometriosis and reduced endometrial receptivity, probably as consequence of reduced human endometrial stromal fibroblast cell proliferation. Finally, in vivo studies demonstrated that high serum BPA levels are associated with increased testosterone, androstenedione, and insulin resistance in PCOS. Image created with Biorender.com.

Diethylstilbestrol (DES) Diethylstilbestrol (DES) is a powerful EDC that can act as a nonsteroidal estrogen. DES was used in the second half of twentieth century as a medication for prevention of miscarriage and/or its complications, but it was later shown that DES can induce different reproductive abnormalities even in the children of mothers to whom it was prescribed. DES was shown to adversely affect the development of female and male offspring, leading to reproductive tract carcinomas, reproductive organ malformation and dysfunction, poor pregnancy outcomes, and immune system disorders (Newbold 2004). DES significantly damages not only ovaries, but also other primary targets, for its toxicant effects are uterus, oviduct, cervix, and vagina. In utero DES exposure induces functional and structural abnormalities of the ovary. Prenatal exposure to DES accelerates follicular development and impairs response to

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gonadotropins which indicates a decreased ability to ovulate. After ovarian stimulation, DES-exposed ovaries have abnormally low number of oocytes and large number of degenerating oocytes. Morphological changes such as paraovarian cysts, hypertrophy of interstitial tissue, hemorrhagic cysts, and absence of corpora lutea are common in women prenatally exposed to DES (Tenenbaum and Forsberg 1985). In CD-1 mice, in utero DES exposure resulted in vaginal adenosis, vaginal adenocarcinoma, and uterine leiomyomas. Rats treated with DES displayed an increase in squamous metaplasia and endometrioses of the uterus. Female Wistar rats exposed in utero to DES had vaginal tumors, including adenocarcinomas, squamous cell carcinomas, and mixed carcinomas. Structural abnormalities in the female reproductive tract induced by DES can be explained by increased expression of HOXA9 and HOXA10 genes that are expressed in the developing Mullerian system. The mutation of HOX genes results in anatomical abnormalities in the female murine reproductive system (Miller et al. 2004).

Effects of EDs on the Steroidogenesis Hypothalamic–pituitary–gonadal axis is the major regulator of female reproductive system, and numerous studies have shown that EDs can alter its activity causing different reproductive disorders, including disturbed steroidogenesis in the ovaries. Effects of EDs on steroidogenesis in the ovaries could be due to direct effects on granulosa or theca cells or due to indirect effects on different steroidogenic enzymes. These alterations could lead to abnormal levels of estrogen and progesterone resulting in different infertility disorders. Many EDs have high affinity to bind to steroid receptors like estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), or glucocorticoid receptor (GR), and to thus affect different signaling pathways in the cell (Gore et al. 2015).

Bisphenol A BPA has estrogenic activity with very low affinity for the ERα and ERβ, but even in low doses it can impact reproductive well-being due to chronic exposure during the life span of humans. In recent years, a number of studies have stated that BPA has different effects on steroidogenesis in the ovary and the levels of reproductive hormones. In line with this, it has been shown that this compound may interfere with granulosa cell steroidogenic activity thus inhibiting estradiol (E2) and progesterone biosynthesis (Chen et al. 2016). Many data using different animal models and cell-lines indicate that BPA adversely affects steroidogenesis in granulosa and theca cells by downregulating mRNA expression of rate-limiting enzymes such as acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc), 3 beta-hydroxysteroid dehydrogenase isomerase type 1 (HSD3B1), and cytochrome P450 aromatase (P450arom), thus preventing cholesterol uptake into mitochondria, as well as conversion to pregnenolone and further hormone production in antral follicles (Pivonello et al. 2020) (Fig. 2). Besides this, the changes at the level of expression of steroidogenic

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Fig. 2 Effects of BPA exposure on steroidogenesis. BPA affects steroidogenesis in granulosa and theca cells by downregulating mRNA expression of rate-limiting enzymes such as acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc), 3 beta-hydroxysteroid dehydrogenase isomerase type 1 (HSD3B1), and cytochrome P450 aromatase (P450arom), thus preventing cholesterol uptake into mitochondria, as well as conversion to pregnenolone and further hormone production in antral follicles and disturbing hormone diffusion from the theca into the granulosa cells (Image created with Biorender.com).

enzymes can affect granulosa-theca cell communication through disturbed hormone diffusion from the theca into the granulosa cells. In addition to this, it was shown that long-term exposure to BPA leads to increase in apoptosis of ovarian cells due to decreased E2 levels and increased follicular atresia and luteal regression in the ovary (Pivonello et al. 2020). Human studies have confirmed positive correlation between serum BPA levels and androgen levels (testosterone, androstenedione, and DHEAS) as seen in women with PCOS (Rutkowska and Diamanti-Kandarakis 2016). This correlation stems, on the one hand, from altering expression of steroidogenic enzymes such as 17α-hydoxylase/lyase, and on the other, from displacing testosterone from sex-hormone binding globulin thus consequently contributing to elevation of free androgens in the circulation. Additionally, BPA interferes with androgen catabolism by reducing levels of enzymes required for testosterone hydroxylation leading to impaired androgen clearance. On the other hand, androgens contribute to the harmful effects of BPA by decreasing the activity of hepatic uridine diphosphateglucuronosyl transferase that is involved in BPA degradation (Takeuchi et al. 2004). Several articles have indicated that EDs also contribute to the development of PCOS, a common endocrine disorder among reproductive-aged women. Linking EDs to PCOS encouraged development of BPA-based animal models of PCOS. It was shown that exposure of rats to BPA in “environmental relevant” doses during perinatal period can induce development of PCOS-like phenotype in adulthood, which includes increased plasma testosterone and estradiol levels, decreased progesterone level, earlier vaginal opening, advanced puberty onset, irregular estrus cycle, impaired ovarian follicle development, and development of polycystic ovaries (Newbold et al. 2009).

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Phthalates It was shown that exposure to di(2-ethylhexyl)phthalate (DEHP) in rodents reduces progesterone and estrogen biosynthesis (due to decreased aromatase gene expression), disturbs estrous cycle, primordial follicle recruitment and growth, and also induces anovulation (Cho et al. 2020). Diethylstilbestrol DES is an ER agonist as it binds with high affinity to ERα and ERβ. It not only induces different reproductive disorders like endometrial hyperplasia/dysplasia, endometrial adenocarcinoma, and uterine anomalies, but it also has metabolic effects since it stimulates adipogenesis (Newbold et al. 2009). Tributyltin Additional environmental EDs, tributyltin and tributyltin chloride, were recently shown to possess a strong androgenic effect. Namely, these compounds are capable of inducing elevation of testosterone (through inhibition of aromatase activity), suppression of estrogens, irregular estrus cycle, and disturbed ovarian development characterized by the presence of more atretic follicles and cysts in treated rats. In addition, Sena et al. (2017) have shown that female rats treated with environmental pollutant tributyltin chloride had altered hypothalamic-pituitary-gonadal axis function with disturbed kisspeptin/leptin signaling. Those results pointed out that treatment with different EDCs could be used for the development of different PCOS animal models due to development of reproductive and metabolic disturbances that are compatible with those seen in human PCOS. EDs and Metabolic Changes in Reproductive Disorders We cannot exclude the possibility that many of the EDs not have only direct effect on reproductive function, by altering HPG axis, but also have indirect effects through disruption of homeostatic control and energy balance, thus inducing obesity and/or type 2 diabetes (e.g., through hyperleptinemia, hyperinsulinemia) (Rutkowska and Diamanti-Kandarakis 2016). In line with this, many studies have shown that EDs like BPA, phthalates, tributyltin, and tributyltin chloride, besides reproductive effects, may also have adverse metabolic effects. These chemicals are also known as “obesogens” due to their obesity-promoting effects. It has been previously shown that BPA, as well as bisphenol S, stimulates adipogenesis, accumulation of lipids, and adipose tissue inflammation and induces alteration of glucose and lipid metabolism. Treatment of 3TL3-L1 adipocytes and human primary preadipocytes showed that both bisphenols A and S induce increased expression of transcription factor peroxisome proliferatoractivated receptor γ (PPARγ), lipoprotein lipase, adipocyte protein 2, and perilipin, thus stimulating lipid storage and proliferation of new adipocytes. Besides this, Wang et al. (2005) have shown that bisphenol A can increase 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) mRNA level and enzyme activity contributing to the elevation of active glucocorticoids, and in this way additionally promoting

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adipocytes differentiation and adipogenesis. Furthermore, prolonged exposure to BPA resulted in metabolic disturbances such as obesity, hyperinsulinemia, insulin resistance, and hyperleptinemia in treated animals (Lin et al. 2011). In line with previous results, similar findings were obtained in the animal model of PCOS, where 5α-dihydrotestosterone treatment of female rats induced metabolic disturbances that were derived from enhanced 11βHSD1 level and glucocorticoid signaling in the visceral adipose tissue, which led to intensified lipogenesis through the induction of prolipogenic factors, SREBP-1 and FAS, and to hypertrophic adipocytes and visceral obesity (Nikolić et al. 2015). Besides their negative effect on reproductive functions, phthalates also modulate metabolic health. Phthalates function as agonists of PPARα, PPARγ, ERα, and ERβ. It has been previously shown that they stimulate lipid accumulation, adipocyte differentiation, and adipogenesis, reduce insulin secretion by downregulation of pancreatic and duodenal homeobox 1 (Pdx-1), and disturb β-cell function and glucose metabolism (Lin et al. 2011). Aside from reproductive disorders, tributyltin chloride-treated rats also develop metabolic disturbances such as increased obesity, elevated serum insulin, and leptin levels. Similar results with increased obesity, hyperinsulinemia, hyperleptinemia, and impaired cardiac insulin signaling were obtained in the animal model of PCOS obtained by 5α-dihydrotestosterone treatment (Nikolić et al. 2015). All these results pointed out that even common molecular mechanisms of the PCOS pathogenesis have not yet been determined, and we cannot exclude environmental obesogenic factors and their role in future studies on this topic. Obesogenic effects of EDs, similarly as high levels of androgens in women with PCOS and in animal models of PCOS, induce metabolic disturbances like dyslipidemia, obesity, insulin resistance, and glucose intolerance and significantly increase the predisposition toward development of cardiovascular diseases and type 2 diabetes (Nikolić et al. 2015).

EDs Actions on Puberty and Menstrual Cycle Puberty as an important transitional phase of childhood into adulthood is driven by the activation of the hypothalamic-pituitary-gonadal axis, regulated by various neuropeptides and transcriptional regulators. The major known neuropeptide that stimulates pulsatile GnRH secretion during puberty is kisspeptin, which exerts its effects via GPR54 receptors. The kisspeptin expression is positively regulated by leptin, a hormone secreted by adipose tissue. Other activators of GnRH neurons are thyroid transcription factor 1 (TTF1) and neurokinin B (NKB), while inhibitors include transcriptional regulator enhanced at puberty 1 (EAP1), Ying Yang 1 (YY1), and RFamide-related peptide-3 (RFRP3) (Ducret et al. 2009). Apart from being implicated in pathogenesis of cancerous tumors, birth defects as well as developmental disorders, among all other reproductive functions, puberty onset and progression as well as menstrual cycle regularity can be affected by endocrine disruptors.

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Bisphenol A The effects of BPA on puberty development are far from being completely understood. More studies have investigated the potential link between precocious puberty and BPA exposure in girls than in boys. In the largest series of studies performed by Wolff et al. (2015) no correlation was found between urinary BPA level and the pubertal development in girls. These studies included girls from general population age 6 to 9, and they were followed through puberty, the longest follow-up being a 7-year period. Additionally, no correlation was found between urinary BPA level and body mass index (BMI). A study by McGuinn et al. (2015) even found that moderate urinary BPA levels correlated with delayed menarche and were associated with increased BMI. However, studies that included both healthy girls and girls with diagnosed precocious puberty found equivocal results. While studies in Turkish, Thai, and Chinese population revealed higher urinary or serum concentrations of BPA in girls with idiopathic precocious puberty, studies in Korean population found no difference in BPA levels in girls with precocious and regular puberty. Even one of the most recent studies performed in Turkish population found no correlation between BPA exposition and the development of both central and peripheral precocious puberty (Buluş et al. 2016). The discrepancy between these findings can be explained by different sample sizes used in these studies, by the lack of standardization of these studies, and by methods used for BPA level determination. Interestingly, none of the aforementioned studies found any association between BPA concentration and LH, FSH, or kisspeptin level. On the other side, the recent study in Chinese school-aged girls revealed an increased risk for precocious puberty in BPA-exposed individuals that may be attributable to low FSH level (Chen et al. 2018). Less studies have been performed to analyze the effects of BPA on male puberty in humans. Deng et al. (2017) found an association between peripubertal BPA exposure and earlier pubertal onset, but delayed pubertal progression. On the other side, Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal cohort study found that BPA exposure was associated with later pubertal onset in girls and earlier puberty in boys; the time of pubertal onset could be potentially altered by obesity in both sexes (Berger et al. 2018). Among pubertal signs, thelarche, pubarche, and menarche have been followed up in girls, while gonadarche and pubarche have been followed up in boys. Animal studies have also shown contradictory results regarding the effects of BPA on pubertal onset. Exposure to BPA was found to be associated with disturbances of germ cell development in male mice, while in females postnatal BPA exposure induced early appearance of pubertal signs (Shi et al. 2017). On the other side, perinatal exposure to BPA was found to delay puberty onset in male mice, associated with impaired maturation of hypothalamic-pituitary-testis axis. In female mice, perinatal exposure to relevant environmental concentrations of BPA for humans caused more advanced vaginal opening, but delayed maturation of kisspeptin and NKB neurons in arcuate nucleus and suppressed LH secretion. In contrast to these studies, some other studies showed that BPA did not affect vaginal

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opening in gestationally, neonatally, and orally exposed Long Evans rats (Ryan et al. 2010) or in lactationally exposed rats (Yu et al. 2010). The mechanisms of BPA effect on puberty are also far from being completely understood. The most studied mechanism is related to its estrogen-like activity due to its structural similarity with 17β-estradiol. However, BPA is a weaker stimulant of estrogen receptors than 17β-estradiol; so in the presence of 17β-estradiol, it can behave as an estrogen receptor antagonist. Both agonist and antagonist actions of BPA on estrogen receptors could explain its opposite effects on pubertal onset and fertility. BPA can also modulate the activity of hypothalamic-pituitary-gonadal axis (Caserta et al. 2014). One of the possible mechanisms of BPA-induced precocious puberty found in some studies may be the stimulation of kisspeptin synthesis, as well as the suppression of EAP1 and YY1 (Mueller and Heger 2014). Epigenetic changes may contribute to alterations in these gene expressions, since BPA has been found to stimulate Dnmt3b, a DNA methylase involved in the methylation of critical puberty genes. Indirect mechanisms of BPA effects on puberty development via obesity cannot also be excluded. It has been shown that BPA exposure may be associated with obesity, earlier increase in leptin levels, which may contribute to earlier appearance of pubertal signs (Wei et al. 2011). In conclusion, the effects of BPA on puberty development are still blurred. The current trend based on many studies points to the possibility that BPA could cause earlier appearance of initial pubertal signs (due to its estrogen-like activity), but the delay of the final stages of pubertal maturation in both sexes. The mechanisms of the BPA effects on hypothalamic-pituitary-gonadal axis are also controversial. Similarly, data on the effects of BPA on menstrual cycles are inconsistent as well. All findings have been reported from decreased to increased time spent in estrus in rodents (Wei et al. 2011). Some studies did not reveal a significant impact of BPA on the length of estrus phase (Tyl et al. 2008).

Phthalates Phthalates were found to alter the synthesis of estrogens and androgens and to exert antiandrogenic effects. Di-n-butyl phthalate (DBP) has also shown strong estrogenic properties and is suggested to stimulate the secretion of kisspeptin. A central site of phthalate action has also been supposed (Buluş et al. 2016). However, findings in human population related to the effects of phthalates on puberty onset are equivocal. A study in Thai girls revealed that high urinary concentrations of phthalate metabolites were associated with precocious puberty in girls (Janesick and Blumberg 2012). Similar findings were obtained in an Iranian population, indicating that precocious puberty could be associated with higher serum di-(2-ethylhexyl)-phthalate (DEHP) concentrations. In CHAMACOS cohort, increased level of monoethyl phthalate (MEP) in mothers’ urine was found to be associated with earlier menarche in female offspring (Harley et al. 2019). A study in Turkish girls found that plasma levels of DEHP and MEHP were significantly higher in participants with central precocious puberty by comparison with peripheral precocious puberty and control girls (Buluş et al. 2016). However, FSH, LH, and estradiol levels were not different among these groups.

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Another CHAMACOS longitudinal cohort study revealed that high-molecularweight phthalate exposure, similar to BPA, contributes to early pubertal onset in boys and later pubertal onset in girls (Berger et al. 2018). Some other studies also suggest that phthalate exposure can be a risk factor for delayed puberty. Wolff et al. (2014) found in a longitudinal study involving US population that high urinary concentration of (DEHP) correlated with later development of pubic hair, while high concentration of monobutyl phthalate (MBP) was associated with later thelarche. Similarly, MEP, mono (2-ethylhexyl) phthalate (MEHP), and total phthalates were found to be significantly correlated with constitutional delay of growth and puberty in Chinese boys, associated with decreased testosterone levels (Xie et al. 2015). Interestingly, Wolff et al. (2010) showed that high molecular weight phthalates were weakly associated with delayed pubic hair development, while low molecular weight phthalates are positively related (also very weak) with pubarche and thelarche. Only one meta-analysis to our knowledge has been performed until nowadays to summarize the results of other studies related to the effects of phthalates on puberty (Wen et al. 2015). This meta-analysis included 14 studies involving 2223 subjects and concluded that DEHP and DBP concentrations either in serum or in urine were significantly higher in girls with precocious puberty by comparison with control group. Exposure to DEHP also increases the risk of precocious puberty. On the other hand, neither serum or urinary concentration of MEHP, MBP, mono(2-ethyl-5oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), monomethyl phthalate (MMP), monobenzyl phthalate (MBzP), nor MEP was associated with earlier development of pubertal signs in this meta-analysis (Wen et al. 2015). Another meta-analysis has been recently published, and it claims that increased concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and MEOHP are related to early breast development in girls (Golestanzadeh et al. 2020). However, this analysis included only 4 studies. In summary, available data suggest that phthalates could influence the timing of puberty development, especially in girls, but this effect appears not to be the same for all metabolites. DEHP is more frequently mentioned as a modulator of puberty onset.

Pesticides The studies related to the effects of pesticides on the time of pubertal onset are very limited. The most studied pesticides are organochlorine pesticides, which can cross placental barrier. A study in Menderes region in Turkey showed that exposure to 4,4dichloro-diphenyldichlorethylene (DDE) was associated with higher serum basal and stimulated LH concentration, higher FSH levels, and increased uterine and ovarian volumes in 45 girls (Ozen et al. 2012). This study suggests the positive correlation between DDE exposure and precocious puberty. On the other side, DDE level was found to be associated with decreased serum LH concentration, while dichloro-diphenyl-trichloroethane (DDT) exposure led to the decline in LH and testosterone levels in CHAMACOS boy cohort including 234 boys (Eskenazi et al. 2017). This points out the potential role of organochlorine pesticides in delaying puberty. One of the recent studies in girls from rural areas of South Kazakhstan has also shown that organochlorine pesticide exposure during childhood

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leads to delayed puberty, associated with decreased levels of gonadotropins and estradiol adjusted for age (Bapayeva et al. 2016). However, this is an observational study. High levels of pesticides are associated with increased serum level of IL-1; the role of it in delaying puberty being still not clear. Finally, exposure to organochlorine pesticides in utero was not shown to be associated with precocious or delayed puberty in Chinese girls. In order to clarify the effects of organochlorine pesticides on puberty development, more studies are required in larger populations. A recent study in Chinese girls and boys investigated the effects of pyrethroids on the time of the development of pubertal signs (Ye et al. 1987). Although pyrethroids exert estrogenic and antiandrogenic effects, higher concentrations of 3-phenoxybenzoic acid (3-PBA), a metabolite of 18 pyrethroids, were associated with later appearance of pubic hair, menarche, and thelarche. Similar findings were obtained in animal studies. Pyrethroids were found to suppress the afternoon rise of LH in female rats (Pine et al. 2008). In contrast, high concentrations of 3-BPA correlated with more advanced stage of puberty in boys, associated with higher levels of urinary gonadotropins (Ye et al. 1987). Animal studies have also shown conflicting results. While ATR and simazine exposure were found to delay vaginal opening, neonatal exposure to the acetochlor accelerated vaginal opening in rats (Bapayeva et al. 2016).

Environmental Pollutants Studies related to the effects of various pollutants on puberty onset are very limited. One group of endocrine disruptors studied are flame retardants/polybrominated diphenyl ethers (PBDE). In the CHAMACOS cohort, prenatal PBDE exposure was found to be associated with earlier pubarche in boys, and delayed menarche in girls. On the other side, pubarche and thelarche were not delayed in prenatally PBDE-exposed girls. Interestingly, postnatal PBDE exposure did not affect the development of pubertal signs in both girls and boys (Harley et al. 2017). A study in Italy found that serum PBDE concentration was significantly higher in girls with early thelarche compared with controls and girls with idiopathic precocious puberty (Deodati et al. 2016). However, this is a cross-sectional study, and the authors did not measure PBDE exposure in subjects during childhood. Few studies have also been performed in animals to determine the effects of environmental contaminants on puberty. Firemaster 550, a fire-retardant mixture, was found to accelerate vaginal opening in female rats, while exposure to polychlorinated biphenyls (PCBs) during pregnancy and lactation was found to induce precocious puberty in female offspring (Sergeyev et al. 2017). Polychlorinated biphenyls (PCBs) and dioxins were also investigated for their influence on reproductive function in humans. PCBs are highly lipophilic organochlorines, which can accumulate in adipose tissue and inhibit androgen synthesis in rats. A study in Akwesasne Mohawk males has confirmed an antiandrogenic effect of PCBs in humans and revealed the negative influence of exposure to highly consistent PCB congeners on testosterone level in adolescent boys. Similarly, PCBs and dioxin-like compounds were found to delay puberty in the longitudinal Russian Boys Study cohort (Sergeyev et al. 2017). Additionally, exposure to 2,3,7,8-

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tetrachlorodibenzodioxin (TCDD) and polychlorinated dibenzodioxins (PCDD) was also found to be associated with reduced sperm concentration, total sperm count, and total motile sperm count in adolescents (Mínguez-Alarcón et al. 2017). Parabens, compounds present in personal care products, have also been reported as endocrine disruptors. A study in Latino population found an association between urinary level of methyl paraben and earlier breast development, menarche, and pubic hair development, and an association between urinary level of propyl paraben and earlier menarche in girls. However, this association does not imply the causal relationship between paraben exposure and precocious puberty. It is possible that precocious puberty caused increased use of personal care products in girls and their increased use contributed to increased paraben exposure. Additionally, parabens are rapidly eliminated from the body, so parabene concentrations in one urinary sample does not reflect long-term exposure to parabens (Harley et al. 2019).

Estrogens Early life exposure to estrogens leads to reproductive and developmental abnormalities. Endocrine disruptors that act on the estrogen component of the endocrine system merit serious concern because estrogens have major effects on mammalian reproduction and neurological functions (Davis et al. 2011). Exposures to estrogenic endocrine disruptors during fetal developmental could interfere with normal organizational differentiation and led to long-lasting harmful effects, and delayed or latent effects in regard of disturbed endogenous hormones balance at maturity or puberty (Toppari and Skakkebaek 1998). Diethylstilbestrol (DES) as a powerful synthetic estrogen was earlier administered in high doses to pregnant women under the mistaken belief it would reduce the risk of pregnancy complications and miscarriages. DES was used in pregnant women in the first trimester (between weeks 7–8 post last menstrual cycle) to prevent progesterone-deficiency-induced miscarriages. During pregnancy, in order to prevent premature labor or to treat breakthrough bleeding, DES was also used. Subsequently, DES use during pregnancy was associated with adverse health effects in the exposed female offspring, including menstrual irregularity, infertility, and an increased frequency of cervicovaginal anatomic abnormalities in the female genital tract, which could led to pregnancy complications in DES-exposed daughters (Toppari and Skakkebaek 1998). Humans are exposed to DES via various sources, such as dietary ingestion from supplemented cattle feed and medical treatment. When estrogenic chemicals are administered to a juvenile animal, they do not cause malformations of the reproductive tract but rather delay pubertal development. The timing of sexual maturation, controlled centrally by hypothalamus via ovarian estrogen production, could be disturbed due to exogenous estrogen treatments in puberty (Golub et al. 2003). Studies of prenatal exposure to DES and menstruation are conflicting. Some studies showed increased cycle length and variability of cycle length, which would suggest endocrine disruption. Other reported menstrual changes are shorter duration of menstrual blood flow, and increased risk of dysmenorrhea in exposed women (Kaufman et al. 2000).

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Androgens The concept that the sex steroid milieu of the brain during gestation and shortly after birth can permanently influence the reproductive cycles and sexual behavior originates from experimental studies (Cohen-Bendahan and Berenbaum 2005). Androgen administration to females during developmental periods masculinizes the brain and induces anovulatory infertility and loss of sexual responsivity to males. Later administration also brings masculinized sexual behavior and abnormal childhood playmate preferences and abnormal types of activities and objects chosen for play. This is also confirmed in studies of males with complete androgen insensitivity, who exhibit female-type behavior in regard to interests, gender identity, and sexual orientation (Hines et al. 2003). Excess androgen exposure in females during fetal development leads to hyperandrogenemia later in life, with consequently irregular or absent menstrual cycles, elevated LH levels, and polycystic ovaries in adult period. In adult women, the role of androgens is not completely clear. Androgens are important in female sexuality, behavior, and body composition. It has been shown that obese girls are often hyperandrogenemic even in early puberty, and the hyperandrogenemia is associated with a rapid progression from pubertal to adult LH secretory patterns. Elevation in LH secretion and irregular menstrual cycle is also found in girls with hyperandrogenemia from other causes, for example, in congenital adrenal hyperplasia (CAH) (Holmes-Walker et al. 1995).

Conclusion An example of endocrine disruption in the wider biological context could be represented through the complex network of sleep quality, behavioral disturbances, and gonadal hormones. Testosterone represents the most important endocrine marker related to sexual functioning and is positively related to sleep disorders, although sleep changes per se affect episodic secretion of gonadotropin hormones. Moreover, even decreased testosterone levels in women are associated with deterioration of sleep and together with consequent decrease in estradiol; thus, lacking inhibition of sleep-promoting neurons is contributing to the state of insomnia. Additionally, the effect of testosterone on obstructive sleep apnea in men confirms the direct relationship between sex steroids and sleep quality, besides clear metabolic consequences mirrored through erectile dysfunction and disturbed ejaculation or libido that are all caused by nocturnal hypoxia and blunted LH levels. In women, hormonal fluctuations during menstrual cycle or continuously in the menopausal period, together with clinical studies analyzing the effects of hormone replacement therapies, indicate direct relationship between sex steroids and sleep quality. As mentioned previously, estradiol may reduce VLPO neuronal activity with consequent shortening periods in REM and NREM sleep. Additionally, decreased melatonin secretion caused by hormonal fluctuations during the luteal phase of the menstrual cycle could explain the sleep complaints as well.

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Modern society is influenced by the number of diverse EDs. Today we are assuming the influence of different combinations of endocrine disruptors on endocrine system. A good example for the deterioration of natural development under the effect of EDs is timing of puberty. Puberty as the most sensitive periods of gonadal development in both sexes is assumed to be affected by different EDs including BPA and phthalates. Moreover, it has been shown that negative effects of EDs induce epigenetic transgenerational inheritance of obesity and reproductive diseases leading toward decline in fertility, disrupted pubertal development, and polycystic ovaries. On the opposite side of the well-recognized animal studies and explanations of the effects of various EDs on the development and function of gonadal axis, we are still lacking translational knowledge into human population and placebo-controlled clinical studies that are limited due to the obvious ethical issues.

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Environmental Impact on Female Fertility and Pregnancy Anastasia-Konstantina Sakali, Alexandra Bargiota, Maria Papagianni, Aleksandra Rasic-Markovic, and George Mastorakos

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Environmental Factors and Impairment of Female Fertility (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . Impairment of Nonassisted Female Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impairment of Assisted Female Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effect of Environmental Factors on Hypothalamic-Pituitary-Ovarian (HPO) Axis Resulting into Negative Pregnancy Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ectopic Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pregnancy Losses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gestational Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypertensive Disorders of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preterm Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intrauterine Growth Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Small for Gestational Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Large for Gestational Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Birth Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transgenerational Epigenetic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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A.-K. Sakali · A. Bargiota Department of Endocrinology and Metabolic Diseases, Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece M. Papagianni 3rd Department of Pediatrics, Aristotle University of Thessaloniki, School of Medicine, “Hippokrateion” General Hospital of Thessaloniki, Thessaloniki, Greece A. Rasic-Markovic Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia G. Mastorakos (*) Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieion Hospital, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece © Springer Nature Switzerland AG 2023 R. Pivonello, E. Diamanti-Kandarakis (eds.), Environmental Endocrinology and Endocrine Disruptors, Endocrinology, https://doi.org/10.1007/978-3-030-39044-0_6

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Abstract

Over the recent years, female fertility problems and number of pregnancies resulting into negative outcomes have been on the rise becoming a matter of particular concern among women of childbearing age. The rise in the above adverse reproductive health outcomes could be partly attributed to the exposure to hazardous factors ubiquitously found in the environment. To investigate this hypothesis, in this chapter, we summarize the current evidence on the impact of environmental factors and endocrine disruptors (EDs) on female fertility (either nonassisted or assisted) and on pregnancy outcomes (ectopic pregnancy, pregnancy losses, gestational diabetes, hypertensive disorders of pregnancy, preterm birth, intrauterine growth restriction, small and large for gestational age, and birth defects). Because it has been established that environmental factors and EDs are capable to induce epigenetic alterations, special care has been given to the exploration of their transgenerational effects on female fertility and pregnancy outcomes. Keywords

Environmental factors · Endocrine disruptors · Female fertility · Pregnancy outcomes · Reproduction · In vitro fertilization

Introduction Environmental factors are external factors, modifiable or not, which greatly affect humans either in a positive way, by promoting health and quality of life, or in a negative way, by being hazardous and by impeding personal and social activities. In general, environmental factors “make up the physical, social and attitudinal environment in which people live and conduct their lives” (WHO/ICF 2001). They include climate, temperature, seasonality, photoperiod, water salinity, radiations, air, water and soil pollutants, nutrition (overfeeding or starvation), social environment (resources, community connections, racial aggregation, and access to health care facilities), working environment, toxic substances (tobacco, alcohol, and drugs), and endocrine disruptors (EDs) (Table 1). Over the last decades, there has been mounting scientific evidence that thousands of chemicals detected in the environment possess endocrine-disrupting properties. The definition of an ED by the World Health Organization is “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations” (WHO/IPCS 2002). Beyond known EDs, there are thousands which have never been tested, but suspected to act in a similar way. Chemicals carrying the potential of disrupting the endocrine system are called potential EDs and are defined as “an exogenous substance or mixture that possesses properties that might be expected to lead to endocrine disruption in an intact organism, or its progeny, or (sub) populations” (WHO/IPCS 2002). Each ED, either independently or as part of a

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Table 1 Environmental factors and endocrine disruptors reviewed Environmental factors Climate, temperature, and seasonality Radiation Air pollution Nutrition and energy balance Race and social environment Working environment Habits (tobacco, alcohol, and drugs)

Endocrine disruptors Plasticizers (BPA and phthalates) Heavy metals (Pb, Cd, Hg, and As) Parabens Pesticides Industrial chemicals and by-products (PCBs, brominated flame retardants, and dioxins) Medications (DES) Perfluorochemicals Antibacterial agents (Triclosan)

mixture, can interfere with hormonal signaling pathways (including those involved with female fertility and pregnancy). These substances exert their disrupting action mainly by binding to hormone or other receptors in an agonistic or antagonistic fashion (stimulating or inhibiting, respectively, their function), by interfering with enzymatic pathways, by creating oxidative stress, and/or by inducing epigenetic transgenerational changes in the expression of many genes. Some of the most studied and recognizable ED categories are summarized in Table 1. Female fertility is the capacity of a reproductively mature woman to establish clinical pregnancy. Infertility of a couple is defined as failure to conceive after 1 year of unprotected sexual intercourse. Around 20–30% cases of female infertility cannot be attributed to well-recognized factors (ovulation disorders, endometriosis, and fallopian tube disorders). In such cases, infertility is considered unexplained. Cumulative evidence over the recent years suggests that a large percentage of unexplained fertility cases may be attributed to the endocrine-disrupting action of environmental chemicals. A healthy pregnancy begins with implantation of an embryo in a woman’s uterus and ends with a delivery, after 37 gestational weeks, of a live born baby not small for gestational age (SGA), without any significant pregnancy complications (Chappell et al. 2013) In this chapter, we are reviewing critically the influence of environmental factors (including EDs) on female fertility and pregnancy. A graphical summary of the effects of bisphenol A (BPA), one of the most investigated and representative reproductive toxicants, on female fertility and pregnancy outcomes is depicted in Figs. 1 and 2. Figures created with BioRender.com.

Environmental Factors and Impairment of Female Fertility (Table 2) Impairment of Nonassisted Female Fertility Most experimental and epidemiological studies examine the overall effect of environmental factors upon nonassisted female fertility. Regarding the effect of seasonality, in a metanalysis of 22 human studies, researchers observed that increased

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Fig. 1 Graphical summary of the effects of bisphenol A (BPA) demonstrated in experimental models. In in vitro cultured mouse ovarian follicles, BPA treatment induced disruption of folliculogenesis, aberrant expression of steroidogenesis enzymes, dysegulation of cell cycle, proliferation and apoptosis, decreased polar body extrusion rate, abnormalities of meiotic spindle, and increased oxidative stress and double-strand DNA breaks and histone modifications. In utero and early postnatal BPA exposure in in vivo animal models induced oocyte apoptosis, multi-oocyte follicles formation, disruption of folliculogenesis, aberrant follicle-type distribution, proliferative fallopian tubes lesions, persistence of Wolffian duct structures in later life, delayed embryos development and transport to the uterus, and reduced uterus receptivity and implantation

temperature at the time of birth either facilitated or disturbed fertility potential later in life depending on the geographic location (Boland et al. 2020). The combination of humidity (rainfall levels) and high altitude at the time of birth promotes female fertility later in life. Regarding the effect of radiation, in a case-control study conducted in Northern Iran, residential proximity of less than 500 meters from high voltage (240–400 kV) electromagnetic fields resulted in fourfold increased risk for unexplained infertility compared to residing more than 1000 meters away after controlling for various confounders (age, occupation, level of education, age at marriage, and living in rural or urban area) (Esmailzadeh et al. 2019). Regarding the effect of various air pollutants, in a systematic review including 11 human studies, the authors concluded that, in spontaneous pregnancies, sulfur dioxide concentrations were negatively associated with conception rate following the first attempt. In addition, residential proximity to major roads, suggesting exposure to increased levels of traffic pollutants, was associated negatively with nonassisted fertility (Conforti et al. 2018). Female obesity has also been related to infertility. More specifically, among ovulatory subfertile women, every 1 unit increase in body

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Fig. 2 Graphical summary of the effects of bisphenol A (BPA) on human female fertility and pregnancy outcomes. Exposure to BPA has been associated to reduced number of metaphase II oocytes, number of retrieved oocytes, peak estradiol concentrations (all with urinary BPA levels) and oocyte fertilization (serum BPA levels), and increased risk of implantation failure (urinary BPA levels) and recurrent early miscarriage (serum BPA levels), in women treated with assisted reproductive technology (ART). Concerning pregnancy outcomes, exposure to BPA has been associated to increased infertility, risk of recurrent early miscarriage, preeclampsia, and preterm birth (female offspring), to reduced (early pregnancy exposure) or increased (late pregnancy exposure) birth weight of female offspring, and to increased gestational length, and risk of chromosomal anomalies and neural tube defects

mass index (BMI) exceeding 29 kg/m2 resulted in a 5% decrease in the probability of spontaneous conception. In the same work, excessive exercise was also found to increase infertility risk regardless of the body adiposity index. On the other hand, weight loss and moderate exercise were found to improve fertility among obese women. Regarding the effect of diet, increased consumption of trans-fatty acids instead of mono- or poly- unsaturated fatty acids (PUFA) is related to ovulatory infertility, probably by increasing insulin resistance and inflammation. Moreover, increased consumption of n-6 over n-3 PUFAs has been associated negatively with female fertility eventually by disrupting ovarian steroidogenesis and prostaglandin production. Increased consumption of animal protein has been associated with increased risk for ovulatory infertility, while consumption of plant-derived protein carried a protective effect. The phenomenon was attributed to improvement of insulin sensitivity (Fontana and Torre 2016). Finally, increased consumption of heat-processed food of animal origin results in increased production and intraovarian deposition of advanced glycation end products (AGEs). The latter lead to increased oxidative stress, disrupt intracellular insulin signaling in human granulosa cells, and are considered a major cause of ovulatory dysfunction and insulin resistance (Rutkowska and Diamanti-Kandarakis 2016). Regarding EDs, in mice, exposure to BPA early in life reduced female fertility potential later in life, while in utero

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Table 2 Negative and positive relationships of environmental factors (including endocrine disruptors, EDs) with nonassisted and assisted fertility and uncomplicated pregnancy in humans Effect Negative relationship

Nonassisted fertility Residential proximity to high-voltage electromagnetic radiation Air pollutants (SO2, residential proximity to major roads) Increased consumption of animal protein, trans-fatty acids and n-6 PUFAs and AGEs Excessive exercise Female obesity Exposure to EDs: Heavy metals (Pb and Cd) Parabens Industrial chemicals and by-products (TCDD and PCBs) Prenatal exposure to DES

Negative and positive relationships

Increased temperature at the time of birth depending on the geographic location

Assisted fertility Air pollutants (PM2,5) Increased maternal BMI Maternal smoking Exposure to EDs: BPA and phthalates (DEHP) Heavy metals (Pb, Hg, and Cr) OC and HCB pesticides Industrial chemicals and by-products (PCBs and PBDE) Triclosan

Uncomplicated pregnancy Extreme highambient temperature Air pollutants Micronutrient deficiencies of the mother Increased maternal weight and paternal obesity Increased gestational weight gain Black race Increased frequency of night shifts Maternal and paternal smoking Maternal increased coffee-caffeine drinking Maternal illicit drug use Periconceptional maternal or paternal alcohol drinking EDs: BPA and phthalates Heavy metals Parabens Pesticides Industrial chemicals and by-products (PBDE and PCB) Prenatal exposure to DES PFOS Triclosan Exposure to cold and preterm birth Exposure to EDs: BPA and birth weight in female neonates (continued)

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Table 2 (continued) Effect

Positive relationship

Nonassisted fertility

Humidity and high altitude at the time of birth Increased intake of plantderived protein Weight loss and moderate exercise in obese women

Assisted fertility

Mediterranean diet

Uncomplicated pregnancy Phthalates and preterm birth Meditteranean diet Periconceptional supplementation with folic acid

exposure to BPA affected negatively not only the fertility of the exposed generation females but also the fertility of the F3 generation females, suggesting epigenetic transgenerational effects. In an extensive review of studies assessing the effect of exposure to low-dose BPA in human female fertility, urinary and serum concentrations of BPA were found increased in infertile women (Ziv-Gal and Flaws 2016). Regarding phthalates, in CD-1 mice, intrauterine exposure to 200 μg/kg/day (estimated occupational exposure levels in humans) di-(2-ethylhexyl) phthalate (DEHP) from gestational day 10.5 until birth resulted in decreased fertility index of the F1 generation females when they mated with untreated males. However, fertility indices of the F2 and F3 generation were not affected. In addition, increased prenatal exposure of the F1 generation to DEHP (500 mg/kg/day) did not affect the gestational index of the F1 and the F3 generations but, instead, resulted in decreased gestational index of the F2 generation. Suppression of corpora lutea function, direct teratogenic effect on the fetus, and inhibition of progesterone production are suggested mechanisms of action. Exposure to DEHP appeared to result in accelerated puberty onset or progress (age at vaginal opening or at first estrus) and disruption of estrous cyclicity in all three generations (Rattan et al. 2018). Regarding the effect of heavy metals, their presence seems to affect inversely human fertility. Significantly greater mean lead (Pb) concentrations were measured in the blood of women in Bangladesh with unexplained infertility as opposed to the mean serum Pb concentrations in fertile women in Rahman’s study (as cited in Rattan et al. 2017). Significantly greater cadmium (Cd) concentrations in endometrium tissue biopsies, collected during cycle days 20–24 (when implantation is supposed to happen) from women with unexplained infertility, were found as compared with fertile controls in Tanrikut’s study. Possible mechanisms of Cd reproductive toxicity include disruption of ovulation, inhibition of steroidogenesis, endometrial dysfunction, and implantation failure (as cited in Rattan et al. 2017). Furthermore, urinary paraben concentrations are associated negatively with pregnancy success rate in the general population (Craig and Ziv-Gal 2018). In the Seveso Women’s Health Study, researchers found that women with a tenfold increase in serum 2,3,7,8-tetrachlorodibenzodioxin (TCDD) concentrations had about twofold increased risk for infertility (Eskenazi et al. 2010). Regarding female fertility and diethylstilbestrol (DES), a synthetic estrogen drug was commonly prescribed in the forepast to prevent

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miscarriages; experimental studies have shown that exposure through diet during the postmating period decreases fertility in mice, by interfering with embryo implantation (Rattan et al. 2017). Moreover, long-term follow-up of 4653 women prenatally exposed to DES revealed that these women carried increased cumulative risk for infertility throughout their reproductive life (Hoover et al. 2011). Specific toxic effects of EDs in the ovary: In vitro treatment of mouse ovarian follicles with BPA disrupted folliculogenesis and altered the expression of genes involved in steroidogenesis and the regulation of cell cycle, proliferation, and apoptosis (Ziv-Gal and Flaws 2016). In mice, exposure to BPA in utero and in early postnatal life resulted in increased oocyte apoptosis, increased number of multi-oocyte follicles, disrupted folliculogenesis, and altered follicle-type distribution. Addition of the fluorinated BPA homolog BPA AF or BPAF (employed as BPA alternative in various products) in mouse oocyte cultures for 14 hours resulted in a dose-dependent decrease in the polar body extrusion rate, an oocyte maturation marker. Moreover, oocyte exposure to 100 μM BPAF was followed by increased appearance of abnormal meiotic spindles, increased production of reactive oxygen species as well as increased frequency of double-strand DNA breaks and histone modification (methylation and acetylation). In conclusion, BPAF is associated with decreased oocyte quality and epigenetic alterations (Ding et al. 2017). Otherwise, exposure of rats to drinking water contaminated with the heavy metal arsenite induced ovarian toxicity, decreased ovarian weight, reduced follicle number, and increased follicular atresia (Rattan et al. 2017). Regarding the role of parabens in rats, in utero exposure to them yielded inconsistent results: in one study, exposure to butylparaben did not affect either the number of follicles or of corpora lutea or ovarian weight or estrous cyclicity of rats, whereas, in another study, increased exposure to butylparaben throughout gestation and lactation reduced ovarian weight in the prepubertal period. Furthermore, in rats, early postnatal exposure to various doses of butyl, methyl, or propyl paraben disrupted folliculogenesis and steroidogenesis, while late postnatal exposure of rats to methyl and butyl but not propyl paraben decreased ovarian weight and the number of corpora lutea and increased the number of cystic follicles (Craig and Ziv-Gal 2018). Regarding pesticides, there is evidence from experimental studies, indicating that some of them are capable to adversely affect ovarian function. In mice and rats, methoxychlor, pyrethroids, and endosulfan were associated with increased incidence of follicular atresia. Methoxychlor was associated with reduced ovarian weight and disrupted follicular growth. Regarding industrial chemicals and by-products, serum concentrations of monoortho polychlorinated biphenyls (PCBs) were increased in women with anovulation. Regarding dioxins, exposure of rats to TCDD resulted in disruption of follicular maturation and ovulation and in reduced ovarian weight. Futhermore, treating mice with DES resulted in disruption of ovarian follicles maturation and in increased number of atretic antral follicles as well as in ovarian atrophy (Rattan et al. 2017). Specific toxic effects of EDs in the fallopian tubes: The effects of EDs and other environmental factors on the oviduct are less well studied. In mice, in utero exposure to BPA may result in the development of proliferative fallopian tubes lesions and

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persistence of Wolffian duct structures in later life, as well as delayed development and transportation of embryos to the uterus (Ziv-Gal and Flaws 2016). Specific toxic effects of EDs in the endometrium: Evidence is limited regarding the effect of EDs upon uterine receptivity and implantation rate. Regarding BPA, experimental studies in mice and rats have shown either reduced number of implantation sites or null effect after early gestational or postnatal exposure to variable BPA doses. Moreover, exposure of mice to BPA after weaning was negatively associated with the expression of factors participating in the progesterone-mediated signaling pathway, which is involved in the regulation of uterine receptivity and implantation (Ziv-Gal and Flaws 2016). Exposure of rats to high dose of a mixture of organophosphate pesticides resulted in endometrial hyperplasia of the treated F0 generation and increased uterine weight of the in utero exposed generation F1 (Yu et al. 2013). Animal studies indicate that among industrial chemicals and by-products, chronic exposure to PCB results in chronic uterine inflammation. Moreover, TCDD can adversely affect endometrium function. Rats treated with TCDD developed uterine inflammation and lesions, while the incidence of embryo implantation failure increased in mice exposed to TCDD (Rattan et al. 2017).

Impairment of Assisted Female Fertility Regarding the influence of specific air pollutants on fertility outcomes of women assisted with reproductive techniques (in vitro fertilization, IVF), exposure to particulate matter of 2.5 mm diameter (PM2.5) affected inversely pregnancy rate, while exposure to nitrogen dioxide (NO2) or ozone (O3) resulted in reduced live birth rate (Conforti et al. 2018). Regarding nutrition, pregnancy rate after IVF, with or without intracytoplasmic sperm injection, appears to increase by 40% in women belonging to subfertile couples who follow Mediterranean diet, probably due to increased intake of vegetable oils and vitamin B6 (Fontana and Torre 2016). Regarding the effect of tobacco smoking, in animal studies of nose-only or whole-body smoking, a decrease in ovarian volume and number of primordial follicles as well as increased oxidative damage of the ovary was reported. Increased apoptotic activity was demonstrated in nose-only smoking cases as well as increased autophagy in whole-body smoking cases. In women undergoing treatment with assisted reproductive technology (ART), some studies associated smoking to decreased oocyte yield, embryo quality, pregnancy, and live birth rates, while others found no association between smoking and any fertility outcome (Camlin et al. 2014). Regarding the effect of EDs, presence of increased BPA concentrations in the urine of women undergoing ART was associated with either decreased or no effect in fertilization rate. However, serum BPA concentrations were found increased among infertile women (Ziv-Gal and Flaws 2016). Furthermore, in women undergoing IVF in the USA from 2006 until 2017, no effect of urinary BPA, paraben, and phthalate concentrations was found in relation with fertility outcomes; however, when data from the first half of the study period (2006–2012) – when exposure to EDs was increased – were examined, inverse associations between quartiles of DEHP and

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implantation success, pregnancy achievement, and live birth were reported (The Environment and Reproductive Health [EARTH] study, Mínguez-Alarcón et al. 2019). In women undergoing IVF, no associations between fertilization rates and serum concentrations of the heavy metals like arsenic (As), Pb, and mercury (Hg), respectively, were found (Rattan et al. 2017). Among women undergoing IVF, urinary paraben concentrations were not associated with embryo quality, number of oocytes retrieved, fertilization rate, implantation success, clinical pregnancy, and live birth rate (Mínguez-Alarcón et al. 2019). Regarding pesticides, administration of a mixture of organophosphate (OP) pesticides at a high dose to rats (F0 generation) during gestation and lactation resulted in decreased pregnancy and live birth rates in the F1 generation (Yu et al. 2013). Furthermore, follicular fluid and serum concentrations of various EDs (including PCBs, polybrominated diphenyl ethers [PBDE], and organochlorine [OC] pesticides) in women undergoing ART were associated negatively with IVF and embryo quality rates (Rattan et al. 2017). Finally, urinary triclosan concentrations were associated negatively with embryo quality and fertilization rate in fertility-assisted pregnancies (Hua et al. 2017). Specific toxic effects in the oocyte number and quality: Mouse oocytes and granulosa cells presented increased apoptosis when animals were exposed to increased doses of fine PM2.5 by intratracheal instillation for a period of 28 days, while oocytes from animals exposed to medium and high doses of PM2.5 exhibited increased rates of mitochondrial dysfunction as well as low blastocyst formation and embryo quality (Liao et al. 2020). However, a systematic review of relevant human studies failed to find associations between the number of retrieved oocytes among women undergoing IVF and their exposure to air pollutants such as NO2, O3, SO2, PM2.5, and PM10 (Conforti et al. 2018). Regarding nutrition and energy balance, excess body weight has negative impact on fertility outcomes following ART. Overweight or obese women undergoing fertility treatments exhibit decreased oocyte quality and impaired endometrium receptivity (Fontana and Torre 2016). Regarding the effect of EDs in humans, in Ehrlich’s study, urinary total BPA concentrations were associated negatively with the number of metaphase II oocytes, the number of retrieved oocytes, and peak estradiol concentrations in women following ART, whereas in Fujimoto’s study serum unconjugated BPA concentrations did not affect oocyte maturation but they affected negatively oocyte fertilization (as cited in Machtinger et al. 2014). Regarding phthalates, in vitro studies provide evidence for disruption of follicular growth, follicular viability, and cell cycle regulation as well as disruption of ovarian steroidogenesis after exposure to dibutyl phthalate (DBT) at concentrations greater than DBT concentrations encountered trivially in humans. Epidemiological studies report no effect in the number of retrieved oocytes in women undergoing IVF following exposure to DBT (Craig and Ziv-Gal 2018). However, urinary DEHP concentrations in the highest quartile were associated negatively to oocyte yield in women undergoing IVF cycles from 2004 until 2012, in the early years of the EARTH study (Hauser et al. 2016). Moreover, heavy metal contamination was also negatively associated to oocyte yield. In a study including women undergoing IVF in Taranto, an industrialized Italian city, follicular fluid concentrations of heavy metals were significantly increased among women

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residing inside the contaminated with various heavy metals (including Pb and Cr) city. The number of retrieved mature oocytes from these women was decreased compared to that from women residing outside the city. Moreover, increased Hg hair concentrations were associated negatively with the number of oocytes retrieved after ovarian stimulation (Rattan et al. 2017). Interestingly, urinary triclosan concentrations in humans were associated with increased baseline antral follicle number and increased number of retrieved oocytes following ART (Craig and Ziv-Gal 2018). Specific toxic effects in implantation: Subcutaneous administration of BPA at high dose to pregnant mice resulted in disordered implantation. Similarly, linear association was found between women’s urinary BPA concentrations or serum hexachlorobenzene (HCB) concentrations and the risk for implantation failure in women undergoing IVF (Machtinger et al. 2014). Regarding triclosan, implantation rate was 27.6% among women with urinary triclosan concentrations at or above the median of the sample versus 50.0% among women with lower than the median of the sample (Hua et al. 2017).

Effect of Environmental Factors on Hypothalamic-PituitaryOvarian (HPO) Axis Resulting into Negative Pregnancy Outcomes Ectopic Pregnancy Ectopic pregnancy results when implantation of the fertilized oocyte occurs outside the uterus. In the Nurses’ Health Study II cohort, significant positive associations were found between tobacco or increased alcohol consumption and the risk for ectopic pregnancy, respectively (Gaskins et al. 2018). Moreover, women exposed prenatally to DES had increased cumulative risk for ectopic pregnancies (Hoover et al. 2011).

Pregnancy Losses The term pregnancy losses comprise miscarriages and stillbirths. Exposure to increased levels of PM2.5 (air pollution) throughout pregnancy was associated positively with increased risk for pregnancy losses in a cohort of 42,952 African women (Xue et al. 2019). In pregnancies achieved by ART, maternal obesity is related to increased risk for pregnancy losses, while paternal obesity was found, in a metanalysis, to decrease the live birth rate by about 10% (Practice Committee of the American Society for Reproductive Medicine, ASRM 2015; Campbell et al. 2015). In a metanalysis, maternal caffeine intake or coffee consumption throughout pregnancy was shown to increase the risk for pregnancy losses in a dose-dependent manner (Li et al. 2015). In a recent metanalysis, increased As concentrations in groundwater (drinking water) were associated with increased risk for pregnancy losses (Quansah et al. 2015). Exposure of female fetuses to DES in utero was found to increase the risk for pregnancy losses later in their reproductive life (Hoover et al. 2011).

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In mice, oral administration of triclosan was associated positively with increased pregnancy losses (Wang et al. 2015). Miscarriage is the spontaneous loss of an intrauterine pregnancy before 20–28th week of gestation. In a systematic review, exposure to the air pollutant PM10 was associated positively with miscarriages in both assisted and nonassisted pregnancies, while exposure to the air pollutants SO2 and NO2 was associated positively with miscarriages in nonassisted pregnancies (Conforti et al. 2018). In a metanalysis, maternal obesity increases the risk for recurrent miscarriages (Cavalcante et al. 2019). Regarding working environment, two or more night shifts in the preceding week were found to increase the risk for miscarriages after eighth week of gestation (Begtrup et al. 2019). In pregnancies achieved by ART, alcohol consumption of either the mother or the father in the week or month preceding IVF or gamete intrafallopian transfer attempt, respectively, is related to increased risk for miscariages (Klonoff-Cohen et al. 2003). In a metanalysis, active maternal smoking during pregnancy increases the risk for miscarriages (Pineles et al. 2014). Regarding EDs, serum BPA concentrations were significantly greater in women with a record of recurrent early miscarriages compared to controls in Sugiura-Ogasawara’s study of 77 women from Japan (as cited in Pergialiotis et al. 2018). In another study, first trimester pregnant women with conjugated serum BPA concentrations in the highest quartile presented 83% greater risk for miscarriages in both spontaneous and medically assisted pregnancies as compared with women showing BPA concentrations in the lowest quartile. Because BPA binds with great affinity to the human placental estrogen-related receptor γ, it is suspected for adverse effects on the placenta (Lathi et al. 2014). Increased PCB and dichlorodiphenyltrichloroethane (DDT) concentrations and/or their metabolites in women from the USA and Germany were related to recurrent miscarriages, while no correlation was found in a study from Japan (Caserta et al. 2011). In the Seveso Women study, where pregnancies with adverse outcomes were recorded for 30 years after an environmental accident resulting in high environmental contamination with TCDD, researchers failed to establish any correlation between exposure to dioxins and miscarriage risk (Wesselink et al. 2014). In 452 women, increased mid-gestation urinary concentrations of triclosan were associated positively with the risk for miscarriages. Increased placental thrombosis probably mediated by the apparent reduction in the activity of the enzyme estrogen sulfotransferase was suggested as possible mechanism (Wang et al. 2015). Stillbirth is the death of a fetus before 20–28th week of gestation. A considerable number of environmental factors can be incriminated for increasing the occurrence of stillbirth. Exposure to extreme hot or cold throughout the whole period of pregnancy was found to increase the odds for stillbirth (Ha et al. 2017). Moreover, in a systematic review comprising only human studies published till 2017, researchers found positive association between levels of air pollution with carbon monoxide (CO) and incidence of stillbirth in the general population as well as negative association between air concentrations of O3 or NO2 and live birth rate in a population undergoing IVF (Conforti et al. 2018). Increased maternal BMI (overweight or obese) was associated with increased stillbirth rates in a metanalysis (Aune et al. 2014). Finally, regarding the association of the factor of race with the risk for

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stillbirth, in a metanalysis, black and mixed couples (Black women/White men) present greater risk for stillbirth compared to White couples (Srinivasjois et al. 2012), while non-Hispanic Blacks run 2.2 times greater risk for intrauterine death as compared to non-Hispanic Whites (Lorch and Enlow 2016). Only a few studies examine the role of EDs on the outcome of stillbirth. Among pesticides, there is evidence that exposure to OPs is associated negatively with live birth rates in rats (Yu et al. 2013).

Gestational Diabetes In a metanalysis of 33 studies, exposure to the air pollutant SO2 during the first trimester of pregnancy was associated positively with the risk for gestational diabetes mellitus (GDM) (Bai et al. 2020). Regarding nutrition and energy balance, adherence to Mediterranean diet during pregnancy lowers the risk for GDM, while high gestational weight gain increases that risk (Amati et al. 2019; Valsamakis et al. 2015).

Hypertensive Disorders of Pregnancy These disorders comprise chronic hypertension, gestational hypertension, preeclampsia or eclampsia, and chronic hypertension with superimposed preeclampsia. Pregnancies with conception during the hottest months of the year and delivery during the coldest months of the year run increased risk for preeclampsia, while increased eclampsia risk was also identified for deliveries during the coldest months (Beltran et al. 2014). However, most studies examining the association of hypertensive disorders of pregnancy and seasonality did not examine the possible effect of confounders such as maternal nutrition, air pollution, and maternal infections which may exhibit, as well, seasonal variation. Regarding the effect of various air pollutants, a metanalysis concluded that exposure to PM2.5 or PM10 during the first trimester of pregnancy is associated positively with preeclampsia and gestational hypertension, respectively, while exposure to PM2.5 throughout pregnancy is positively associated with hypertensive disorders of pregnancy (Bai et al. 2020). Regarding nutrition, Mediterranean diet appears to be protective against preeclampsia and gestational hypertension (Amati et al. 2019). Folic acid supplementation has also protective effects against gestational hypertension (Amoako et al. 2017). On the other hand, maternal obesity increases the risk for preeclampsia. In the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, increased pregestational BMI was associated positively with preeclampsia risk. Not only pregestational ΒMΙ but also increased gestational weight gain among obese and nonobese subjects increase the risk for gestational hypertension (Valsamakis et al. 2015). Regarding EDs, placental but not maternal serum or cord blood BPA concentrations were increased in women with preeclampsia in Leclerc’s case-control study although in Ye’s study increased maternal serum BPA concentrations were

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associated positively with the risk for preeclampsia in Chinese women (cited in Rosen et al. 2018). Accordingly, urinary BPA and monoethyl phthalate concentrations during the first trimester of pregnancy were associated positively with increased risk for preeclampsia but the effect was significant only among women carrying female offspring. The same effect was observed for average maternal urinary concentrations of DEHP phthalate metabolites throughout pregnancy (Kahn and Trasande 2018). Urinary concentrations of mono-benzyl phthalate (MBzP) at 16 weeks of pregnancy were found to correlate significantly with increased diastolic blood pressure at 4 weeks apart, and its prevalence is about 1% in women before the age of 40 (European Society for Human R et al. 2016). Etiologies of POI are still poorly defined because in more than 75% of cases, the cause is undetermined. Genetic, iatrogenic, immunologic, metabolic, and infectious causes have been reported, and four main mechanisms have been implicated in the etiology of POI, including exhaustion of the pool of resting primordial follicles, increased follicular atresia, increased activation of primordial follicles, and blockage of folliculogenesis before the antral stages preventing ovulation (Vabre et al. 2017). Since environmental factors can be major determinants of the ovarian reserve, acting during prenatal period or adult life, and given the multiple effects of EDCs in gonadal development and folliculogenesis, it is reasonable to assume that EDCs can be catalytic in POI pathogenesis (Richardson et al. 2014). In fact, in a cross-sectional survey using the NHANES data from 1999 to 2008 with 31,575 women enrolled, it was shown that women with high levels of phthalate metabolites and/or β-HCH and mirex (pesticides) had an earlier mean age at menopause compared to women with low levels of phthalate and/or pesticide metabolites (Grindler et al. 2015). Analogously, a prospective cohort study of women undergoing infertility treatments showed that higher BPA levels were associated with lower antral follicle counts, suggesting that BPA exposure accelerated ovarian failure (Souter et al. 2013). Urinary concentrations of BPA were positively associated with markers of oxidative stress and inflammation in women, suggesting that BPA exposure promotes oxidative stress and inflammation and may make postmenopausal women susceptible to other BPA-induced health effects related to aging (Yang et al. 2009). Finally, in another prospective cohort study of women seeking fertility treatment at Massachusetts General Hospital, it was shown that urinary paraben concentrations, commonly found in personal care products, were associated with a trend toward lower antral follicle counts as well as higher day-3 FSH levels, both established indicators of ovarian aging (Smith et al. 2013). All the above reinforce the notion that the environment and, in particular, substances acting as endocrine disruptors seem to play a key role in the onset of mechanisms likely to cause POI. Among the mechanisms involved, the induction of follicular atresia during follicular growth via an increase in oxidative stress and apoptotic phenomena has been observed after BPA, phthalates, pesticide, and dioxin exposure. Secondly, a decreased pool of primordial follicles can originate from its massive atresia consecutive to exposures to PAHs or from a default in its assembly in the fetal ovary as shown for genistein and BPA. Finally, an increase in the recruitment of primordial follicles has been reported for phthalates and BPA (Vabre et al. 2017).

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It should be highlighted that the majority of the conclusion made so far regarding the role of EDCs in POI pathogenesis derive mainly from animal and experimental data. There is a paucity of human data, due to the known limitations of endocrine disruption research. It is well documented that a single toxicant exposure can be accompanied by different effects depending on time and dose of exposure. In female reproductive system, this phenomenon can be observed as well and serve as a pertinent example of the difficulties that may arise in EDC research. For example, in rodents, prenatal exposure to BPA affects assembly of primordial follicles in the fetal ovary, neonatal exposure increases the activation of follicle growth from the pool of primordial follicles, while prepubertal exposure increases atresia in growing follicles. Overall, although the above data may be rather limited, they are adequate enough to support a potential relationship between environmental contaminants and POI. However, there is no doubt that more studies are needed in order to establish this causal association and to further delineate the underlying pathogenetic mechanisms.

Fibroids Uterine fibroids are the most frequent gynecologic tumor, affecting 70% to 80% of women over their lifetime. They arise from the uterine myometrium and belong to a class of tumors whose primary morbidity is associated with local disease rather than distant metastasis. Despite their benign nature, they constitute a significant cause of morbidity, as they can cause a variety of symptoms such as pain, bleeding, and bladder dysfunction, and lead to gynecologic complications, including infertility and miscarriage (Segars et al. 2014). As a result, fibroids are one of the leading indications for hysterectomy in premenopausal women, with over 200,000 per year performed in the United States, with an estimated cost of up to $34 billion/year (Mauskopf et al. 2005). However, the mechanisms that initiate uterine leiomyoma growth and pathogenesis are still not completely understood. Apart from genetic alterations and hormonal factors, environmental parameters have also been implicated in uterine fibroids etiology. The risk of the development of leiomyoma tumors increases with age during the premenopausal years, but tumors typically regress and/or become asymptomatic with the onset of menopause. In addition to menopausal status, several other hormone-associated risk factors for uterine leiomyoma have been identified. Obesity, age at menarche, and unopposed estradiol exposure have been linked to an increased risk for uterine leiomyoma, whereas cigarette smoking, use of oral contraceptives, and parity have been identified as protective factors. Since fibroids are hormone-dependent tumors, EDC implication in their etiology was extensively investigated. DES association with uterine fibroid development has been evaluated in a few recent studies. In the Nurses’ Health Study II, 11831 cases of fibroids were diagnosed in 1.3 million person-years of follow-up (over 20 years), making this the largest prospective study investigating the influence of prenatal DES exposure on fibroids. In this study, prenatal exposure to DES increased risk for UFs

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by 13% in women aged over 35 years (Mahalingaiah et al. 2014). Similarly, in the NIEHS Uterine Fibroid Study, the odds ratio for developing fibroids for Caucasian women exposed to DES was 2.4, which was even higher for large fibroids (Baird and Newbold 2005). Analogous results were found for other classes of EDCs. For example, a Chinese human study showed that the mean concentrations and ranges of distribution of BPA, nonylphenol, and octylphenol were higher in women with fibroids compared to women without fibroids (Shen et al. 2013). A positive association between MBP and an increased risk of fibroids has also been established in a cross-sectional study of 1227 women (Weuve et al. 2010). Finally, in a cohort study of women undergoing laparoscopy or laparotomy at 14 hospital centers, PCB levels were positively associated with fibroids in the absence of other gynecological disorders (Trabert et al. 2015). Beyond epidemiological studies, the best-characterized animal model for study of uterine leiomyomas is the Eker rat, which develops spontaneous uterine fibroids at a 65% incidence due to a germline retroviral insertion in the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene. Furthermore, the resulting tumors have a similar presentation as seen in women, occurring with high frequency, and often in multiples, they are hormone responsive, expressing estrogen and progesterone receptors, and histologically well differentiated and benign. When Eker rats were exposed to DES neonatally, fibroid incidence, multiplicity, and their tumor size were statistically significantly increased. Specifically, experimental studies in Eker rats have identified a window of susceptibility to environmental exposure that coincides with key periods of myometrial development. Postnatal days 3–12, when the inner circular myometrium is differentiating and the uterine glands are developing, have been shown to be a critical window of susceptibility for promotion of uterine fibroids by DES. During this time, the developing uterus is normally protected from estrogens, which are bound by circulating steroid hormone-binding proteins such as alpha-feto protein. This allows differentiation to proceed largely independent of steroid hormone exposure until much later in development, when alpha-feto protein production ceases and is cleared by the liver, which occurs around postnatal day 17 in rats. Because DES and other xenoestrogens do not bind alpha-fetoprotein, even low-dose exposures to these estrogenic chemicals can be very potent and lead to adverse effects. Developmental reprogramming and epigenetic alterations by early life EDC exposure is another putative etiologic mechanism of uterine fibroids. Specifically, DES, BPA, and genistein can act as estrogen receptor (ER) ligands and induce ER-mediated gene transcription in Eker rat model, but only DES and genistein induce nongenomic ER signaling to activate PI3K/AKT in the developing uterus. This activation has been shown to induce phosphorylation of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), which represses EZH2 activity and reduces levels of the histone 3 lysine 27 trimethyl (H3K27me3) repressive mark on chromatin and promote uterine tumorigenesis. Additionally, altered DNA methylation patterns have also been observed in fibroids from both rodents and humans and can serve as another possible mechanism of endocrine disruption (Vabre et al. 2017).

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Overall, uterine fibroids as hormone-dependent tumors can be potentially promoted by exposure to hormone-active environmental agents such as EDCs, especially when EDC exposure takes place in critical windows of myometrial development. Although bibliographic data are rather indicatory, the precise mechanisms underlying the EDC-dependent effects on the uterus are still not known, warranting further research and clinical observation.

Impact of Environmental Factors on Disorders of Puberty in Females: Focusing on Endocrine Disruptors Puberty constitutes a hormonally unique period of a human’s life, during which a child evolves into a sexually mature adult, accompanied by a growth spurt and development of secondary sexual characteristics. Various physiological, morphological, and behavioral changes take place, as gonadal activity gradually increases. The onset of puberty requires an intact hypothalamic–pituitary–gonadal axis. Reactivation of the secretion of gonadotrophin-releasing hormone (GNRH) from its stage of childhood quiescence stimulates luteinizing hormone (LH) and folliclestimulating hormone (FSH) secretion, which in turn activates the production of gonadal sex steroids, leading to the development of secondary sexual characteristics. GnRH is released by a small population of GnRH neurons, which extend axons from the preoptic area and the infundibular nucleus (IFN) of the hypothalamus and act as the common output pathway integrating several internal and external cues, giving rise to pulsatile GnRH secretion, which subsequently regulates the pituitary–gonadal axis. The perplexing process of pubertal onset has traditionally been considered an etiological puzzle for medical community, which is gradually being elucidated. Currently, there are increasing amounts of evidence showing that the pulsatile secretion of GnRH by GnRH neurons, which is responsible for the changes of puberty, is attributed to that kisspeptin neurons in the arcuate nucleus, which release neurokinin B and dynorphin to generate pulsatility. These three supra-GnRH regulators compose the kisspeptin, neurokinin B, and dynorphin neuron (KNDy) system, a key player in pubertal onset and progression. However, recent studies have highlighted the relative roles of the GABA, glutamate, neuropeptide NPY, and other central neurotransmitters in the hiatus of GnRH secretion during the prepubertal period of primates, which counteract harmonically and regulate pubertal onset. Indeed, the exact molecular machinery underlying puberty initiation in humans is under intensive investigation, with more and more parameters involved in the hormonal process being unraveled (Livadas and Chrousos 2016). While genetic factors remain the predominant determinant of pubertal timing, the shift towards an earlier age of puberty in the past century coincided with improvements in public health and nutrition, and more recent changes have been attributed to obesity. Based on the universal action of EDCs in the female reproductive system and the above observations, it was easily assumed that EDCs will also somehow

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affect pubertal onset and contribute to the observed shifts in pubertal timing. In this context, various experimental and epidemiological studies have focused towards elucidating the role of EDCs in the hormonal control of puberty. Research on BPA and puberty has produced inconsistent and equivocal results both in experimental and epidemiological studies. Experimental models neonatally exposed to BPA ICR mice, Sprague-Dawley rats, and Long Evans rats showed that BPA exposure was associated with accelerated vaginal opening, while other studies show that BPA did not affect vaginal opening in gestationally, neonatally, and orally exposed Long Evans rat or in lactationally exposed rats, and BPA did not affect the onset of puberty inCD-1 mice. Analogously, in an epidemiological study of Turkish girls, BPA levels were associated with idiopathic central precocious puberty, while in a study of 1151 girls ages 6 to 8 years and a study of 192 girls age 9, BPA exposure was not associated with accelerated breast or pubic hair development. Studies on phthalate exposure and puberty in humans are also equivocal. More analytically, a review by Jurewicz and Hanke reported an association between urinary levels of phthalates and pubertal gynecomastia and between serum levels of phthalates and premature thelarche and precocious puberty in girls. In a multiethnic longitudinal study of 1151 girls in the United States, phthalate metabolites were borderline associated with pubic hair development and inversely associated with hair stage. Furthermore, girls with precocious puberty had higher levels of kisspeptin, suggesting that phthalates may promote female puberty by increasing kisspeptin activity. However, phthalates may also be associated with delayed puberty. Two studies, one from the United States (New York City, Cincinnati, and San Francisco) and one from Denmark, showed that phthalate exposure is associated with later pubic hair development, older age at first breast development, and delayed age at puberty. Concerning experimental data, significant discrepancies are observed here as well. Some studies showed that DBP and benzyl butyl phthalate (BBP) exposure did not affect vaginal opening in rats, whereas others show that DBP exposure induced earlier pubertal timing in female Sprague-Dawley rats, or that it delayed vaginal opening and completely blocked vaginal opening at high doses (750 and1000 mg/kg/d) in Wistar rats. Regarding pesticides, the existing bibliography is limited and analogously equivocal. Interestingly, animal studies suggest that several herbicides/pesticides can alter puberty. A high dose of atrazine (ATR) during prenatal life delayed vaginal opening in Sprague-Dawley rats, while, similarly, exposure to simazine for 21 days delayed vaginal opening, decreased the number of estrous cycles, and delayed the first day of estrus in Wistar rats. In contrast to the effects of ATR and simazine, neonatal exposure to the herbicide acetochlor accelerated vaginal opening and caused irregular cyclicity in female rats. Focusing on epidemiological data, bibliography is extremely limited and insufficient to prove any causal association. In a small study of 78 children with idiopathic precocious puberty and 100 control children, the levels of p,p,-DDE did not differ between children with precocious puberty and normal age at puberty. Similarly, a small study of 45 girls living in the Menderes region in Turkey did not show an association between pesticide levels and

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precocious puberty, but the authors suggested that pesticide exposure may be associated with obesity and that obesity may be the underlying cause for precocious puberty (Gore et al. 2015). Lastly, the Breast Cancer Environmental Research Program (BCERP) group, a longitudinal US puberty cohort study group based at three centers (the Bay Area in Northern California,Cincinnati, Ohio, and Manhattan, New York), created to examine the role of EDCs on pubertal development, published two studies on the effects of tobacco exposure and air pollution. Prenatal and contemporary second-hand tobacco exposure was assessed by questionnaire and urinary cotinine measurement at enrollment. Girls with higher prenatal and second-hand smoke exposure have earlier pubarche but not thelarche. Pubarche occurred 10 months earlier in the highest vs. the lowest prenatally exposed groups. To examine the effects of exposure to the polycyclic aromatic hydrocarbons in air pollution, residential proximity to traffic metrics was used as a proxy measure. Proximity to major roads at age 6–8 years was associated with earlier pubarche across all ethnic groups, controlling for confounders. Higher exposed girls had pubarche 2–9 months earlier than lower exposed. There was no association with thelarche timing (Lee et al. 2019). Analogous experimental and epidemiological studies have been extensively conducted for other environmental contaminants such as TCDD, tributyltin, PCBs, and PFOA. Significant discrepancies in findings are observed in those EDC classes as well, highlighting the necessity for more and well-designed studies to unravel the role and the impact of environment in the pubertal outcomes in humans as well as animal models.

Precocious Puberty Precocious puberty is defined as the development of secondary sexual characteristics earlier than two standard deviations of the mean value. The most common type is known as idiopathic central precocious puberty, in which the process is identical to normal puberty, but happens earlier. It has been proposed that it may be caused by the interactions between genetics, neurotransmitters in central nervous system, hormonal factors, environmental parameters, and general health condition. However, the real trigger of the idiopathic central precocious puberty remains unknown. Peripheral precocious puberty is a rarer and much different condition, where the etiological factors derive from the periphery. Specifically, hypothalamus and pituitary remain intact, while ovaries, testicles, adrenal gland, and a severely underactive thyroid gland contribute to abnormal estrogen and/or testosterone production, hampering the normal process of puberty. In recent times, children, especially girls, have been attaining sexual maturity earlier than they would in the past, and the incidence of precocious puberty is rising worldwide. Direct or indirect exposure to environmental contaminants has been incriminated in this worldwide increasing trend. Epidemiological data regarding

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the prevalence of precocious puberty and the existence of a secular trend is scarce, but rather indicatory. In Denmark, an epidemiological study based on national registries conducted in 2005 estimated that 0.2% of Danish girls and 4 h/day. Accordingly, Lewis et al. (2017) found no association between mobile phone use and semen quality.

Conclusions Although there is not a univocal consensus regarding the role of EDCs in male reproductive system, most of the studies showed an association between EDCs and semen quality (Table 1). It should be noted that there are some limitations in the studies that contributed to the contradictory results observed in the literature. For instance, only a single dose of EDCs has been tested in most of the studies.

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Table 1 Summary of the papers on EDC effect on human semen quality cited in text References Mendiola et al. (2010)

EDCs BPA

Participants 375

Country U.S.

Meeker et al. (2010)

BPA

190

U.S.

Li et al. (2011)

BPA

218

China

Lassen et al. (2014)

BPA

308

Denmark

Knez et al. 2014)

BPA

146

Slovakia

Goldstone et al. (2015)

BPA

501

U.S.

Vitku et al. (2015)

BPA

174

Czech Republic

Radke et al. (2018)

Phthalates

5623

China, U.S., Europe, Taiwan

Caporossi et al. (2020)

Phthalates

105

Italy

Joensen et al. (2009) Toft et al. (2012)

PFC

105

Denmark

PFC

588

Poland, Ukraine, Greenland

Results No significant associations between semen parameters and urinary BPA concentration Urinary BPA concentration associated with declines in sperm concentration and motility, and alterations in morphology Increased urine BPA level associated with decreased sperm concentration, decreased total sperm count, decreased sperm motility and decreased sperm viability Higher urinary BPA concentration associated with lower percentage of progressive motile sperm Increased natural logarithm transformed urinary BPA concentration associated with lower natural logarithm transformed sperm count, sperm concentration and sperm viability No significant associations between semen parameters and urinary BPA concentration Seminal BPA, but not blood plasma BPA, negatively associated with sperm concentration and total sperm count Overall studies (19 papers) showed a moderate or robust evidence of an association between increased phthalates (DBP, BBP, DEHP, and DINP) and decreased semen quality Semen volume positively associated with MnBP, MnOP and BPA but negatively associated with MiNP. MEP levels negatively associated with sperm concentration High perfluoroalkyl acids levels associated with few normal sperm Negative association between PFOS and sperm morphology among men from Poland and Ukraine but not among Inuit population (continued)

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Table 1 (continued) References Raymer et al. (2012)

EDCs PFC

Participants 256

Country U.S.

Joensen et al. (2013) Vested et al. (2013)

PFC

247

Denmark

PFC

169

Denmark

Governini et al. (2015)

PFC

59

Italy

Louis et al. (2015)

PFC

501

U.S.

Perry et al. (2007) Recio-Vega et al. (2008) Meeker and Stapleton (2010) Perry et al. (2011) MirandaContreras et al. (2013)

OP

18

U.S.

OP

52

Mexico

OP

50

U.S.

OP

94

China

OP

64

Venezuela

OP

116

Spain

OP

60

Iran

PCB

170

U.S.

Melgarejo et al. (2015) GhafouriKhosrowshahi et al. (2019) Bush et al. (1986)

Results No significant association between PFOS and PFOA and semen parameters No significant association between PFOS and semen paramenters In utero exposure to PFOA associated with lower adjusted sperm concentration and total sperm count Increased alterations of sperm parameters in PFC-positive subjects PFOSA associated with smaller sperm head area and perimeter, lower percentage of DNA stainability, and a higher percentage of “bicephalic” and immature sperm. PFDeA, PFNA, PFOA, and PFOS associated with a lower percentage of sperm with coiled tails Negative association between OP/PYR and sperm concentration Decreased total sperm count after the highest exposure to OPs OP concentration in house dust associated with decreased sperm concentration Association between DMP and sperm concentration Association between occupational exposure to organophosphate (OP) and carbamate (CB) pesticides and semen quality Decreased sperm parameters after dialkylphosphates exposure Sperm concentration and motility lower in occupationally exposed rural farmers than in urban population PCB 153, 138, and 118 inversely related to sperm motility among subjects with sperm count less than 20 million/mL (continued)

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Table 1 (continued) References Guo et al. (2000)

EDCs PCB

Participants 12

Country Taiwan

Dallinga et al. (2002)

PCB

65

Holland

Richthoff et al. (2003)

PCB

305

Sweden

Hauser et al. (2003)

PCB

212

U.S.

Hauser et al. (2005)

PCB

303

U.S.

Paoli et al. (2015)

PCB

228

Italy

Petersen et al. (2018)

PCB

263

Faroe Islands

Results Increased abnormal sperm morphology, reduced sperm motility, and reduced sperm penetration of hamster oocytes, in exposed adolescent Sperm count and sperm progressive motility inversely related to PCB metabolite concentrations Negative correlation between PCB-153 and both testosterone: SHBG ratio and sperm motility Dose-response relationship among PCB-138, sperm motility and morphology Greater interaction between monobenzyl phthalate and PCB-153, sum of PCBs and cytochrome P450 (CYP450)inducing PCBs in relation to sperm motility Higher percentage of semen samples with total sperm number < 39  106 in testicular cancer patients with detectable PCB levels No association between serum PCB and semen parameters

BPA bisphenol-A; PFC perfluorochemical; OP organophosphate; PCB polychlorinated biphenyl

Considering the long half-life and ubiquity of EDCs, the single dose may not be representative of EDC human exposure during their life, including the fetal development. In addition, the effects of combined exposure to different EDCs have not been sufficiently considered. However, these mixing cocktails may cause dramatic alterations to the hormonal axis and spermatogenesis. Furthermore, co-exposure of EDCs to other toxic environmental compounds may frequently occur, and this aspect should be considered in future studies. Finally, epigenetic transgenerational effect of EDCs on male reproduction may have also occurred. Despite these limitations, overall the studies indicate that EDC exposure plays a crucial role on male infertility in both animals and human, affecting male reproductive health even during fetal development that may persist in subsequent generations (Figs. 2 and 3). In the last decades, anthropogenic activities contributed considerably to environmental contamination, and beside the role of EDCs, the importance of heavy metal, air pollution, and electromagnetic field on male reproductive outcome is becoming

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Fig. 2 Sources and transgenerational effects of endocrine-disrupting chemicals (EDCs). The figure shows the different sources of EDCs and their effects on male fertility from prenatal exposure to adult life and future generations

relevant. Several studies showed the correlation between the exposure to these toxic factors and male reproductive disorders. Although the results of in vitro and animal model studies are almost consistent, epidemiological findings in humans are quite conflicting due to the high heterogeneity of study designs. The selection of study populations, the quantification approaches, and the dose/duration of human exposure varied greatly among the studies, causing serious difficulties in comparison. Moreover, simultaneous exposure to multiple pollutants, either with additive or antagonistic toxic effect, may have influenced the results reported. Considering that the exposure of these environmental pollutants is dramatically increasing, further experimental investigations in humans are required to overcome the inconsistencies among studies in order to better clarify the role of these pollutants on male reproductive system and human health.

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Fig. 3 Schematic representation of pre- and postnatal effects of common environmental of endocrine disrupting chemicals (EDCs) Acknowledgment This study was funded by a grant from the Italian Ministry of Education and Research (MIUR-PRIN 2017-2017S9KTNE_003) and the University of Rome “Sapienza” Faculty of Medicine.

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The Role of the Environment in Testicular Dysgenesis Syndrome

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Renata S. Auriemma, Davide Menafra, Cristina de Angelis, Claudia Pivonello, Francesco Garifalos, Nunzia Verde, Giacomo Galdiero, Mariangela Piscopo, Annamaria Colao, and Rosario Pivonello

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine Disrupting Compounds: General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Estrogen Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Androgen Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endocrine Disrupting Compounds Targeting the Male Reproductive System . . . . . . . . . . . . . . . . . Exposure to Endocrine Disrupting Compounds with Estrogenic Properties . . . . . . . . . . . . . . . Exposure to Endocrine Disrupting Compounds with Anti-Androgenic Properties . . . . . . . . Exposure to Endocrine Disrupting Compounds with Mixed Properties . . . . . . . . . . . . . . . . . . . The Environment-Genes Component in Testicular Dysgenesis Syndrome: Contribution to Testicular Cancer Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Renata S. Auriemma and Davide Menafra equally contributed to the manuscript. R. S. Auriemma · D. Menafra · C. de Angelis · N. Verde · G. Galdiero · M. Piscopo Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy e-mail: [email protected]; [email protected] C. Pivonello · F. Garifalos Dipartimento di Sanità Pubblica, Università Federico II di Napoli, Naples, Italy Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy A. Colao · R. Pivonello (*) Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, Unità di Andrologia e Medicina della Riproduzione e della Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli, Naples, Italy Health Education and Sustainable Development, Federico II University, Naples, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2023 R. Pivonello, E. Diamanti-Kandarakis (eds.), Environmental Endocrinology and Endocrine Disruptors, Endocrinology, https://doi.org/10.1007/978-3-030-39044-0_10

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

Abstract

In the last 50 years a significant progressive decline of male reproductive health has been documented, with increasing occurrence of semen quality impairment and of some interlinked male genital abnormalities, such as hypospadias, cryptorchidism, and testicular germ-cell cancer, which probably share a common origin during prenatal life and are therefore grouped in a unique pathological condition named testicular dysgenesis syndrome. Since in animal studies endocrine disrupting compounds exerting estrogenic and/or anti-androgenic effects have been demonstrated to significantly impair male reproductive function, a potential etiological role in the occurrence of testicular dysgenesis syndrome has also been postulated. Human studies focusing on the potential role of endocrine disrupting compounds in the development of testicular dysgenesis syndrome are clearly based on prenatal exposure, mainly and heterogeneously assessed by quantification of these compounds in maternal samples at various pregnancy stages; nevertheless, studies are fragmented and very often do not account for multiple exposures, therefore commonly resulting in controversial results. This chapter aimed at providing a summary of available animal and human evidence concerning the association between prenatal exposure to endocrine disrupting compounds, including compounds with estrogenic (diethylstilbestrol, bisphenol A), anti-androgenic (phthalates, pesticides, heavy metals), and mixed estrogenic and anti-androgenic (pesticides dichlorodiphenyltrichloroethane and dichlorodiphenyldichloroethylene, flame retardants, polychlorinated biphenyls, dioxins) properties, and the development of specific components of testicular dysgenesis syndrome, particularly, hypospadias, cryptorchidism, and testicular germ-cell cancer, by outlining their effect per se, independently on genetic and lifestyle factors. Keywords

Testicular dysgenesis syndrome · Cryptorchidism · Hypospadias · Testicular germ-cell cancer

Introduction Over the last 50 years growing evidence highlighted the progressive decline of male reproductive health. Results from epidemiological studies documented adverse trends with increasing occurrence of hypospadias, cryptorchidism, and testicular germ-cell cancer (TGCC), together with impairment of semen quality, mainly in specific geographical areas of Western countries (Matlai and Beral 1985; Bujan et al. 1996; Chilvers et al. 1984; Adami et al. 1994; Auger et al. 1995; Carlsen et al. 1992; Andersen et al. 2000; Jensen et al. 2000; Jorgensen et al. 2002; Jouannet et al. 2001;

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Swan et al. 2000; Toppari et al. 2001; Boisen et al. 2004; Richiardi et al. 2004). These male reproductive disorders appear interlinked, as they can present in combination and are reciprocal risk factors (Main et al. 2009). Several lines of evidence have shown hypospadias, cryptorchidism, TGCC, and an impairment of semen quality to result from aberrant testicular development during prenatal life, as supported by studies investigating male reproductive system development since embryonic and fetal life. By the eighth gestational week, penile and urethral development begins to take place under the stimulatory effects of androgens produced by Leydig cells of the fetal gonads (Baskin 2000). Hormonal disrupting at stages of embryonic life (first trimester) may result in the occurrence of hypospadias, characterized by the emergence of the urethral orifice on the ventral surface of the penis or of the scrotum or on the perineum (Baskin 2000). By the 20th gestational week, the transabdominal phase of testicular descent begins to take place mainly under the stimulatory effects of the Leydig cell-deriving hormone insulin-like factor 3 (INSL3) (Barteczko and Jacob 2000; Virtanen and Toppari 2014), whereas by the 23rd gestational week the inguinoscrotal phase of testicular descent begins to take place mainly under the stimulatory effects of the Leydig cell-deriving androgens (Virtanen and Toppari 2014; Sampaio and Favorito 1998). Hormonal disrupting at stages of fetal life (second and third trimester) may result in the occurrence of unilateral or bilateral cryptorchidism, characterized by absence of one or both testes from the scrotum (Bay et al. 2006). On the other hand, virtually all TGCC have been reported to originate from the cells of a common precursor lesion, namely, germ-cell neoplasia in situ (GCNIS) (Bay et al. 2006; Sonne et al. 2008). These cells display morphological similarities with primordial germ cells and with the precursors of spermatogonia, the gonocytes, and are supposed to escape normal differentiation during prenatal life and to enter a neoplastic transformation (Bay et al. 2006; Sonne et al. 2008). The peculiar association of male reproductive system disorders sharing a common origin during fetal life has been hypothesized to be not casual, and a new entity, the testicular dysgenesis syndrome (TDS), has been thus suggested to identify the entire cohort of disorders (Skakkebaek et al. 2001). Besides genetic factors, such as 45,X/46,XY mosaicism, androgen insensitivity syndrome, and mutations in INSL3 and its receptor, and intrauterine factors, such as intrauterine growth retardation, low birth weight or small for gestational age, prematurity, placental insufficiency, and pre-eclampsia, several environmental synthetic chemical compounds able to mimic or to block hormones and to disrupt physiologic hormonal actions, referred to as endocrine disrupting compounds, have been proposed to play a role in the pathogenesis of TDS (Bay et al. 2006; Foresta et al. 2008; Schug et al. 2011). Particularly, endocrine disrupting compounds may adversely affect testicular development and induce neoplastic transformation by exerting estrogenic or anti-androgenic properties. On these bases, the “estrogen hypothesis” and the “anti-androgen hypothesis” have been proposed in the past years after the demonstration that developmental exposure to variable levels of estrogenic or anti-androgenic compounds negatively impact male reproductive function (Foresta et al. 2008; Virtanen and Adamsson 2012). More specifically, the

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exposure since embryonic life to endocrine disrupting compounds able to mimic estrogen function, or to suppress androgen production, androgen receptor (AR) expression and INSL3 production, is strongly interconnected with the development of hypospadias, cryptorchidism, and TGCC (Foresta et al. 2008), thus supporting the hypothesis of a prenatal basis for a postnatal disease. Anogenital distance (AGD) is a sexually dimorphic trait established during fetal life in response to the hormonal milieu, and is defined as the distance from the anus to the genitals; this distance becomes evident by gestation week 11–13 and increases until week 17, by remaining approximately 50–100% longer in males than in females. Shortening of AGD is a clinical sign considered as a surrogate marker of potential prenatal exposure to estrogenic or anti-androgenic compounds; therefore, AGD is frequently measured to address endocrine sensitive outcomes in studies addressing the impact of endocrine disrupting compounds affecting sex steroid hormones signaling on male reproductive and sexual development (Sathyanarayana et al. 2010). Nevertheless, investigations of the effects of endocrine disrupting compounds on male reproductive system disorders are hampered by the wide endocrine disrupting compounds distribution and the numerous exposure sources, such as professional exposure, environmental exposure, diet, cosmetics, cleaning substances, electronic devices, daily-use products, thus limiting the analysis of true consequences of endocrine disrupting compounds exposure per se independently on genetic and lifestyle factors (Main et al. 2009). Lastly, a strong caveat has been proposed for endocrine disrupting compounds mixture able to promote the so-called “cocktail effect”: combined exposure to several endocrine disrupting compounds may lead to adverse health effects, even if single substances in the mixture are below their individual safety levels (Christiansen et al. 2008). These observations are of particular concern for humans, as they reflect more realistically the consequences of human exposure to endocrine disrupting compounds. Figure 1 shows the role of genetic, intrauterine, hormonal, and environmental factors in the pathogenesis of TDS.

Endocrine Disrupting Compounds: General Considerations Endocrine disrupting compounds are defined as chemical substances able to interfere with the endocrine system by diverse mechanisms of action, including (1) activation of signaling pathways through binding to nuclear and non-nuclear steroid hormone receptors and/or binding to non-steroid receptors such as neurotransmitter receptors (i.e., serotonin receptor, dopamine receptor, norepinephrine receptor) and orphan receptors (i.e., aryl hydrocarbon receptor – AhR); (2) interference with enzymatic pathways involved in steroid biosynthesis and/or metabolism; (3) additional mechanisms that converge upon the regulation or functioning of the endocrine system (De Coster and van Larebeke 2012). Some intrinsic features of endocrine disrupting compounds challenge the interpretation of the potential effects on human health, the inference of specific causality, and the identification of linear dose–effect relationships; moreover, the same

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Fig. 1 Pathogenesis of testicular dysgenesis syndrome. Besides genetic factors, such as 45,X/46, XY mosaicism, androgen insensitivity syndrome, and mutations in INSL3 gene and its receptor, and intrauterine factors, such as intrauterine growth retardation, low birth weight or small for gestational age, prematurity, placental insufficiency, and preeclampsia, several environmental synthetic chemical compounds are capable to disrupt physiologic hormonal actions (endocrine disrupting compounds), thus playing a role in the pathogenesis of TDS, as endocrine disrupting compounds may exert estrogenic, anti-androgenic, or mixed actions. Main endocrine disrupting compounds actions include the decrease of Leydig cells function, determining reduced or completely inhibited physiological effects of INSL3-INSL3 receptor and androgen-AR pathways, prompting the development of cryptorchidism, hypospadias, reduced AGD, reduced testosterone production, and, with the contribution of direct and indirect (Sertoli cells impairment-mediated) aberrant germ cells development, impaired spermatogenesis. Moreover, endocrine disrupting compounds-induced Sertoli cells impairment, by affecting germ cells development, also drives the occurrence of gonadoblastoma and testicular cancer

intrinsic features also drive the alarm concerning the potential consequence of exposure, even to low but persistent concentrations. Collectively, these intrinsic features comprise (1) endocrine disrupting compounds act on an endogenous hormonal substrate, which can be, per se, highly diversified in the population, therefore exerting differential dose-dependent effects depending on the underlying physiological or pathological endogenous endocrine status; (2) contemporary exposure to multiple endocrine disrupting compounds as well as the phenomena of bioaccumulation and biomagnification establish the so-called “cocktail” action, strictly dependent on the type and concentration of each co-present compound, which may exert synergism or additivity, or by opposite antagonistic actions; (3) endocrine disrupting compounds with weak hormonal activity may induce significant effects for the coexistence of endocrine disrupting compounds with similar characteristics, by complicating the identification of safety thresholds

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and/or the definition of dose–effect curves; (4) endocrine disrupting compounds may exert opposite effects at low or high doses for the phenomenon of hormesis; (5) the existence of time windows of differential susceptibility over the course of life, as well as the possible latency of effects and disease onset, may modulate the extent of induced alterations and therefore complicate the interpretation of observed associations; (6) the lack of targeted interventional studies on humans, for obvious ethical reasons, requires the use of preclinical in vitro and/or in vivo models for the elucidation of the mechanisms of action, with the inherent limitations correlated to the human–animal translation of experimental results (Gore et al. 2015). The group of substances identified as endocrine disrupting compounds is highly heterogeneous and includes plastic compounds and plasticizers, agricultural products such as pesticides, insecticides, fungicides, herbicides, and phytoestrogens, synthetic chemicals used as industrial solvents or lubricants and their secondary products, and heavy metals such as cadmium, lead, arsenic, and chromium. The most relevant concerns regarding the potential harmful effects of endocrine disrupting compounds on male reproductive system are related to compounds acting as estrogens and anti-androgens, although most often the same compound might exert mixed actions.

Estrogen Receptors Estrogens are involved in a plethora of biological processes, including reproductive function. Estrogens exert their multiple actions by directly or indirectly modulating gene expression (direct and indirect genomic pathway) through binding to specific estrogen receptors (ERs), comprising two nuclear receptors, namely, the nuclear ERα and ERβ (Fuentes and Silveyra 2019). The direct genomic pathway represents the classical mechanism of estrogen signaling, resulting in the transcriptional activation of target genes. Estrogens can enter the plasma membrane and interact with ERα and ERβ in the cytoplasm; ligand binding determines a conformational change in ERs and induce receptor dimerization, translocation to the nucleus, and direct binding to the chromatin at estrogenresponsive element (ERE) sequences, enhancer regions within or close to promoters, and/or at 30 -untranslated region (30 -UTR) of target genes, therefore, ERα and ERβ acting as ligand-activated transcription factors (Fuentes and Silveyra 2019). Both ERα and ERβ comprise different functional domains: the amino-terminal domain (NTD) includes a zinc-finger motif mediating the binding to target sequences and therefore involved in gene transcription transactivation; the DNA binding domain (DBD) contributes to ERs dimerization and binding to specific chromatin sequences; the nuclear localization signal domain is unmasked upon estrogens binding and allows receptor–ligand complexes translocation to the nucleus; the ligand binding domain (LBD) at the carboxy-terminal region contains the estrogen binding sites and co-activators and co-repressors binding sites; the activation function (AF) domains AF1 and AF2 located within the NTD and

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DBD, respectively, contribute synergistically to transcriptional regulation (Fuentes and Silveyra 2019). ERα is encoded by the ESR1 gene located on chromosome 6, coding for a fulllength ERα isoform (66 kDa) and several shorter isoforms produced by the presence of alternate start codons or alternative splicing; some of the shorter isoforms lack the AF1 or AF2 or both, therefore, they form heterodimers with the full-length isoform by inhibiting its transcriptional activation. ERβ is encoded by the ESR2 gene located on chromosome 14, coding for a full-length ERβ isoform (59 kDa) and five known shorter isoforms with no transcriptional activity that can form heterodimers with ERα, by suppressing its activity (Fuentes and Silveyra 2019). Differences in ERE sequences within genes, due to inter-individual variability or genetic mutations, may determine differential affinity for ERs or induce allosteric changes in ERs, which impact on the recruitment of co-activator and/or co-repressor, therefore affecting ERs biological activity (Fuentes and Silveyra 2019). As an alternative genomic mechanism, estrogens interact with nuclear ERα and ERβ by determining the recruitment of different transcription factors, which in turn activate transcriptional processes not requiring ERs binding to DNA (indirect genomic pathway) (Fuentes and Silveyra 2019). Besides the classical genomic pathway, estrogens may also exert their actions by activating intracellular signaling cascades mediating fast estrogen-induced biological responses (non-genomic pathway); these actions are initiated by estrogens binding to the membrane G protein-coupled ER (GPER1), which has a low binding affinity for estrogens, compared to nuclear ERs. GPER1 gene is located on chromosome 7 and encodes for a typical G protein-coupled receptor comprising seven transmembrane α-helical regions, four extracellular segments, and four cytosolic segments. Activation of GPER1 upon estrogens binding determines the activation of signal-transduction mechanisms involving downstream production of intracellular second messengers, cAMP regulation, and protein-kinase activation, ultimately resulting in modulation of gene expression; the four major networks involved in estrogens non-genomic signaling include the phospholipase C/protein kinase C pathway; the Ras/Raf/MAPK pathway; the phosphatidyl inositol 3 kinase/Akt kinase pathway, and the cAMP/protein kinase A pathway (Fuentes and Silveyra 2019). Figure 2 shows a schematic representation of estrogen signaling mediated by nuclear ERs and GPER1.

Androgen Receptors Androgens, mainly testosterone, and dihydrotestosterone (DHT), are required for the development of the male reproductive system and establishment of secondary sexual characteristics; testosterone can be converted to its more biologically active form, DHT, by 5α-reductase enzyme and to estradiol by aromatase enzyme (Davey and Grossmann 2016).

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Fig. 2 Schematic representation of estrogen (E2) signaling mediated by nuclear E2 receptors (ERα) and membrane G protein-coupled ER (GPER1). Genomic pathway: the E2/ERα complex binds to E2-responsive elements (ERE) within the promoter region either directly, or by interacting with other transcription factors (TF), both resulting in transcriptional activation of target genes. Non-genomic pathway: E2-activated GPER1 determines rapid tissue responses via phosphorylation of cytosolic signaling cascades involving several kinases, such as protein kinase C (PKC), mitogenactivated protein kinase (MAPK), Akt kinase, and protein kinase A (PKA)

Androgens exert their actions by directly modulating gene expression (genomic pathway) through binding to the nuclear AR. In the absence of androgens, AR is located within the cytoplasm where it is associated with chaperone proteins. Upon ligand binding, a conformational change occurs in AR determining dissociation of chaperone proteins, receptor translocation to the nucleus, and dimerization, followed by direct binding to the chromatin at specific androgen-responsive element (ARE) sequences, enhancer regions within or close to promoters, and/or 30 -UTR; therefore, as in the case of ERs, AR acts as a ligand-activated transcription factor whose activation results in enhanced transcriptional processes of target genes (Davey and Grossmann 2016). The AR comprises several functional domains: the NTD is the most variable domain and is involved in gene transcription transactivation; the DBD is the most conserved domain and contributes to AR binding to specific chromatin sequences by facilitating direct AR binding to the ARE sequences; the LBD at the carboxyterminal region contains the androgens binding sites and co-activators and co-repressors binding sites; the nuclear localization signal allows receptor–ligand complexes translocation to the nucleus; the nuclear export signal allows AR

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exporting to the cytoplasm upon ligand withdrawal. Similar to nuclear ERs, two transcriptional AF domains have been identified, located within the NTD (AF1) and the LBD (AF2) (Davey and Grossmann 2016). AR gene is located on the X chromosome and encodes a 110-kDa protein. The NTD accounts for more than half of the size of the AR and contains polyglutamine (CAG) and polyglycine (GGC) repeat region, highly variable in length; the length of the CAG repeat region is one element determining AR function plasticity, since it has been shown to affect the folding and structure of the AR NTD, therefore affecting protein–protein interactions and AR transactivation activity, with shorter repeats generally imposing a higher, and longer repeats causing a reduced activity (Davey and Grossmann 2016). The androgen/AR complex may also exert non-genomic fast responses to even low doses of androgens, a molecular mechanism which has not been studied extensively so far, initiated by membrane-bound AR and mediated by the activation of intracellular signaling cascades, including MAPK, ERK, and Akt pathways (Davey and Grossmann 2016). Figure 3 shows a schematic representation of androgen signaling mediated by nuclear AR.

Endocrine Disrupting Compounds Targeting the Male Reproductive System Among endocrine disrupting compounds, diethylstilbestrol and bisphenol A, capable of exerting estrogenic activity, diesters of phthalic acid commonly known as phthalates, capable of exerting anti-androgenic activity, and pesticides, flame retardants, polychlorinated biphenyls (PCB), and dioxins, capable of exerting mixed estrogenic and anti-androgenic activity, are undoubtedly the most extensively investigated compounds related to male reproductive function, and deserve a detailed description of their characteristics, source, and route of exposure before dissertation of specific effects. Diethylstilbestrol is a synthetic non-steroidal compound with estrogenic activity, specifically, a trans-hex-3-ene in which the hydrogens at positions 3 and 4 have been replaced by p-hydroxyphenyl groups; diethylstilbestrol presents as an odorless white crystalline powder at room temperature readily absorbed and distributed to the whole organism after oral administration. Once in the human body, diethylstilbestrol has a primary biological half-life of 3–6 hours and a terminal half-life of 2–3 days, due to entero-hepatic circulation, and is primarily excreted in urine. Diethylstilbestrol is used in veterinary medicine as a growth promoter and administered in the form of food supplement or subcutaneous implant in cattle, sheep, and poultry. Diethylstilbestrol was also previously employed in human medicine in particular for hormone replacement therapy, control of menstrual disorders, prevention of miscarriage and pregnancy-related complications, relief or prevention of post-partum breast engorgement, palliative therapy for prostate cancer in men and breast cancer in postmenopausal women, and as a post-coital contraceptive (Report on Carcinogens – Diethylstilbestrol 2021). In 1971, the U.S. Food and Drug Administration (FDA)

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Fig. 3 Schematic representation of androgen signaling mediated by nuclear androgen receptors (AR). Genomic pathway: testosterone (T) is converted within the cell to the more biologically active form dihydrotestosterone (DHT) by the 5α-reductase enzyme; DHT binds to AR by displacing chaperone (Ch) proteins bound to the AR in the absence of ligand. DHT/AR complex binds to androgen-responsive elements (ARE) within the promoter region resulting in transcriptional activation of target genes

issued a drug bulletin advising physicians to stop prescribing diethylstilbestrol during pregnancy, because of its association with a rare vaginal cancer, clear-cell adenocarcinoma, in the female descendants of treated mothers (Cancer Prevention During Early Life 2021); nevertheless, diethylstilbestrol use was not discontinued in different fields of human medicine until the U.S. FDA withdrew, in 1978, the approval for any estrogen-containing drug for the suppression of post-partum breast engorgement and for the treatment of advanced prostate cancer, because of its cardiovascular toxicity, the emergence of safer agents, and manufacturers’ economic considerations (Report on Carcinogens – Diethylstilbestrol 2021). Nevertheless, it has been estimated that between five million and ten million Americans received diethylstilbestrol during pregnancy or were exposed to the drug during prenatal life (DES Research Update 1999). Bisphenol A is an organic compound with a weak estrogenic activity belonging to the group of phenols, specifically, a diphenylmethane derivative with two hydroxyphenyl groups which is produced synthetically by the reaction of phenol

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with acetone in the presence of a strongly acidic ion exchange resin as a catalyst. Bisphenol A is used as a major component in the production of polycarbonates, epoxy resins and polyester resins, as well as in the production of thermal printer paper, and is also extensively used within industrial processes, in particular in the manufacturing of daily-use products that might contaminate food and water by contact (i.e., plastic food and drink containers, plastic baby bottles), toys, medical equipment, compact discs, and window panels (Mikolajewska et al. 2015). Widespread applications of bisphenol A in plastic industry determine an increased demand for this chemical substance and, in consequence, may pose a risk to human health, besides from the daily contact with this compound, also because of an increased exposure deriving from environmental pollution (Mikolajewska et al. 2015). Bisphenol A may enter the human body by ingestion, inhalation, or dermal contact; nevertheless, it is believed that the main route of exposure to bisphenol A is ingestion, occurring through contaminated foods and drinks contained in polycarbonate bottles and cans coated with epoxy resins. Ingested bisphenol A is rapidly conjugated with glucuronic acid and minor amounts might also be conjugated with sulfate; as a result, bisphenol A is almost exclusively excreted as a bisphenol A-glucuronide conjugate, which has a terminal half-life of less than 6 h, in urine (Mikolajewska et al. 2015). Phthalates are a group of synthetic chemicals with anti-androgenic activity widely used in industrial processes. They are primarily used as plasticizers in the manufacture of flexible vinyl plastic which, in turn, is used in consumer products, flooring and wall coverings, food contact materials, and medical devices; moreover, phthalates are also used in personal-care products, as solvents and plasticizers for cellulose acetate, and in making lacquers, varnishes, and coatings, including those used to provide timed releases of some pharmaceuticals (Toxicological profile for din-octyl phthalate (DNOP) 2002). Human exposure to phthalates occurs through ingestion, inhalation, and dermal contact; moreover, parenteral exposure from medical devices and products containing phthalates are important sources of high exposure to phthalates (De Coster and van Larebeke 2012). Phthalates have biological half-lives measured in hours, are rapidly metabolized, and are excreted in urine and feces, and the most common biomonitoring approach for investigating human exposure to phthalates is the measurement of urinary concentrations of phthalate metabolites (Toxicological profile for di-n-octyl phthalate (DNOP) 2002). Pesticides include a series of synthetic chemical compounds exerting a mixed estrogenic and anti-androgenic activity. Dichlorodiphenyltrichloroethane (DDT) is one of the most widely used and well-studied synthetic pesticides; DDT is a chlorophenylethane that is 1,1,1-trichloro-2,2-diphenylethane substituted by additional chloro substituents at positions 4 of the phenyl substituents. Commercial grade DDT also contains the compounds dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), both of which are also metabolites of DDT and have similar chemical properties (Toxicological Profile for DDT, DDE, and DDD 2002). DDT is an organochlorine compound that was introduced for commercial use in 1945 and was heavily used in densely populated areas and among both military and civilian populations for the control of malaria, typhus, and different insect-borne human diseases, as well as for insect control in crops, livestock

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productions, institutions, houses, and gardens. DDT is extremely persistent in the environment, due to its near insolubility in water and tendency to bioaccumulate in fatty tissue (DDT and related compounds 2011). By 1972, upon a cancellation order issued by the U.S. Environmental Protection Agency based on the adverse effects of DDT for the environment, wildlife, and humans, the use of DDT was prohibited in the U.S. and worldwide; nevertheless, DDT is still produced, and its global production still seems to be increasing (DDT and related compounds 2011). Human exposure to DDT primarily occurs through the ingestion of contaminated food, in particular, the food sources with the highest DDT concentrations are meat, poultry, fish, and dairy products (Toxicological Profile for DDT, DDE, and DDD 2002); although DDT residues in food have declined since it was universally banned, it is expected that low levels of chemical will be present in food products for decades, because of the extreme persistence of DDT and DDE. Furthermore, relevantly high DDT concentrations are most likely to be found in food productions from countries that currently use DDT for vector control. The major route of excretion of absorbed DDT in humans appears to be the urine, but some excretion also occurs by feces via biliary excretion, sweat, and breast milk; the biological half-lives of DDT, DDE, and DDD are ranked as DDE > DDT > DDD, and can be measured in decades in the human body, collectively accounted by the chemical stability of each compound due to relatively low metabolic efficiencies, and by the relative efficiencies of excretory mechanisms (Toxicological Profile for DDT, DDE, and DDD 2002). Heavy metals are defined as metallic elements that have a relatively high density compared to water; assuming that heaviness and toxicity are inter-related, the group of heavy metals also include metalloids, such as arsenic (As), able to induce toxicity at low levels of exposure. Although heavy metals are naturally occurring elements found in the earth’s crust, most environmental contamination and human exposure result from anthropogenic activities, including mining and smelting, metal processing in refineries, industrial production and use, agricultural use in pesticides, petroleum combustion, and textiles, microelectronics, wood preservation, and paper processing plants. Heavy metals are considered systemic toxicants known to induce multiple organ damage even at low levels of exposure, and are also classified as known or probable human carcinogens. Heavy metals such as cadmium, lead, arsenic, and chromium have been proposed to play a role in the pathogenesis of male reproductive system dysfunction; the general population might be exposed by ingestion, inhalation, and dermal contact, according to the type of heavy metal, and toxicokinetics and toxicodynamics is highly heterogeneous and is influenced by several factors including valence state, particle size, solubility, biotransformation, and chemical form, with biological half-lives which can reach decades in the human body (Tchounwou et al. 2012). Flame retardants are a group of chemicals applied since the 1970s to prevent or slow ignition of various materials and products, such as furnishings including mattresses, carpets, curtains, and fabric blinds, electronics and electrical devices including computers, laptops, phones, televisions, wires and cables, construction and insulation materials, and transportation products including seats, seat covers, and fillings, overhead compartments, and parts of cars, airplanes, and trains. Many

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flame retardants have been removed from the market or are no longer produced; nevertheless, due to their persistence in the environment for years, they can bioaccumulate over time in organic matter. Among flame retardants, 1,2-dibromo4-(1,2 dibromoethyl) cyclohexane (TBECH), polybrominated biphenyls (PBB), and polybrominated diphenyl ethers (PBDE) have been studied in relation to male reproductive system. The general population may be exposed to flame retardants by ingestion of contaminated food and waters and by inhalation of home dust and contaminated air, also due to uncontrolled burning and dismantling of electronic and electric waste, and by contact with consumer products; biological halflife in the body is estimated to range from few days up to few months (National Institutes of Health U.S. Department of Health and Human Services – Flame Retardants 2021). PCB are a group of chemically similar compounds exerting a mixed estrogenic and anti-androgenic activity, formed when 1  10 hydrogen atoms on a biphenyl molecule are replaced with chlorines, producing up to 209 individual compounds or congeners. The use of PCB in the electrical, electronic, plastic, paint, and pesticide industries began in the 1930s but was discontinued in various countries between the 1970s and the 1980s, in response to an increasing awareness on the environmental and human health impact of these compounds, on a global scale (Faroon et al. 2001); indeed, human health effects associated with PCB exposure were widely demonstrated and included a potential damage to the male reproductive system in both the offspring of exposed mothers and exposed male adults, and a potential role in human carcinogenesis at different sites (Faroon et al. 2001). Despite being banned, PCB are still widely present because of equipment leakage and continuing environmental redistribution; as a result, PCB exposure still continues to be a relevant issue, favored by a strong environmental and biological persistence, and the general population may be exposed to PCB by ingestion of contaminated food, particularly fish, and contaminated waters and by inhalation of contaminated air. Greater amounts of PCB are excreted in the feces than in the urine following oral absorption, whereas no data addressed specifically excretion upon inhalation but there is no reason to assume differences in such processes; biological half-lives are highly heterogeneous, depending on PCB congeners and mixtures, and range from as low as less than 1 year to as long as infinity, with no apparent loss in body burden, despite removal of a known source of exposure (Faroon et al. 2001). Dioxins are a group of chemically related compounds that are persistent environmental pollutants accumulating in the food chain, mainly in fat tissue of animals; more than 90% of human exposure occurs by ingestion of contaminated food, mainly meat and dairy products, fish and shellfish, and dioxins biological half-life in the body is estimated to be 7–11 years. More than 400 types of dioxinrelated compounds have been identified, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) being the most toxic (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans – Polychlorinated Dibenzo-para-Dioxins and Polychlorinated Dibenzofurans 1997). Figure 4 shows a schematic representation of the reported associations between endocrine disrupting compounds exposure and the pathogenesis of the three components of TDS object of this chapter, namely, cryptorchidism, hypospadias, and

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Fig. 4 Schematic representation of the associations between endocrine disrupting compounds exposure and the pathogenesis of hypospadias, cryptorchidism, and testicular germ-cell cancer (TGCC), as reported by studies in animal models (red) and humans (black). Abbreviations: DES, diethylstilbestrol; DBP, di-n-butyl phthalate; DEHP, di-2-ethylhexyl phthalate; DDT, dichlorodiphenyltrichloroethane; DDE, dichlorodiphenyldichloroethylene; PCB, polychlorinated biphenyls; PBDE, polybrominated diphenyls ethers; PBB, polybrominated biphenyls. “¼”, no association; “?”, uncertain/controversial association

TGCC. Figure 5 shows a schematic representation of the mechanisms driving male reproductive dysfunction upon exposure to endocrine disrupting compounds.

Exposure to Endocrine Disrupting Compounds with Estrogenic Properties Evidence collected in animal models demonstrated that the exposure to endocrine disrupting compounds with estrogenic properties can promote the development of TDS and affect male reproductive system function. Particularly, mouse male offspring from mothers exposed on days 9.5–19.5 of pregnancy to diethylstilbestrol was reported to develop hypospadias (Stewart et al. 2018). Such effect has been proposed to result from the impaired differentiation of the male urogenital mating protuberance cartilage, constituting the urethral meatus (Sinclair et al. 2016). Moreover, rat male offspring born from mothers exposed on days 17 and 19 of pregnancy to diethylstilbestrol was reported to develop cryptorchidism and to display testicular underdevelopment (Emmen et al. 2000; McLachlan et al. 1975; Nomura and Kanzaki 1977). Such effects have been proposed to result from the

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Fig. 5 Schematic representation of the mechanisms driving male reproductive dysfunction upon exposure to endocrine disrupting compounds. Abbreviations: INSL3, insulin-like factor 3; PRL, prolactin; E2, estradiol; SHBG, sex hormone binding globulin; DBP, di-n-butyl phthalate; DEHP, di-2-ethylhexyl phthalate; TGCC, testicular germ-cell cancer; OCT 3/4, octamer-binding transcription factor 3/4; DES, diethylstilbestrol; ERα, estrogen receptor α; AR, androgen receptor

combination of different pathogenetic mechanisms. Indeed, male mice exposed to diethylstilbestrol during prenatal life displayed a three-fold decrease in the messenger expression level of testicular INSL3, a factor involved in the transabdominal phase of testicular descent, as compared to untreated controls (Emmen et al. 2000). Moreover, ERα was shown to be activated (Cederroth et al. 2007; Couse and Korach 2004), and AR expression to be suppressed (McKinnell et al. 2001), following diethylstilbestrol treatment. Altogether, these findings suggest that diethylstilbestrol may act as a disruptor of the estrogen–androgen balance in the reproductive system, therefore contributing to male congenital reproductive disorders. Similarly, mouse male offspring born from mothers exposed on days 12–16 of pregnancy to estradiol benzoate, an estrogen medication used in the treatment of gynecological disorders, was reported to develop hypospadias (He et al. 2015), although the underlying mechanisms remain largely unknown at present. Moreover, rat male offspring born from mothers exposed on day 14 of pregnancy to estradiol benzoate was reported to develop cryptorchidism, due to incomplete gubernaculum development, leading to a lower gubernaculum length and thus to the inhibition of transabdominal testicular descent (Shono et al. 1996); the precise mechanisms driving such effects are unknown, however, it is argued that estradiol benzoate might cause the retention of Müllerian duct structures, which has been proposed as

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an additional cause of isolated cryptorchidism (Josso et al. 1993), by interfering with anti-Müllerian hormone (AMH) (Shono et al. 1996). Little is known about the effects of endocrine disrupting compounds with estrogenic properties on the development of TGCC in experimental studies, due to the absence of a suitable animal model for human TGCC. In mice, exposure to diethylstilbestrol was shown to be associated with the development of TGCC, together with non-neoplastic lesions of the test is and epididymis (Newbold et al. 2000), whereas no studies addressed the effects of estradiol benzoate exposure on the development of TGCC in animal models, so far. In humans, discordant results, varying from no increased risk to a 21-fold higher risk, of developing hypospadias after the exposure to diethylstilbestrol were reported (Klip et al. 2002; Martin et al. 2008), after controlling for confounders such as a potential effect of hormonal therapy for assisted reproductive techniques couples (Klip et al. 2002); conversely, the exposure to diethylstilbestrol during prenatal life was shown to be associated with a two-fold increase in the risk of developing cryptorchidism (Martin et al. 2008). Besides diethylstilbestrol, no clear association was documented between exposure to different endocrine disrupting compounds with estrogenic properties and occurrence of hypospadias (Storgaard et al. 2006; Vidaeff and Sever 2005), whereas partially controversial and/or inconclusive results were reported about the association between exposure to different endocrine disrupting compounds with estrogenic properties and development of cryptorchidism (Storgaard et al. 2006; Vidaeff and Sever 2005). Among endocrine disrupting compounds with estrogenic properties, the levels of bisphenol A were found higher in placenta samples of newborns with hypospadias or cryptorchidism recruited between 2000 and 2002, as compared to healthy controls; consistently, the risk of congenital malformations was found significantly increased in the third tertile of exposure, thus demonstrating a significant association between bisphenol A exposure and TDS (Fernandez et al. 2016). Conversely, another study, based on the measurement of bisphenol A levels in cord blood from boys with cryptorchidism, failed to find a similar association (Chevalier et al. 2015). However, a negative correlation between bisphenol A levels and INSL3 but not testosterone was demonstrated, suggesting a potential direct impact of bisphenol A on human Leydig cells during fetal testicular development (Chevalier et al. 2015). It is noteworthy that, besides the increase in prolactin, estradiol, and sex hormone binding globulin levels (Xiang et al. 2018), exposure to bisphenol A was also reported to induce a direct detrimental effect on Leydig cells, by reducing INSL3 messenger expression and testosterone production (Adegoke et al. 2020), and on Sertoli cells, by altering sperm morphology and reducing sperm count and motility (Adegoke et al. 2020), thus contributing to male hypogonadism and infertility (Xiang et al. 2018; Adegoke et al. 2020). Evidence nowadays available about the potential role of endocrine disrupting compounds with estrogenic properties in the pathogenesis of TGCC is yet to be fully exhaustive. Some polymorphic variants in genes involved in hormone metabolism and signaling, including ER, have been hypothesized to contribute to testicular carcinogenesis by changing the hormonal environment (Ferlin et al. 2010). However, only a weak association between prenatal exposure to endocrine disrupting

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compounds with estrogenic properties and TGCC was documented so far, thus providing the basis for further investigation (Storgaard et al. 2006). On the other side, TGCC was proposed to have an environmental cause related to endogenous estrogenic components acting during prenatal life and reflecting the maternal uterine environment and associated exposure to estrogens, such as maternal age, obesity, birth weight, birth order, twin pregnancies, preeclampsia, and nausea during pregnancy (Storgaard et al. 2006; Giannandrea et al. 2013). Indeed, the risk of TGCC was shown to be increased by 1.5–2 times in low-birth-weight children, first-born sons, and dizygotic twin pregnancies, whereas no definitive conclusion could be ruled out about the role of maternal age and nausea during pregnancy (Giannandrea et al. 2013). Taken these findings altogether, prenatal exposure to endocrine disrupting compounds with estrogenic properties negatively impacts male reproductive system function and increases the risk of developing TDS. However, considering the lack of consistency among studies, future research is required to better elucidate the burden and the role of endocrine disrupting compounds with estrogenic properties in the pathogenesis of TDS. Table 1 shows the endocrine disrupting compounds with estrogenic properties; Table 2 shows a summary at a glance of clinical studies focusing on the effects of exposure to endocrine disrupting compounds with estrogenic properties.

Exposure to Endocrine Disrupting Compounds with Anti-Androgenic Properties Evidence collected in animal models demonstrated that the exposure to endocrine disrupting compounds with anti-androgenic properties can promote the development of TDS and affect male reproductive system function. Particularly, rat male offspring born from mothers exposed on days 14–18 of pregnancy to di-n-butyl phthalate (DBP), a phthalate ester widely used as plasticizer, was reported to develop hypospadias (Jiang et al. 2016). Such effect has been proposed to result from decreased testosterone and AR levels, and decreased expression of key signaling molecules including sonic hedgehog, fibroblast growth factor, and transforming growth factorbeta family members, as well as from increased oxidative stress and calcium concentrations, and inhibition of epithelial to mesenchymal transition in urethral epithelial cells, therefore blocking the fusion process of the urethral groove (Mattiske and Pask 2021). Moreover, rat male offspring born from mothers exposed during late gestation to DBP displayed small intra-abdominal testes at birth, for exposures occurring on days 12–21 (Mylchreest et al. 2000), or reduced INSL3 expression in fetal Leydig cells. for exposures occurring on days 13.5–21.5 (McKinnell et al. 2005), albeit no significant correlation between INSL3 levels and abnormal testes position was found (McKinnell et al. 2005). Exposure to DBP during prenatal life was also demonstrated to decrease AGD, Sertoli and Leydig cells number in seminiferous tubule, and spermatozoa production (Ma et al. 2017). Rat male offspring exposed during prenatal life to di-2-ethylhexyl phthalate (DEHP) was

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Table 1 Endocrine disrupting compounds with estrogenic and anti-androgenic properties Property Estrogenic

Anti-androgenic

Mixed

Endocrine disrupting compound Chlorinated hydrocarbon pesticides Alkylphenols Bisphenol A Endosulfans Atrazine Butylhydroxyanisole Phthalates Di-n-butyl phthalate Di-2-ethylhexyl phthalate Mono-ethyl phthalate Mono-n-butyl phthalate Monobenzyl phthalate Mono(2-ethylhexyl) phthalate Monoisononyl phthalate Pesticides Inuron Iprodione Chlozolinate Ketoconazole Fungicides Vinclozolin Procymidone Heavy metals Cadmium Mercury Cobalt Arsenic Chromium Lead Dichlorodiphenyldichloroethylene Dichlorodiphenyltrichloroethane Polychlorinated biphenyls 2,3,7,8-tetrachlorodibenzo-p-dioxin 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane Polybrominated biphenyls Polybrominated diphenyl esters

reported to develop hypospadias and cryptorchidism (Martino-Andrade and Chahoud 2010). Such effects have been proposed to result from decreased testicular testosterone biosynthesis mediated by changes in gene expression of enzymes involved in testosterone production by fetal Leydig cells and from decreased INSL3 expression in fetal Leydig cells (Martino-Andrade and Chahoud 2010). Rat pups postnatally exposed to DBP and DEHP were reported to develop testicular abnormalities varying from testicular atrophy to agenesia, together with an impairment of spermatozoa production, the toxicity of DEHP being even higher than that of DBP (Wolf et al. 1999). Mouse male offspring born from mothers exposed on days

Groups 1 and 2: M 30

Brucker-Davis et al. (2008)

PCB, DDE, DBP/cord blood, colostrum

PCB/umbilical cord

Environmental prenatal exposure Environmental prenatal exposure

Group 1: M 13.9

Group 1: 78 cryptorchid boys Group 2: 86 control boys

Self-questionnaire administered to mothers reporting exposure to DES during pregnancy

Prenatal exposure

NA

Type of exposure/sample for measurement BPA/cord blood PCB and DDE/breast milk

BPA and 4 BP (methyl-, ethyl-, propyl-, and butyl-BP)/placenta

Timing of exposure Environmental prenatal exposure

Environmental prenatal exposure

Age Group 1: M 38.5 weeks (gestational age) Group 2: M 39.1 weeks (gestational age) Group 1: M 39 weeks (gestational age) Group 2: M 40 weeks (gestational age)

Group 1: 28 cryptorchidism and/or hypospadiasaffected boys Group 2: 51 control boys Klip et al. (2002) Group 1: 205 boys DES-exposed boys Group 2: 8729 control boys Mol et al. (2002) Group 1: 196 boys

Fernandez et al. (2016)

Chevalier et al. (2015)

N subjects/group Group 1: 52 cryptorchid boys Group 2: 128 control boys

The Role of the Environment in Testicular Dysgenesis Syndrome (continued)

5 genital stage, testicular volume, pubic hair stage, and hormonal status " risk of cryptorchidism in boys exposed to PCB

" risk of hypospadias in the sons of women exposed to DES

" risk of fetal malformations in the higher tertile of exposure to BPA and propyl-BP

Main outcomes Cord blood levels of BPA were negatively correlated with INSL3 in the whole population

Table 2 Summary at a glance of clinical studies focusing on the effects of exposure to endocrine disrupting compounds with estrogenic, anti-androgenic, and mixed estrogenic and anti-androgenic properties

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Weidner et al. (1998)

Carbone et al. (2006) Damgaard et al. (2006)

Andersen et al. (2008)

Group 1: 7522 cryptorchidism and/or hypospadiasaffected boys Group 2: 23,273 control boys Group 1: 8981 boys

N subjects/group Group 1: 91 boys Group 2: 22 control boys Group 1: 8199 boys Group 1: 62 cryptorchid boys Group 2: 22 control boys

Table 2 (continued)

NA

Group 1: M 277 days (gestational age) Group 2: M 281.5 days (gestational age) NA

Age Group 1: M 3.09 Group 2: M 3.07 NA

Environmental exposure

Professional parental exposure

Environmental exposure Environmental exposure

Timing of exposure Professional exposure during pregnancy

Heavy metal air pollutants (manganese, lead, cadmium, mercury, nickel, arsenic, and chromium)/ecological criteria of exposure

Chemicals employed in farming and gardening; anamnestic exposure

Pesticides/ecological criteria of exposure Pesticides/breast milk

Type of exposure/sample for measurement Pesticides/anamnestic exposure

" risk of hypospadias at: -medium-high exposure to manganese and lead, cadmium, mercury, and nickel -low and high exposure to arsenic and chromium

" risk of cryptorchidism but not hypospadias in the sons of women working in gardening

" risk of hypospadias with increasing “pesticide impact” Pesticide levels in breast milk were significantly higher in boys with cryptorchidism

Main outcomes " risk of micropenis in the sons of women professionally exposed to pesticides

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Group 1: 464 boys

Small et al. (2009)

Group 1: R 34-45 weeks (gestational age)

NA

Environmental exposure

Professional paternal exposure during prenatal life Dioxin-contaminated chlorophenols exposure/ estimations of hours of exposure in specific time windows prior to birth PBB/maternal serum

" risk of cryptorchidism with dioxin-contaminated chlorophenols exposure in pre-conceptional but no other prenatal phases " risk of genitourinary malformations, particularly hernia and hydrocele, but not cryptorchidism and hypospadias, in sons of highly PBB-exposed women

Abbreviations: R, range; M, mean; m, median; PCDD, polychlorinated dibenzo-p-dioxins; BPA, bisphenol A; PCB, polychlorinated biphenyls; DDE, dichlorodiphenyldichloroethylene; BP, biphenyls; DES, diethylstilbestrol; DBP, di-n-butyl phthalate; PBB, polybrominated biphenyl. ", increased; #, decreased; ¼, no change/not correlated

Group 1: 19,675 boys

Dimich-Ward et al. (1996)

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12.5–16.5 of pregnancy to the pesticide atrazine was reported to develop hypospadias and cryptorchidism (Tan et al. 2021). Such effects have been proposed to result from decreased maternal serum testosterone levels and decreased steroidogenic enzymes and INSL3 expression in the developing reproductive system, as well as from changes in the expression of genes involved in the development of male reproductive system (Tan et al. 2021). Similarly, some fungicides, such as vinclozolin and procymidone, have been shown to act during prenatal life as competitive antagonists of AR and to induce hypospadias, cryptorchidism, and prostate dysgenesis or underdevelopment (Wolf et al. 1999; Ostby et al. 1999; Shono et al. 2004; Metzdorff et al. 2007). Little is known about the effects of endocrine disrupting compounds with antiandrogenic properties on the development of TGCC in experimental studies, due to the absence of a suitable animal model for human TGCC. In rats, exposure to DBP and DEHP early in gestation (days 13.5–15.5) was shown to promote the pathogenesis of TGCC by inducing germ-cell apoptosis and prolonged hyperexpression of the oncogenic octamer-binding transcription factor 3/4 (Jobling et al. 2011). Evidence collected in human biological and epidemiological studies showed endocrine disrupting compounds with anti-androgenic properties, including phthalates, pesticides, and heavy metals, to be associated with the occurrence of TDS. Levels of phthalates and their metabolites mono-ethyl phthalate, mono-n-butyl phthalate (mBP), monobenzyl phthalate (mBzP), mono(2-ethylhexyl) phthalate (mEHP), and monoisononyl-phthalate (miNP) measured in breast milk were found to positively correlate with sex hormone binding globulin (SHBG), luteinizing hormone (LH), and LH/testosterone ratio levels and negatively with free testosterone levels, thus suggesting that phthalate might adversely impact Leydig cell function (Main et al. 2006). Levels of phthalates measured in maternal urine were demonstrated to negatively correlate with AGD (Swan et al. 2005), therefore supporting the hypothesis of incomplete virilization following phthalate exposure. Very few studies investigated a possible association between urine phthalates metabolites and hypospadias or cryptorchidism, demonstrating that male offspring of mothers with higher levels of DEHP metabolites had a higher risk of developing either condition (Yu et al. 2022); conversely, data derived from case–control studies demonstrated that perinatal exposure to phthalate did not increase the risk of developing congenital cryptorchidism (Main et al. 2006; Swan et al. 2005). Ecological studies in the Mediterranean area hypothesized the association between exposure to persistent pesticides and the development of hypospadias and cryptorchidism (Carbone et al. 2006; Carbone et al. 2007; Garcia-Rodriguez et al. 1996). However, studies investigating the potential role of parental pesticide exposure and occurrence of hypospadias and cryptorchidism in offspring failed to clearly confirm the possible effects of pesticide exposure. Indeed, paternal (Pierik et al. 2004) or maternal (Carbone et al. 2007; Andersen et al. 2008; Biggs et al. 2002; Restrepo et al. 1990; Weidner et al. 1998) exposure to pesticides was found to be not associated with an increased risk of hypospadias and cryptorchidism in sons, and no significant difference in the prevalence of cryptorchidism between sons of exposed and non-exposed mothers was reported (Andersen et al. 2008). Levels of pesticides

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measured in maternal breast milk were found to be higher, although not significantly, in cryptorchid patients as compared to controls (Damgaard et al. 2006; BruckerDavis et al. 2008), suggesting the potential role of pesticide exposure as a proxy for TDS. However, in sons from mothers exposed to pesticides, testicular volume, and testosterone and inhibin B levels were found to be reduced, whereas follicle stimulating hormone and SHBG levels, and LH/testosterone ratio were found to be increased, thus suggesting that fetal exposure to pesticides might alter Sertoli and Leydig cell function (Andersen et al. 2008). Heavy metals, such as cadmium, lead, arsenic, and chromium, have also been proposed to play a role in the pathogenesis of TDS. Particularly, cadmium and lead levels were higher in blood samples from boys with hypospadias as compared to healthy controls (Sharma et al. 2014). Similarly, in an American exposure model, high arsenic and chromium levels were reported in boys with hypospadias in the Texas Birth Defects Registry (White et al. 2019), suggesting the necessity for future studies to better elucidate the role of these pollutants in the pathogenesis of TDS. The few studies addressing maternal heavy metals exposure in relation to the risk for cryptorchidism in boys are insufficient to allow any firm conclusion. Evidence nowadays available about the potential role of endocrine disrupting compounds with anti-androgenic properties in the pathogenesis of TGCC is yet to be fully exhaustive. Little is known about the potential role of phthalates as risk factors for TGCC, and no clear etiological association was demonstrated (Sharpe 2001; Toppari et al. 2010). Similarly, discordant results were provided about the association between pesticides exposure and TGCC; maternal levels of organochlorine pesticides were higher in mothers of TGCC patients, as compared to control mothers (Hardell et al. 2006), but no clear etiological association between fetal pesticides exposure and TGCC was reported, since no difference was found in organochlorine pesticides levels in TGCC patients, as compared to controls (Hardell et al. 2006; McGlynn et al. 2008). Scarce evidence is nowadays available about the potential role of exposure to heavy metals in the pathogenesis of TGCC; however, evidence collected so far does not support a direct etiological role of heavy metals as main contributors for the development of TGCC and is insufficient to draw definitive conclusions on the possible effects of heavy metals exposure on testicular carcinogenesis (Togawa et al. 2016; Verhoeven et al. 2011). Taken these findings altogether, prenatal exposure to endocrine disrupting compounds with anti-androgenic properties negatively impacts male reproductive system function and appears to be associated with an increased risk of developing TDS, mainly hypospadias and cryptorchidism, whereas there is still a considerable lack of consistency amongst studies about the association of exposure to endocrine disrupting compounds with anti-androgenic properties and TGCC, thus requiring further investigation to better elucidate the burden and the role of such endocrine disrupting compounds in the pathogenesis of TDS. Table 1 shows the endocrine disrupting compounds with anti-androgenic properties; Table 2 shows a summary at a glance of clinical studies focusing on the effects of exposure to endocrine disrupting compounds with anti-androgenic properties.

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Exposure to Endocrine Disrupting Compounds with Mixed Properties Evidence collected in animal models demonstrated that the exposure to endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties, including the pesticides DDT and its metabolite DDE, and the flame retardants TBECH, PBB, and PBDE, can affect male reproductive system function by potentially promoting the development of TDS, although for some of them evidence is not fully conclusive. Particularly, rat male offspring from mothers exposed on days 14–18 of pregnancy to DDE was reported to develop hypospadias, and rabbits exposed during prenatal life to DDE were reported to develop unilateral or bilateral cryptorchidism, the toxicity being even greater after combined gestational and postnatal exposure to this chemical (Wolf et al. 1999). No direct evidence is available concerning the direct mechanisms underlying such effects on male reproductive development; nevertheless, in different in vitro experimental models, DDT and DDE were demonstrated to directly affect Leydig cell function by disrupting early steps of testicular steroidogenesis, independently on cell viability, to antagonize DHT binding to – and activation of – AR, and to bind ER by stimulating ER-dependent transcriptional activation, therefore potentially interfering with fetal hormonal environment (Enangue Njembele et al. 2014; La Merrill et al. 2020). Exposure to flame retardants, which are persistent, bio-accumulative, and toxic compounds including different classes such as minerals, organohalogen compounds, organophosphorus compounds, and organic compounds, was also shown to exert estrogenic, anti-estrogenic, or anti-androgenic activities in animal models. Particularly, in chicken and zebrafish models, the flame retardant TBECH was shown to bind AR and to modulate AR-mediated gene transcription, displaying an antiandrogenic activity (Asnake et al. 2014; Asnake et al. 2015; Pradhan et al. 2015; Pradhan et al. 2013). In rats, exposure during prenatal life to brominated flame retardants, such as PBDE, was associated with an estrogenic action with a consequent increased expression of estrogen-responsive genes (Ceccatelli et al. 2006), together with an anti-androgenic action through binding AR and negatively modulating expression of androgen-responsive genes (Stoker et al. 2005). This mixed effect was therefore demonstrated to induce alterations in testicular development with detrimental effects on spermatogenic process (Talsness et al. 2009), AGD and puberal onset (Lilienthal et al. 2006). Worth to note, no effects on the development of hypospadias and cryptorchidism are clearly reported in animals exposed to TBECH, PBB, and PBDE or to different endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties, such as PCB and TCDD, despite their high capability to bioaccumulate and act as persistent organic pollutants (Wolf et al. 1999). No effects on the development of TGCC are clearly reported in animals exposed to endocrine disrupting compounds with mixed estrogenic and antiandrogenic properties. Evidence collected in human studies, although controversial and with non-univocal results, suggested that endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties might be associated with the risk of TDS development, with

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some specific differences for the single compounds. Exposure to DDT and DDE, as assessed in pregnant mother’s serum samples, was reported to be not associated with an increased risk of hypospadias in studies performed in geographically distinct populations, although a small sample size was included (Raghavan et al. 2018; Flores-Luevano et al. 2003; Longnecker et al. 2002); conversely, a larger study adjusted for potential confounding factors found an increased risk of hypospadias in male offspring of women with serum DDE concentrations in the highest quartile, compared to women in the first quartile during the 14th week of pregnancy (RignellHydbom et al. 2012). Moreover, a study from the Nice area demonstrated that DDE exposure, as assessed in maternal breast milk, was associated with an increased risk of congenital cryptorchidism in male offspring, but no significant association emerged when exposure to DDE was assessed in maternal cord serum samples (Brucker-Davis et al. 2008). However, the exposure to DDT and DDE, as assessed in pregnant mother’s serum samples, was reported to be not associated with an increased risk of cryptorchidism in male offspring in the U.S. (Virtanen et al. 2012). No clear association between exposure to flame retardants and hypospadias and cryptorchidism was generally reported; in particular, no significant association between PBB maternal serum levels and cryptorchidism occurrence in male offspring was reported (Small et al. 2009), whereas a higher risk of developing cryptorchidism was found associated with maternal exposure to PBDE, as assessed in breast milk but not in placenta samples (Main et al. 2007). Maternal exposure to PCB, assessed in maternal serum (McGlynn et al. 2009) and in umbilical cord (Mol et al. 2002), was correlated to a significantly increased risk of hypospadias (McGlynn et al. 2009) and cryptorchidism (McGlynn et al. 2009; Mol et al. 2002) in male offspring. Similarly, another study from the Nice area demonstrated that PCB exposure, as assessed in maternal breast milk, was associated with an increased risk of congenital cryptorchidism in male offspring, but no significant association emerged when exposure to PCB was assessed in maternal cord serum samples (Brucker-Davis et al. 2008). No clear association between exposure to dioxins and hypospadias was documented, whereas association between exposure to 17 different dioxin compounds, as assessed in maternal placenta, and cryptorchidism (Virtanen et al. 2012) and between paternal exposure to dioxincontaminated chlorophenols and genital abnormalities, including cryptorchidism, were documented (Dimich-Ward et al. 1996). Currently available knowledge about the potential role of endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties and TGCC development appears to be heterogeneous and differently consistent according to the specific compounds. Scientific evidence supports no association for DDT exposure, and a positive association for fetal DDE exposure, and TGCC (McGlynn et al. 2008; Cook et al. 2011). No data are currently available about exposure to flame retardants and dioxin compounds and their possible direct role in TGCC development, and controversial and inconclusive data exist for PCB exposure. Nevertheless, the comparison between the Danish population, characterized by a high prevalence of TDS disorders, and the Finnish population, characterized by a low prevalence of TDS disorders, demonstrated significantly higher levels in maternal breast milk of TCDD, but not of PBB and PBDE, in the Danish than in the Finnish population,

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therefore suggesting a possible role of dioxin compounds, but not flame retardants, in TDS and, possibly in case of simultaneous exposure to multiple endocrine disrupting compounds, also in TGCC (Hanna and Einhorn 2014). Taken these findings altogether, controversial and inconclusive results are nowadays available about the association between prenatal exposure to endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties, male reproductive system function and TDS, with heterogeneous association between specific compounds and specific aspects of TDS, and fragmented or absent evidence for different compounds. Further studies are therefore required to better elucidate the role and the burden of such endocrine disrupting compounds in the pathogenesis of TDS. Table 1 shows the endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties; Table 2 shows a summary at a glance of clinical studies focusing on the effects of exposure to endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties.

The Environment-Genes Component in Testicular Dysgenesis Syndrome: Contribution to Testicular Cancer Etiology The concept of TDS as a distinct clinical entity including male reproductive system disorders sharing a common origin during prenatal life has been widely accepted, and the relative role of environmental exposures, with particular reference to endocrine disrupting compounds, has been extensively reviewed in the current chapter; nevertheless, despite the inherent limitations of available literature, the implication of environmental influences in the etiology of TDS has also been argued so far, in light of the more robust and historically described inference by different non-environmental factors. This is the case for testicular cancer (TC), which represents a clinically relevant disorder in the context of TDS, being the most prevalent tumor in males of reproductive age and displaying a progressively increasing prevalence throughout the last four decades (Hanna and Einhorn 2014; Znaor et al. 2014). The current pathophysiological hypothesis, based on clinical and experimental evidence, that better explains this epidemiological trend, relies on the increased exposure to environmental factors, particularly, to endocrine disrupting compounds putatively impairing the hypothalamus-pituitary-testis axis, the major endocrine system driving testicular development and function from gestational age (De Toni et al. 2019). Nevertheless, it is widely acknowledged that TC susceptibility is also dependent on genetic factors, which strongly explain familiarity of TC. Despite the evidence that 90% of males affected by TC have no previous familiar cases of this disease, population-based studies in the late 1990s–early 2000s demonstrated that having a father affected by TC increases the risk of the disease for the male child from four- to six-fold and, moreover, having a brother with a positive history of TC increases the risk of the disease from eight- to ten-fold, compared to the general male population (Westergaard et al. 1996; Hemminki and Chen 2006; Gundy et al. 2004). Consistently, a recent study based on a population-based registry investigated

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monozygotic and same-sex dizygotic twins and concluded on a possible familial risk of heritability for TC of nearly 40%, with a significant proportion of risk, however, attributable to shared environmental factors (Mucci et al. 2016). In addition, in an interesting population-based registry study including 9.6 million individuals from the nationwide Swedish Family-Cancer Database, essentially relying on epidemiological considerations, and aimed at identifying the relative genetic, pureenvironmental and childhood-environmental contribution to the development of tumors, TC was surprisingly one of the tumors mostly associated (25%) with genetic etiologies, right after thyroid tumors (53%) and endocrine tumors (28%) (Czene et al. 2002). Nevertheless, it should be considered that despite the epidemiological evidence supports a familial background for TC development, no clear evidence is available concerning the qualitative and quantitative changes in specific genetic factors potentially underlying the genetic basis of familial TC. The current paragraph specifically focuses on the genetic component of TC risk and development, as opposed to the environmental component, by highlighting the results of compelling and recent studies in the field of genetics; a final comment on the potential role of epigenetics in the interaction between genetic and environmental risk factors for TC is also enclosed. A linkage study on 237 pedigreed families with history of one or more cases of TC identified six genetic regions on chromosomes, including Xq27, 2p23, 3p12, 3q26, 12p13-q21, and 18q21-q23, as susceptibility loci; however, further evidence demonstrated that no single locus was responsible for the majority of the familial predisposition observed in TC and, conversely, suggested a major role for multiple susceptibility genetic loci with individual weak effects (Crockford et al. 2006). A significant contribution to the topic was provided by genome-wide association studies (GWAS) that progressively enlarged the range of susceptibility loci with a potential role on TC genetic predisposition and subsequent development (Chung et al. 2013; Kristiansen et al. 2015; Ruark et al. 2013; Dalgaard et al. 2012; Nathanson et al. 2005; Litchfield et al. 2015). A recent GWAS also including a meta-analysis of previous GWAS, globally evaluating 7,319 TC cases and 23,082 controls from northern Europe, confirmed the previously reported existence of 25 TC risk loci and implemented these findings by the identification of 19 new TC risk loci (Litchfield et al. 2017); in clinical terms, the 44 identified TC risk loci were responsible for 34% of the father-to-son familial risk for TC development, whereas the top 1% genetic risk at a polygenic risk scores model had a relative risk of 14% and 7% lifetime risk of developing TC (Litchfield et al. 2017). In addition, through a specific molecular analysis on TC cells, a study of chromatin interactions between predisposing SNPs and target genes was performed, identifying three possible pathogenic mechanisms through which these loci could be involved in TC development (Litchfield et al. 2017); a first pool of 10 risk loci could be grouped since they included genes involved in the transcriptional regulation of cell development and comprised GATA4 and GATA1, PRDM14, DMRT1, and POU5F1 as genes significantly associated with TC development risk (Litchfield et al. 2017; Rao et al. 2010). GATA4 and GATA1 genes are transcription factors contributing to differentiation and development of postnatal testis and were previously reported as potentially

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involved in tumor progression (Litchfield et al. 2017); PRDM14 and DMRT1 genes are involved in germ-cell specification–sex determination (Litchfield et al. 2017); POU5F1 gene is associated with the maintenance of pluripotency in embryonic stem cells (Litchfield et al. 2017; Rao et al. 2010). In addition, five TC risk loci were associated with genes involved in microtubule constitution, particularly, the WDR73 gene encoding a key protein for microtubule assembly during interphase (Colin et al. 2014), the TEX14 gene contributing to kinetochore microtubule assembly in testicular germ cells (Bojesen et al. 2013; Jinks et al. 2015; Mondal et al. 2012), and the microtubule assembly–related genes CENPE, PMF1, and PCNT (Barisic et al. 2015; Petrovic et al. 2010; Rao et al. 2009; Ma and Viveiros 2014). Furthermore, three additional TC risk loci suggested a possible role of KIT–MAPK signaling pathway, consistently with previously reported evidence subtending KIT gene as a major somatic driver for TC development (Litchfield et al. 2015). Another recent metaanalysis, including five GWAS evaluating the X-chromosome, demonstrated further 12 TC risk loci and suggested the possible role of different genes involved in specific cell pathways, in particular the ZWILCH gene involved in the regulation of the kinetochore function, the TFCP2L1 and ZFP42 genes involved in germ-cell development and pluripotency, the TIPIN gene regulating cell response to DNA damage, and TKTL1 and LHPP genes involved in the regulation of mitochondrial function (Wang et al. 2017). Recently, a great interest has been raised on the role of gene copy number variations (CNVs) in the risk of cancer development and progression, particularly as concerns TC (Stadler et al. 2012; de Smith et al. 2008; Edsgard et al. 2013). A recent study investigated the possible role of E2F1 gene CNVs as a TC risk factor (Rocca et al. 2017). E2F1 gene is a transcription factor regulating the progression of cell cycle from G1 to S phase, by interacting with the retinoblastoma tumor suppressor protein (pRB) (Bertoli et al. 2013; Johnson 2000; Sengupta and Henry 2015); disruption of E2F1pRB interaction increases the access of E2F1 to E2F1-response elements, and this is thought to enhance cell susceptibility to tumor development (Giacinti and Giordano 2006). According to this hypothesis, overexpression of E2F1 in tumor cell lines was demonstrated to increase cell proliferation through mTOR signaling pathway (Ladu et al. 2008). Consistently, a recent study demonstrated a global prevalence of 6.5% of E2F1 gene duplications only in patients with history of TGCC, but not in a control group; moreover, an increased expression of E2F1 was detected only in tumor tissues, whereas surrounding non-tumor tissue showed lower E2F1 expression and downstream mTOR activation (Rocca et al. 2017). These results strongly suggested an etiological role of E2F1 CNVs in TC risk through the hyperactivation of downstream Akt/mTOR signaling pathway. Besides an intrinsic genetic component in TC risk, it should be recognized that also some clinical risk factors for TC, such as cryptorchidism, have a genetic component-based risk; in particular, specific genetic factors involved in testicular migration during embryonal development were identified as genetic risk factors for cryptorchidism (Purdue et al. 2005). Genetic studies in cryptorchid boys demonstrated a 2% and 4% prevalence of mutations in the INSL3 and RXFP2 genes, more frequently found in bilateral forms of cryptorchidism, whereas unclear evidence is

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available concerning the potential causative involvement of CNVs (Ferlin et al. 2008; Krausz et al. 2000; Mamoulakis et al. 2014); on the other side, a poor association was found between AR mutations, such as poly CAG and GGN repeats, and the occurrence of cryptorchidism and, consistently, the prevalence of such genetic alterations in cryptorchid males is estimated to be lower than 2% (Wiener et al. 1998; Radpour et al. 2007; Ferlin et al. 2005). Moreover, one of the most relevant causes of cryptorchidism is Klinefelter syndrome (KS), a genetic syndrome affecting about 1 every 700 men presenting with a typical clinical picture characterized by small testes, infertility, high levels of gonadotrophins, testosterone at the lower levels of normality, and cryptorchidism, which is about six times more prevalent in KS than in the general male population (Bojesen et al. 2006). Nevertheless, the few available studies concerning a possible association between KS and TC, mainly Leydig cell tumors, are mainly represented by case reports, therefore providing no conclusive insights into their association (De Toni et al. 2019; Ferlin et al. 2008). Additional genetic causes of isolated cryptorchidism are represented by mutations of AMH gene or its receptor in the persistent Müllerian duct syndrome (Josso et al. 1993; Abduljabbar et al. 2012). In addition, hypospadias has been also considered a risk factor for TC (Lymperi and Giwercman 2018), accounting for about 10% of familial clustering, whereas the estimated heritability of this disease ranges from 57% to 77% (Schnack et al. 2008; Stoll et al. 1990). Epigenetics refers to the inheritance of genetic marks that do not rely on variation of genetic sequence, but rather on the regulation of gene expression trough DNA methylation, histone modifications, and by the silencing action of microRNAs (miRNAs); this branch of genetics was recently invoked to integrate the knowledge on the interactions between environmental and genetic risk factors for TC, and to address the relative impacts. Recent studies demonstrated that DNA deriving from TGCC is characterized by a significantly aberrant methylation pattern, which appears to be correlated with TGCC subtypes and histological features; in particular, hypomethylation is detected in seminoma, GCNIS, and gonadoblastoma, whereas hypermethylation is detected in teratoma, yolk sac tumor, and choriocarcinoma, and embryonal carcinoma display intermediate methylation patterns, as compared to normal germ cells (Landero-Huerta et al. 2017). These methylation changes, particularly those occurring in the most common forms of TGCC, are likely due to aberrant expression of demethylating factors that are generally suppressed after fetal germ cell development (Kristensen et al. 2014). Specifically, two crucial genes involved in the maintenance of pluripotency in embryonic stem cells, NANOG and POU5F1, are normally hypomethylated in spermatogonia and hypermethylated in spermatozoa, by reflecting the requirement of deleting pluripotency in these cells to prevent malignant transformation; interestingly, the same genes were found hypermethylated in TC (Landero-Huerta et al. 2017). Histone modifications, including both methylation and acetylation, and fluctuations in miRNA expression were also identified as potential pathogenetic mechanisms in TC, and, particularly in the case of miRNA, are being investigated as novel diagnostic, prognostic, and response to treatment markers (LanderoHuerta et al. 2017).

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Table 3 Genetic factors associated with testicular cancer and involved mechanisms GATA4, GATA1 PRDM1, DMRT1 POUF5 WDR73, TEX14, CENPE, PMF1, PCNT

Mechanism Differentiation and development of postnatal testis Germ-cell specification–sex determination Maintenance of pluripotency in embryonic stem cells Microtubule assembly; kinetochore microtubule assembly; microtubule assembly-related

KIT ZWILCH TFCP2L1, ZFP42 TKTL1, LHPP E2F1 INSL3, RXFP2

KIT-MAPK signaling pathway Kinetochore function Germ-cell development and pluripotency Mitochondrial function Cell cycle progression Cryptorchidism

AR

Cryptorchidism; steroidogenesis; disorders of sex development Cryptorchidism; disorders of sex development

AMH

Reference Litchfield et al. (2017) Litchfield et al. (2017) Litchfield et al. (2017), Rao et al. (2010) Colin et al. (2014), Bojesen et al. (2013), Jinks et al. (2015), Mondal et al. (2012), Barisic et al. (2015), Petrovic et al. (2010), Rao et al. (2009), Ma and Viveiros (2014) Litchfield, K. (2015) Wang et al. (2017) Wang et al. (2017) Wang et al. (2017) Wang et al. (2017) Ferlin et al. (2008), Krausz et al. (2000), Mamoulakis et al. (2014) Weidner et al. (1998), Radpour et al. (2007), Ferlin et al. (2005) Abduljabbar et al. (2012), Josso et al. (1993)

This evidence of a potential contribution of epigenetics to TC etiology provides the rationale for the mechanistic hypothesis that environmental factors might contribute to TC development by altering epigenetic landmarks, a mechanism widely acknowledged among those exerted by endocrine disrupting compounds (LanderoHuerta et al. 2017; Schagdarsurengin and Steger 2016). Table 3 shows a list of genetic factors associated with TC and involved mechanisms. Figure 6 shows the schematic representation of epigenetic changes proposed to be involved in TC development.

Conclusions Prenatal exposure to several endocrine disrupting compounds was demonstrated to interfere with the male endocrine and reproductive system, mainly inducing TDS, which is a unique syndrome comprising a spectrum of male genital disorders such as impairment of semen quality, hypospadias, cryptorchidism, and TGCC. Evidence deriving from animal studies widely demonstrated and supported a specific role for endocrine disrupting compounds with estrogenic, anti-androgenic, and mixed estrogenic and anti-androgenic properties in the pathogenesis of TDS. Evidence collected

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Fig. 6 Schematic representation of epigenetic changes proposed to be involved in testicular cancer (TC) development. DNA deriving from testicular germ-cell cancer is characterized by a significantly aberrant methylation pattern, including both hypermethylation (SPRY4, BAK1, PDE11A, DND1, APOLD1, RGAG1, PCDH10) and hypomethylation (KITLG, NANOG, POU5F1) of target genes, by histone modifications, including both abnormal methylation (H2A, H3, H4) and reduced acetylation (over-expression of deacetylases), and by fluctuations in miRNA expression, including both up-regulation (miR-302, miR-367, miR-371, miR-373, miR-301, miR-106b, miR-21, miR-221, miR-222) and down-regulation (miR-17-5p, miR-154, miR-1297), compared to non-tumoral cells. Abbreviations: HDACs, deacetylases; TC, testicular cancer

in human studies appears to be heterogeneous, and often provides a non-univocal interpretation according to different study methodologies and classes of compounds. Based on the current knowledge, prenatal exposure to endocrine disrupting compounds with estrogenic and anti-androgenic properties negatively impacts male reproductive system function, whereas controversial and inconclusive results are available concerning compounds with mixed estrogenic and anti-androgenic properties. A clear association between prenatal exposure to endocrine disrupting compounds and development of hypospadias and cryptorchidism was demonstrated for selected compounds having estrogenic and anti-androgenic properties, specifically, bisphenol A and hypospadias, diethylstilbestrol and cryptorchidism, DEHP metabolites and both hypospadias and cryptorchidism, and heavy metals and hypospadias, whereas for endocrine disrupting compounds with mixed estrogenic and anti-androgenic properties a similar association is only weakly supported, based on studies with partial and controversial results, for PCB and hypospadias and dioxin and cryptorchidism. Moreover, in the last 50 years, studies investigating the role of endocrine disrupting compounds as potential risk factors for TGCC, a disease with a more pronounced genetic component, provided unclear, inconsistent, and sometimes scarce findings, except for some specific compounds, such as DDE, whose

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association with the development of TGCC was clearly documented. In most cases, this discrepancy is the result of the so-called “cocktail effect,” which hampers a clear interpretation of the detrimental effects of single compounds in conditions of predetermined mixed exposure. Future research is therefore required to confirm the partially unclear observed associations between exposures and TDS; the availability of novel strategies of investigation and the contribution of an integrated environment-gene research approach are of paramount importance to clarify the key aspects of TDS and its related diseases development, in order to further improve prevention strategies and treatment options for these overall curable diseases, characterized by a still partially unexplained increasing prevalence.

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Environmental Impact on Sexual Response

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Carlotta Cocchetti, Dominik Rachoń, and Alessandra D. Fisher

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EDCs and Sexual Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology of Sexual Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Influence of EDCs on Sexual Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EDCs and Sexual Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology of Sexual Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EDCs and Sexual (Dys)function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EDCs, Sexual Orientation, and Gender Identity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological Basis of Sexual Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological Basis of Gender Identity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Influence of EDCs on Sexual Orientation and Gender Identity . . . . . . . . . . . . . . . . . . . . . . . Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

By interfering with sex hormone signaling, endocrine-disrupting compounds (EDCs) may affect several levels of reproduction, such as the development of reproductive organs and secondary sexual characteristics, sexual function, and sexual orientation/core gender identity. Results from the studies conducted on animals provide insights into the potential mechanisms of EDCs on the sexual differentiation and function and point to the differential sensitivity, timing, and C. Cocchetti · A. D. Fisher (*) Andrology, Women’s Endocrinology and Gender Incongruence Unit, Careggi University Hospital, Florence, Italy e-mail: carlotta.cocchetti@unifi.it; afisher@unifi.it; fi[email protected] D. Rachoń Department of Clinical and Experimental Endocrinology, Medical University of Gdańsk, Gdańsk, Poland e-mail: [email protected] © Springer Nature Switzerland AG 2023 R. Pivonello, E. Diamanti-Kandarakis (eds.), Environmental Endocrinology and Endocrine Disruptors, Endocrinology, https://doi.org/10.1007/978-3-030-39044-0_11

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type of exposure to these compounds across the species. Luckily, reports on the environmental or domestic EDCs’ exposure and impaired sexual differentiation or function in humans are scarce. The evidence that EDCs can also influence the developing brain in a way that interferes with sexual behaviors has considerably grown in the last decade. Data from recent rodent studies point to a possible etiological link between prenatal exposure to EDCs and the development of sexual orientation and core gender identity. Nevertheless, most of the data come from animal experiments and therefore further studies are warranted. Keywords

EDCs · Sexual differentiation · Sexual function · Sexual orientation · Gender identity

Introduction Endocrine-disrupting chemicals (EDCs) are defined by the Endocrine Society expert group as “exogenous agents that mimic, block, or interfere with hormones in the body’s endocrine system” (Zoeller et al. 2012). These molecules are extremely heterogeneous and include both synthetic and natural chemicals. Synthetic chemicals are widespread in the environment and can be found in plastics [bisphenol A (BPA) and phthalates], flame retardants, personal care products/household chemicals, industrial chemicals such as polychlorinated biphenyls (PCBs), and include pesticides and fungicides. Thus, humans are exposed to EDCs from several sources, and this may be dangerous especially during critical life stages, such as in fetuses or children. EDCs may interfere with body’s endocrine functions and affect fertility, sexual health, thyroid function, metabolism, or promote the development of hormone-sensitive cancers (i.e., prostate, breast, endometrium) (Zoeller et al. 2012). In particular, EDCs can interfere with the hormonal system by binding to hormone receptors and acting as agonists or antagonists (Gore et al. 2015). Additionally, some EDCs are able to affect hormone metabolism or degradation (Aluru and Vijayan 2006). Due to their lipophilic nature, most EDCs cross cell membranes, including the blood–brain barrier, and exert actions within neural cells, also binding intracellular receptors (Fernandez et al. 2004). At the same time, they can cross the placenta, leading to possible long-term consequences in case of in utero exposure. In the circulatory system, EDCs may travel as free chemicals or associated with several binding proteins, showing a high bioavailability. In particular, among the known pleiotropic effects of EDCs on hormonal system, their interference with the estrogen (ER) and androgen receptor (AR) signaling pathways is a subject of several studies. Due to these effects, early exposure of a fetus or infant to EDCs may have several consequences since in these phases of development endogenous hormones are critical for growth, maturation, and sexual differentiation. In fact, by interfering with the aforementioned signals, EDCs may influence different levels of reproduction, including the development of the reproductive organs, hormone release, and regulation, and thus development of secondary sexual characteristics. Sex hormone

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concentrations during prenatal period also play a critical role in the development of sexual orientation and core gender identity (Ristori et al. 2020). The developing brain is highly sensitive to endogenous hormones, thus disruptions caused by prenatal exposure to EDCs may deeply affect the organizational effects of sex steroids on the brain. For this reason, in the last years a growing body of literature explored the possible impact of EDCs exposure on sexual differentiation, function, and development of brain sexual differentiation, evaluating also the development of sexual orientation and core gender identity. However, research in this field is limited by the difficulty to establish a strict cause-and-effect relationship between developmental EDC exposure and endocrine disease. In fact, to date available evidence is rather scarce and mainly focused on preclinical studies, with very few cases of accidental environmental/occupational exposure to EDCs reported in literature.

EDCs and Sexual Differentiation Physiology of Sexual Differentiation Human sexual differentiation is a complicated and dynamic process, regulated by genetic and endocrine factors. Establishment of the chromosomal sex – on the basis of the presence of a Y or X chromosome – represents the first step in sexual differentiation by influencing the differentiation of the bipotential gonadal ridge into testes or ovaries. In this process, the testes determining gene SRY, which is located on the distal part of the short arm of the Y chromosome, plays a key role in inducing the differentiation of the bipotential embryonic gonad into testes, with the development of Sertoli and Leydig cells (Sinisi et al. 2003). At this point, Sertoli cells produce the anti-Müllerian hormone (AMH), which is responsible for the regression of the Müllerian ducts, avoiding the development of the uterus, fallopian tubes, and the distal portion of the vagina. On the other hand, Leydig cells begin to produce testosterone, which promotes the differentiation of Wolffian ducts into vasa deferentia, epididymis, and seminal vesicles. Furthermore, through testosterone conversion into dihydrotestosterone (DHT) by the tissue-specific 5-alpha-reductase type 1 and 2, masculinization of the fetus external genitalia occurs. This process leads to phallic enlargement and closure of the urethral folds and scrotum development. In contrast, in 46,XX individuals, the absence of SRY gene drives the sexual differentiation in the female direction. In this case, in the absence of the AMH, the uterus, fallopian tubes, and the distal portion of the vagina develop from the Müllerian ducts; whereas, due to the lack of testosterone, the Wolffian ducts regress (Sinisi et al. 2003). Furthermore, external genitalia differentiate in the female direction, with the development of clitoris from genital tubercle, labia minora and majora from urethral folds and labioscrotal swellings. It is known that the process of sexual differentiation does not end with the development of genitalia. In fact, once the differentiation of sexual organs happened, sexual differentiation of the brain starts, through permanent organizing effects of sex hormones on the developing brain. During human development, the crucial periods in which testosterone levels

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are known to be higher in males are two: mid-pregnancy and the first 3 months after birth (Ristori et al. 2020). These two peaks have a role in organizing brain structures and signaling.

The Influence of EDCs on Sexual Differentiation Considering the above, it seems logical that fetal exposure to any compounds, which will block or mimic the action of testosterone, will significantly interfere with sexual differentiation in the male direction. Inhibition of AR signaling in the developing male fetus will usually lead to its feminization and such disorders as hypospadias, cryptorchidism, and micropenis can be encountered (Sharpe 2006). On the contrary, in utero exposure to androgen-mimics will lead to masculinization of the fetus and ambiguous or virilized external genitalia (Sharpe 2006). Nowadays, unintentional exposure to several EDCs has been shown to have deleterious effects on several wildlife species and data from the studies conducted on reptiles and fish provide insights into the potential mechanisms of EDCs on the sexual differentiation (summarized in Table 1) (Sun et al. 2017; Murray et al. 2016; Jandegian et al. 2015). Sun et al. (2017) evaluated the impact on zebrafish of nonylphenol – an EDC that can bind estrogen receptors acting like endogenous estrogen mimics – which has been detected in the surface water and sea (Sun et al. 2017). By exposing three generations of zebrafish to progressively increasing concentrations of nonylphenol, researchers found that higher concentrations may alter transcriptional expression of sexual differentiation-related genes. Particularly, transcription of cyp19a1a and esr1 genes – which are related to aromatase function – resulted upregulated in exposed zebrafish (Sun et al. 2017). Murray et al. (2016) evaluated the effect of embryonic exposure to 17α-methyltestosterone – a synthetic androgen – on sexual differentiation in American alligators (Murray et al. 2016). This EDC is typically used in tilapia farming to bias sex ratio toward male sex because males are more profitable. Authors demonstrated that exposition to 17α-methyltestosterone resulted in a higher rate of hermaphroditic primary sex organs and delayed renal development and masculinization of the clitero-penis in exposed embryos (Murray et al. 2016). Furthermore, Jandegian et al. (2015) demonstrated that developmental exposure to BPA – a well-known EDC with estrogenic properties – disrupts sexual differentiation in painted turtles (Jandegian et al. 2015). Evidence regarding the impact of exposure to EDCs on sexual differentiation in humans remains scarce. Diethylstilbestrol (DES), used to prevent miscarriages in the 1950s and 1960s, was one of the first compounds that turned out to have deleterious effects on sexual differentiation of the male and female offspring. This compound is a synthesized stilbene with biological properties similar to those of naturally occurring estrogens, which can easily cross the placenta and be metabolized in the fetus. In utero exposure to this synthetic nonsteroidal estrogen resulted in hypospadias, micropenis, and in testicular and prostate tumors in males, whereas in females it leads to the cervical canal malformations, ovarian tumors, and cervicovaginal cancer (Giusti et al. 1995). Luckily nowadays, reports on the environmental or domestic

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Table 1 Data from animal studies on the impact of exposure to EDCs on sexual differentiation and function Ref. Effects on sexual differentiation Exposure to nonylphenol (NP) can alter transcriptional expression of sexual differentiation-related genes in zebrafish Embryonic exposure to 17α-methyltestosterone results in hermaphroditic primary sex organs, delayed renal development and masculinization of the clitero-penis in American alligators Developmental exposure to BPA disrupts sexual differentiation in painted turtles (Chrysemys picta) Effects on sexual function Female eastern mosquitofish (Gambusia holbrooki) exposed to trenbolone approached males less and spent more time swimming away from them then nonexposed females Exposure of male Xenopus laevis to 17α-methyldihydrotestosterone enhanced levels of advertisement calling and decreased the relative proportions of rasping. In females at low doses, it did not have any effects while at high increased female receptivity was observed Estradiol administered by embryonic day 12 demasculinized male sexual behavior and methoxychlor or vinclozolin impaired male sexual behavior in Japanese and northern bobwhite quail. Also, methoxychlor impaired sexual behavior and had reproductive consequences observable in F1 and F2 generations Singing and pairing patterns were impaired due to the exposure to the two pesticides (mancozeb and imidacloprid) in male red munia (Amandava amandava), which could be linked to direct toxicity at the level of hypothalamus, pituitary, and testis (HPT axis) Exposure to EDCs with estrogenic/antiestrogenic or antiandrogenic properties impairs sexual behavior and function in rodents and is due to the effects of these substances on the expression and the signaling pathways of the sex hormone receptors (ERs, ARs, and PRs) Effects on brain sexual dimorphism The sex difference in AVPV size and tyrosine hydroxylase expression (higher in female than male rats) was diminished by BPA exposure BPA exposure during pregnancy decreased SDN-POA volume in male rats and calbindin-immunoreactive neurons in male rats. No effects were demonstrated in female rats Phthalates exposure induced an increase in Kiss1, ESR2 gene expression in a dose-dependent manner in adult female rats BPA exposure in newborn rats resulted in increased number of cells expressing tyrosine hydroxylase in males and no change in ERα neurons in either sex in AVPV Effects on sexual dimorphic behaviors and skills BPA exposure during pregnancy led to a reduction in the sexual dimorphism in play behaviors

Sun et al. (2017) Murray et al. (2016)

Jandegian et al. (2015)

Saaristo et al. (2013)

Hoffmann and Kloas (2012)

Ottinger et al. (2005)

Pandey et al. (2017)

Mhaouty-Kodja et al. (2018)

Rubin et al. (2006)

McCaffrey et al. (2013)

Hu et al. (2013) Patisaul et al. (2006)

Kundakovic and Champagne (2011) (continued)

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Table 1 (continued) BPA administration during gestation and lactation was associated with an increase in social exploration and decreased social grooming and play in female rats BPA exposure during gestation and lactation determined no effect regarding sexual preference between a sexually experienced male and a receptive female rat, increased intromissions and genital sniffing in male rats, decreased exit latency, and increased lordosis frequency in female rats Phthalate-exposed male rats spent less time in social play, whereas females spent more time alone Phthalate-exposed male rats spent less time sitting side-by-side and more time sniffing and exploring (in both sexes) PCBs’ exposure interfered with partner preference in female rats. No effects were observed with regard to sexual behavior Gestational and lactational exposure PCBs determined spatial deficits in adolescence and adulthood in male rats Prenatally BPA exposed rodents showed a reversal of sex differences in exploratory activity in a novel open field, elevated plus maze, and social interactions with a conspecific PCBs’ exposure was associated with sexual behavior changes in female rats (reduced lordosis quotient, reduced approach latency in a paced mating paradigm)

Ref. Porrini et al. (2005)

Farabollini et al. (2002)

Kougias et al. (2018) Quinnies et al. (2017) Cummings et al. (2008) Schantz et al. (1995) Gioiosa et al. (2013)

Wang et al. (2002)

EDCs’ exposure and impaired sexual differentiation in humans are uncommon. During a neonatal screening program of ambiguous genitalia, Paris and colleagues (2006) found a condition of male pseudo-hermaphroditism (MPH) in three newborns, whose mothers reported exposure to EDCs during pregnancy because they lived in regions with intensive agricultural activity where pesticides and other chemicals were widely used (Paris et al. 2006). All subjects had normal testosterone production after human chorionic gonadotrophin stimulation testing and abnormalities in the 5α reductase and androgen receptor genes were excluded by sequencing the whole genes. When using an ultrasensitive bioassay, the authors found a higher serum estrogenic bioactivity in these newborns compared to controls and concluded that ambiguous genitalia in these three male newborns were related to fetal exposure to EDCs with the estrogenic potential (Paris et al. 2006). A nested case–control study over a 16-month period on 1615 full-term newborn males conducted in France reported 39 cases of genital malformation (2.7%; particularly 18 cases of cryptorchidism, 14 of hypospadias, 5 of micropenis, and 2 of 46,XY differences of sexual differentiation). A significant relationship was found between parental occupational exposure to pesticides and the presence of cryptorchidism, hypospadias, or micropenis (OR 7.25, 95% CI 1.21, 16.00) (Gaspari et al. 2011). The authors hypothesized that the spread of environmental pollutants with estrogenic and antiandrogenic activity (including organochlorine pesticides, bisphenol A, phthalates, dioxins, and furans) could be associated with an increasing trend in male external genital

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malformations (Gaspari et al. 2011). Another study also conducted in France from 2011 to 2014 evaluated 57 full-term newborns with hypospadias and three selected controls for age-matched for gestational age and found a strong association between hypospadias and maternal exposure to domestic hair cosmetics and occupational endocrine disruptors (Haraux et al. 2016). In fact, taking medications during pregnancy, exposure to human/veterinary insecticides, or living