REPRODUCTIVE TOXICOLOGY: Endocrine disruption and reproductive disorders: impacts on sexually dimorphic neuroendocrine pathways

in Reproduction
View More View Less
  • 1 Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina, USA

Correspondence should be addressed to H B Patisaul; Email: hbpatisa@ncsu.edu

This paper forms part of a special section on Reproductive toxicology. The guest editors for this section were Dr Adam Watkins (The University of Nottingham, UK) and Dr Aileen Keating (Iowa State University, IA, USA)

Free access

We are all living with hundreds of anthropogenic chemicals in our bodies every day, a situation that threatens the reproductive health of present and future generations. This review focuses on endocrine-disrupting compounds (EDCs), both naturally occurring and man-made, and summarizes how they interfere with the neuroendocrine system to adversely impact pregnancy outcomes, semen quality, age at puberty, and other aspects of human reproductive health. While obvious malformations of the genitals and other reproductive organs are a clear sign of adverse reproductive health outcomes and injury to brain sexual differentiation, the hypothalamic-pituitary-gonadal (HPG) axis can be much more difficult to discern, particularly in humans. It is well-established that, over the course of development, gonadal hormones shape the vertebrate brain such that sex-specific reproductive physiology and behaviors emerge. Decades of work in neuroendocrinology have elucidated many of the discrete and often very short developmental windows across pre- and postnatal development in which this occurs. This has allowed toxicologists to probe how EDC exposures in these critical windows can permanently alter the structure and function of the HPG axis. This review includes a discussion of key EDC principles including how latency between exposure and the emergence of consequential health effects can be long, along with a summary of the most common and less well-understood EDC modes of action. Extensive examples of how EDCs are impacting human reproductive health, and evidence that they have the potential for multi-generational physiological and behavioral effects are also provided.

Abstract

We are all living with hundreds of anthropogenic chemicals in our bodies every day, a situation that threatens the reproductive health of present and future generations. This review focuses on endocrine-disrupting compounds (EDCs), both naturally occurring and man-made, and summarizes how they interfere with the neuroendocrine system to adversely impact pregnancy outcomes, semen quality, age at puberty, and other aspects of human reproductive health. While obvious malformations of the genitals and other reproductive organs are a clear sign of adverse reproductive health outcomes and injury to brain sexual differentiation, the hypothalamic-pituitary-gonadal (HPG) axis can be much more difficult to discern, particularly in humans. It is well-established that, over the course of development, gonadal hormones shape the vertebrate brain such that sex-specific reproductive physiology and behaviors emerge. Decades of work in neuroendocrinology have elucidated many of the discrete and often very short developmental windows across pre- and postnatal development in which this occurs. This has allowed toxicologists to probe how EDC exposures in these critical windows can permanently alter the structure and function of the HPG axis. This review includes a discussion of key EDC principles including how latency between exposure and the emergence of consequential health effects can be long, along with a summary of the most common and less well-understood EDC modes of action. Extensive examples of how EDCs are impacting human reproductive health, and evidence that they have the potential for multi-generational physiological and behavioral effects are also provided.

Introduction: reproductive disorders and chemical exposures

Human reproductive health is in trouble. The need for assisted reproductive technology, rates of reproductive cancers, malformations, and similar adversities continue to rise (Swan & Colino 2021). All bodies are also continuously polluted with hundreds if not thousands of chemicals coursing through our tissues and cells every day, including the human placenta and the unborn (Ragusa et al. 2021, Wang et al. 2021). Are these phenomena related? Extensive evidence from across the globe suggests that they are. Although it can be difficult to explicitly link specific chemical exposures to specific reproductive outcomes in humans, the warning signs that show reproductive health is declining as chemical contamination of our environment and ourselves increases, particularly in the last 20–30 years, are irrefutable and concerning. This chapter summarizes this evidence and explores the potential mechanisms by which this occurs with a specific focus on the development and function of the reproductive neuroendocrine system.

Adverse reproductive trends potentially linked to chemical exposures are numerous. One of the most highly publicized is reduced sperm counts in men, which have declined by half in the past 40–50 years (Carlsen et al. 1992, Swan et al. 2000, Geoffroy-Siraudin et al. 2012, Mínguez-Alarcón et al. 2018, Sengupta et al. 2018). Among young Swiss men, only 38% have sperm concentration, motility, and morphology values that meet the WHO semen reference criteria (Rahban et al. 2019). A phenomenon first thought confined to Western populations, the multi-decadal decline in sperm count and quality is now also reported in Africa (Sengupta et al. 2017). Incidence of testicular germ cell cancer, cryptorchidism and hypospadias are rising (Toppari et al. 2010, Manfo et al. 2014), particularly in Nordic countries and other Caucasian populations, signifying a multifaceted decline in male reproductive health.

There are also hints that couple fecundity is declining, with an estimated 10–15% of couples experiencing conception difficulties, but it is extraordinarily difficult to identify its causal factors (Snijder et al. 2012, Buck Louis 2014). Although birth rates in the United States for women aged 20–34 years are falling, elective postponement is a significant driver of that trend, making impacts of chemical exposures difficult to assess. The industrial chemical TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) has dose-dependently been linked to causing longer time to pregnancy in women living in the heavily polluted community of Seveso, Italy (Eskenazi et al. 2010), and there is some evidence that other common pollutants may have similar effects (Wesselink et al. 2018, Kim et al. 2019). Adverse pregnancy outcomes are also increasing, including preterm birth which, in the United States, has been rising for years and exceeded 10% in 2018 (Martin et al. 2019). Disgracefully, it is among the highest in the developed world, disproportionally impacts people of color, and has been linked, at least in part, to air, agricultural and industrial pollution common in low-income communities (Stieb et al. 2012, Burris & Hacker 2017, Ling et al. 2018).

Female reproductive development, aging, and health is also suffering. According to the American Cancer Society (https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html), in the US women, breast cancer rates have risen to one in eight, and it is now the second most common cancer among the US women. A 2000 study of nearly 45,000 pairs of twins from Sweden, Denmark, and Finland concluded that the environment, not genetics, played a principal role in sporadic cancers of the breast, female reproductive system, and prostate (Lichtenstein et al. 2000). Exposure to dichloro-diphenyl-trichloroethane (DDT), bisphenol A (BPA), and other pollutants have long been suspected to be contributory to rising rates of breast cancer (Davis et al. 1993, Cohn et al. 2015, Rodgers et al. 2018), and there is growing interest in understanding how combined chemical exposures might heighten breast cancer risk (Calaf et al. 2020). It is now irrefutable that aspects of female puberty are advancing (Herman-Giddens 2006, Bourguignon et al. 2016, Boeyer et al. 2018, Fudvoye et al. 2019). In the United States, the median age of breast development and sexual precocity has steadily advanced, especially among minority populations (Herman-Giddens et al. 1997, Partsch & Sippell 2001), a phenomenon that has negative long-term effects on sexual health (Ibitoye et al. 2017). Similar trends have been noted in Europe and among children adopted from developing countries by Western parents (Proos et al. 1991, Parent et al. 2003, Aksglaede et al. 2009). It is less clear if puberty is also advancing in boys (Ohlsson et al. 2019, Reinehr & Roth 2019).

Undoubtedly, the causal factors underlying these and other adverse reproductive health trends for men, women, and couples are complex and multifaceted, but the rapidity of their increased prevalence unequivocally signifies that the primary drivers are environmental. Of these, because the reproductive system is so heavily dependent on steroid and other hormones to develop and function normally throughout life, of greatest concern are chemicals that have the capacity to act on or disrupt endocrine action, a group collectively called endocrine-disrupting compounds (EDCs) (Gore et al. 2015), It was recently estimated that the economic costs of male reproductive disorders and other diseases in men associated with EDC exposure exceed €15 billion annually in the European Union (Hauser et al. 2015). Phthalates and flame retardants were identified as particularly problematic. Similar work has estimated that the burden of these and other EDC-related diseases including intellectual disability, obesity, and neurodevelopmental disorders cost the European Union upwards of €160 billion annually (Bellanger et al. 2015, Trasande et al. 2015). There is also emerging concern that assisted reproductive efforts are compromised in women with higher body burdens of EDCs including phthalates and bisphenols (Al-Saleh et al. 2019, Jin et al. 2019, Mínguez-Alarcón et al. 2019, Shen et al. 2020). Thus, EDCs are likely contributing to a wide range of reproductive maladies in both sexes, along with the extensive emotional, physical and monetary health care costs related to them. When, to how many chemicals, and at what dose levels individuals have been exposed matters in terms of long-term reproductive health risks. Unfortunately, since the 1940s, our collective exposures have only steadily increased with no sign of abating.

Our polluted selves

Chemicals are the words of complex conversations in nature. All living things evolved in a stew of exogenous chemicals, many of which have endocrine action and/or toxicity in extant vertebrates. For example, plants and animals generate potent neurotoxins, including venoms and poisons, for both predatory and defensive purposes. CYP enzymes, required for steroid hormone synthesis and to metabolize toxins, appear to have evolved as a defense against botanical poisons and then repurposed over evolutionary history (Gonzalez & Nebert 1990). Even GABA, the primary inhibitory neurotransmitter of the brain, is an ancient molecule and has a role in plant communication, particularly when the plant is stressed (Ramesh et al. 2015). Plants produce numerous steroids and sterols, most notably the brassinosteroids and phytoestrogens, for a variety of purposes. Not surprisingly, some are hormonally active in vertebrates, including humans (Bishop & Koncz 2002). Notably, some species, particularly those living in perilous environments, evolved mechanisms to leverage endocrine active plant-produced compounds as potent signals of environmental quality and, therefore, optimal times to invest in reproduction. In that sense, 'endocrine disruption' could enhance fitness in hard times (e.g. by suppressing ovulation) or (by enhancing puberty, fertility, or similar) in abundant times. Humans also took advantage of the biological activity of botanicals in traditional and ancient medicine for a variety of purposes including manipulation of reproductive health including assisted labor and elective miscarriage (Kamatenesi-Mugisha & Oryem-Origa 2007, Yazbek et al. 2016, Mbuni et al. 2020). This chemical exchange long conferred evolutionary advantage and heightened fitness. A preliminary form of 'endocrine disruption', in some sense, this evolved interplay also signifies how vulnerable our bodies can be to environmental signals including exposure to exogenous chemicals.

Unfortunately, chemicals of our own making are leveraging those evolved relationships to compromise our reproductive health. We blithely eat, breathe, and absorb thousands of chemicals all day, every day, with little to no awareness of their existence, let alone knowledge about their biological activity or potential toxicity. There is no way to know how many chemicals humans have invented or are in commercial use, but there are over 167 million in the CAS Registry, a database maintained by the American Chemical Society, and close to 90,000 on the Environmental Protection Agency’s (EPA) inventory of substances regulated under the Toxic Substances Control Act (TSCA). The vast majority of chemicals in use commercially have not undergone any toxicity testing of any kind. They better our lives in myriad ways and have a wide range of applications including use as plasticizers, surfactants, disinfectants, food preservatives, cleaners, degreasers, fire retardants, solvents, and fragrances. Some have the capacity to interfere with the development and function of the endocrine system and, consequently, reproductive function.

Humans are now born pre-polluted with hundreds to thousands of anthropogenic chemicals (Wang et al. 2016). A landmark study, conducted by the Environmental Working Group in 2005, identified 287 industrial chemicals in umbilical cord blood. A follow-up 2009 study focusing on infants of color confirmed the ubiquity of prenatal pollution. Subsequent studies by multiple groups have repeatedly found harmful chemicals including pesticides and biocides, flame retardants, and per- and polyfluoroalkyl substances (PFAS) in maternal serum and cord blood, with levels sometimes higher in fetal than maternal blood (Wang et al. 2016, van de Bor 2019, Wang et al. 2021). The Centers for Disease Control’s (CDC) National Biomonitoring Program (accessible at: http://www.cdc.gov/nchs/nhanes/index.htm) regularly assesses more than 300 environmental chemicals in Americans and by 2009 indicated universal exposure to many. Significantly, nearly all pregnant women in the United States have at least 43 chemicals with known toxicity in their bodies including polybrominated diphenyl ethers (PBDEs) and other brominated flame retardants, some polychlorinated biphenyls (PCBs) and PFAS, organochlorine pesticides including DDT and its metabolites, BPA, perchlorate, and a variety of phthalates (Woodruff et al. 2011). All 43 have well-documented experimental evidence of toxicity or endocrine disruption and have repeatedly been linked to human health consequences including adverse birth outcomes, childhood morbidity, reproductive cancer risk, and reproductive abnormalities (Wang et al. 2016). Even though some have been phased out of use (e.g. PCBs, DDT, PBDEs), they remain in all of us because their use was so widespread, and they are environmentally persistent. The rapidly expanding catalog of PFAS will also be with us for years and centuries to come. Thus, our 'exposome', which is the totality of our bodily exposures, remains poorly defined and easily contains thousands of chemicals (Wishart et al. 2015, Vermeulen et al. 2020).

The earliest evidence that EDCs could adversely impact reproduction largely came from wildlife studies in the 1970s and 1980s including seminal work by Charles Broley, Theo Colborn and Louis Guillette Jr., who linked exposure to DDT, PCBs, and other persistent organic pollutants to reduced fertility in birds, genital abnormalities in alligators, and feminization of numerous species of fish (Leatherland 1992, Guillette et al. 1994, 1995, Beans 1997, Semenza et al. 1997). Around the same time, the clearest evidence that endocrine disruption is plausible in humans emerged from the tragic and misguided use of the potent synthetic estrogen diethylstilbestrol (DES) in pregnancy. Initially prescribed to prevent miscarriage (for which it was ineffective (Reed & Fenton 2013)), it was ultimately dispensed to upwards of 6 million pregnant women in the United States to enhance fetal weight gain (Smith 1948, Karnaky 1953, Kuchera 1971, Palmlund 1996). It was also used as a growth promoter in chicken, cattle, and other livestock, and even used as an ingredient in shampoos, soaps and other personal care products. Human use was suspended in 1971 when prenatal exposure was linked to an extremely rare type of cervicovaginal clear-cell adenocarcinoma (CCAC) in young women (Herbst et al. 1970, 1971). Other uses were phased out years later. In women, prenatal DES exposure has subsequently been linked to vaginal dysplasia, vaginal and cervical adenosis, abnormalities of the cervix, vagina, and uterus, reduced fertility, and greater risk of ectopic pregnancy, late spontaneous abortions, and premature delivery (Reed & Fenton 2013). DES sons have elevated rates of urogenital malformations, undescended testes, testicular cancer, and poor sperm quality (Gill et al. 1976, Stenchever et al. 1981, Wilcox et al. 1995, Palmer et al. 2005).

These and other examples were detailed in the seminal 1996 book Our Stolen Future, Are we Threatening Our Fertility, Intelligence and Survival? – A Scientific Detective Story written by Colborn and colleagues, that argued EDCs were most certainly impacting the reproductive capability of wildlife and, by extension, humans and could impact reproductive health for generations. The quantity of experimental and epidemiologic evidence linking EDC exposure with compromised human reproductive health has subsequently compounded, leading the WHO and the United Nations Environmental Programme to conclude in its 2012 state of the science report that 'Exposure to EDCs could impair the health of our children and their children (WHO/UNEP 2012)'. The UC San Francisco Program on Reproductive Health and the Environment maintains a database of Professional Statements from health and medical organizations regarding the risks industrial chemicals pose to human health (accessed Oct. 10, 2020; https://prhe.ucsf.edu/professional-statements-database) and, as of 2016, had cataloged similarly cautionary statements from the American Congress of Obstetricians and Gynecologists, the International Federation of Gynecology and Obstetrics and the Endocrine Society, among others.

Endocrine disruption defined

There are many working definitions of what constitutes an EDC, some of which are presented in Table 1. The Endocrine Society defines them simply as: chemicals that mimic, block, or interfere with hormones in the body’s endocrine system (Diamanti-Kandarakis et al. 2009, Gore et al. 2015). Others require evidence of an adverse effect on a whole animal. Because our chemical regulatory framework was built decades ago to detect overt poisons and chemicals that cause lethality or cancer, it has struggled to identify a common working definition. EDCs challenge keystone principles of toxicology, including our understanding of what constitutes an 'adverse' effect and the long-held axiom 'the dose makes the poison'. EDCs are not poisons per se (most are not lethal, even at high doses), but rather something else entirely (Schug et al. 2016, Demeneix et al. 2020). The lack of consensus on how EDCs should be defined (Zoeller et al. 2014) has hindered efforts to identify a common list of EDCs. In 2018, the Danish Centre on Endocrine Disruptors published a list (http://cend.dk/files/DK_ED-list-final_2018.pdf) identifying nine chemicals that meet the WHO’s definition of an EDC (Table 2) and four others suspected of meeting it (deltamethrin, 2-(4-tert-butylbenzyl)-propionaldehyde, bifenthrin, hexachlorophene). To date, the USA EPA has failed to identify any, while lists published by other governmental and non-governmental groups contain anywhere from 26 to over 1000 (summarized in a 2020 UNEP report: https://wedocs.unep.org/bitstream/handle/20.500.11822/33807/ARIC.pdf?sequence=1&isAllowed=y). Some of the most well-studied putative EDCs linked to adverse reproductive outcomes in animals and humans are listed in Supplementary Table 1 (see section on supplementary materials given at the end of this article). Identified EDCs include numerous pesticides, bisphenols and phthalates, which have multiple applications but are widely used in plastics, and parabens which are often used as preservatives in personal care products. Most identified EDCs that impair reproductive health are estrogenic, anti-androgenic, or, particularly in the case of the phthalates, decrease gonadal steroid synthesis. Compounds produced in nature rather than by humans, such as the phytoestrogens, behave similarly and thus can also be considered EDCs.

Table 1

EDC definitions currently in use globally.

AgencyYearDefinitionReference
US Environmental Protection Agency (EPA)1996An exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body which are responsible for the maintenance or homeostasis, reproduction, and the regulation of developmental processes.Kavlock and Ankley (1996), Kavlock et al. (1996)
European Commission Workshop on the Impact of Endocrine Disrupters on Human Health and the Environment19971. An endocrine disrupter is an exogenous substance that causes adverse health effects in an intact organism or its progeny, secondary to changes in endocrine function.European Workshop on the Impact of Endocrine Disrupters on Human Health and Wildlife 1996
2. A potential endocrine disruptor is a substance that possesses properties that might be expected to lead to endocrine disruption in an intact organism.
US EPA Endocrine Disruptor Screening and Testing Advisory Committee1998An exogenous substance that changes endocrine function and causes adverse effects at the level of the organism, its progeny, and/or (sub)populations of organisms based on scientific principles, data, weight-of-evidence, and the precautionary principleEDSTAC 1998
The World Health Organization (WHO) and the Inter-Organization Programme for the Sound Management of Chemicals (IOMC)2002An endocrine disruptor 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. A potential endocrine disruptor is 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/PCS/EDC/0.2.2 (WHO 20002)
The Endocrine Society2012An exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action.Zoeller et al. (2012)
Table 2

A summary of the nine chemicals identified as EDCs by the Danish Center on Endocrine Disruptors in 2018.

EDCSourceAdverse effectsMode of actionCitations
Bisphenol AFPolycarbonate plastics, epoxy resins, food containers, dental fillings, medical devices, eyeglass lenses, thermal paper receipts, electronicsDecreased fertilityEstrogenicCatenza et al. (2021)
DeltamethrinPyrethroid ester insecticideMalformations of male reproductive organs including the testisAndrogen receptor antagonistHodgson and Rose (2007), Ismail and Mohamed (2012)
Di-n-pentylphthalate (DnPP)Additive in polyvinylchloride (PVC) and other plastics. No longer in use.Decreased AGD; increased nipple retention in male rats; decreased sperm count; malformations of male reproductive organsAnti-estrogenicGangolli (1982), Hannas et al. (2011)
FenitrothionOrganophosphate insecticideDecreased AGD; increased nipple retention in male rats; malformations of the testis sperm, and male reproductive organs; reduced testosteroneAnti-androgenicCurtis (2001)
Isobutyl parabenPreservatives in personal care products and pharmaceuticals; food preservativesDecreased sperm count and motility; altered sexually dimorphic behaviorEstrogenicKawaguchi et al. (2010), Gonzalez et al. (2018)
ProchlorazImidazol fungicide; not authorized for use in the United States.Skewed sex ratios in fish and amphibians; disrupted sex determination in fish and amphibiansAromatase inhibitor; anti-androgenic; anti-estrogenicVinggaard et al. (2006)
Salicylic acidPhenolic acid; aspirin; personal care productsReduced spermatogenesisAnti-androgenicKristensen et al. (2016)
Triclocarban (TCC)Antibacterial; soaps, lotions and other personal care products; largely phased out of useIncreased weight of male accessory sex organsAndrogenicRochester et al. (2017)
Tris(methylphenyl) phosphateOrganophosphate used as a flame retardant and in lacquers, varnishes and as a plasticizer.Reduced fertility/fecundity in adult malesDisrupted steroidogenesis; elevates circulating estrogen levelsReers et al. (2016)

Identifying putative EDCs using our current regulatory framework is challenging because of outdated methodologies and other practical limitations (Solecki et al. 2017). Historically, assessments made for regulatory and public health decision-making regarding what is 'dangerous' to humans have focused on gross malformations and birth defects such as tumor formation, malformed organs or limbs, severe weight loss, gross motor deficits, fetal loss, and death (Vogel 2013). As the DES story illuminated, EDCs challenge this method of identifying reproductive toxicants because perturbation of the endocrine system may not necessarily lead to overtly obvious teratogenicity post-exposure but rather can set the body on a path to long-term morbidity. This is particularly likely if exposure occurs during developmental periods when hormones are actively shaping neuroendocrine and other reproductive systems. A powerfully potent estrogen receptor agonist developed as a pharmaceutical, and there are no anthropogenic EDCs that pose a health risk anywhere near as extreme as DES. Nonetheless, most of the reproductive outcomes of prenatal DES exposure are similar to those elicited in many animal models by early-life exposure to some of the most potent phytoestrogens including coumesterol and genistein (Patisaul & Jefferson 2010, Patisaul 2017a); a literature dating back to the 1940s (Bennetts et al. 1946). Additionally, nearly all the human DES outcomes were predicted by or reproduced in animal models (McLachlan et al. 1982, Newbold & McLachlan 1982, Newbold 2008, McLachlan 2016). As such, this work rapidly established a set of endpoints by which reproductive endocrine disruption could be identified, plus a basic mechanistic understanding of how adverse outcomes arise. Moreover, complementary, fundamental work in neuroendocrinology identified more precisely the critical windows in which specific aspects of the reproductive neuroendocrine system differentiate and undergo sexual differentiation (Simerly 2002, Wallen 2009, McCarthy 2016, 2020). Thus, by the close of the 20th century, an experimental framework for testing a broader set of compounds for endocrine disrupting activity across a range of reproductive endpoints was firmly established as well as approaches to establish causality between exposure and adverse reproductive outcomes, and probe mechanisms of action. While EDC scientists have embraced these methodologies and developed new ones as -omics tools advanced and concepts like epigenetic inheritance matured, regulatory testing has largely failed to evolve in either their testing strategies or incorporation of new data streams for the purpose of human risk assessment (Vandenberg et al. 2016, 2019, Solecki et al. 2017, Tweedale 2017, Fritsche et al. 2018). Thus, controversy as to how to precisely define what constitutes an EDC unfortunately remains.

Mechanisms of reproductive endocrine disruption

When the term 'EDC' was first coined in the early 1990s, most chemical examples were estrogenic and thought to act via agonism or antagonism of canonical steroid receptor signaling (Hotchkiss et al. 2008, McLachlan 2016). Thanks to convergent work in endocrinology, toxicology, and behavioral neuroendocrinology, significant progress has been made identifying potential mechanisms of reproductive endocrine disruption beyond classic steroid hormone receptor agonism/antagonism. These 'key characteristics' (Fig. 1) include changes in steroid metabolism and biosynthesis, receptor degradation and expression level changes, DNA methylation and other epigenetic modifications, interference with signal transduction in hormone-responsive cells and disruption of rapid hormone signaling via non-canonical pathways (Tabb & Blumberg 2006, Schug et al. 2015, La Merrill et al. 2020).

Figure 1
Figure 1

A summary of the ten 'key characteristics' of endocrine disrupting activity as summarized in a 2020 consensus statement (La Merrill et al. 2020). Each of the ten key characteristics is depicted with some example EDCs listed for each one. It is important to note that the way in which EDCs produce the key characteristic can occur via multiple and cell-specific mechanisms.

Citation: Reproduction 162, 5; 10.1530/REP-20-0596

While it is beyond the scope of this review to address them all in detail, it is important to note that for each key characteristic, there can be multiple mechanisms of disruption. For example, the earliest identified EDCs were estrogen disruptors. These EDCs were presumed to act by interfering with direct genomic signaling, where an estrogen (17β-estradiol, estrone, or estriol) binds to either major form of the estrogen receptor (ERα, ERβ), and the complex dimerizes and translocates to the nucleus inducing transcriptional changes in estrogen-responsive genes via estrogen response elements (EREs). To this day, most in vitro assays that screen for estrogen-disrupting EDCs only test this mechanism of action. It is now known, however, that endogenous estrogens can act via indirect genomic signaling, where another transcription factor mediates DNA binding at a non-ERE site. Additionally, membrane-bound receptors, including a membrane form of ERα, can induce cytoplasmic events such as modulation of membrane-based ion channels, second-messenger cascades, or transcription factors (Fig. 2). Notably, the G protein-coupled estrogen receptor (GPER, also known as GPER1 or GPR30), first discovered in 1996, is expressed in the cell membrane as well as the endoplasmic reticulum and plays an important role in many of the rapid non-genomic estrogen actions including heightened production of cyclic AMP, promotion of intracellular calcium mobilization, and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus (Filardo & Thomas 2012, Qie et al. 2021). EDCs known to bind or interfere with GPER include BPA and other bisphenols, some pesticides including DDT and its metabolites, many flame retardants including PBDEs and some organophosphate esters (OPEs), phthalates, and some endocrine active metals such as cadmium (Qie et al. 2021). Additionally, ER-independent and estrogen-independent actions are also known to exist and could be impacted by EDCs (Fig. 2). This is why some tissues which primarily express only one form of the estrogen receptor (e.g. ERβ in granulosa cells, ERα in thecal cells, and membrane ERs in some brain regions such as the nucleus accumbens) respond differently to endogenous estrogens and, consequently, vary in their vulnerability and response to estrogen-disrupting EDCs (Fucic et al. 2012, Hewitt & Korach 2018). Emerging work is also demonstrating that organs other than the gonads can make their own estrogens, most significantly the brain (Barakat et al. 2016). Similar receptor signaling complexities exist for androgens (Mittelman-Smith et al. 2017) and progestins as well (Piette 2020), with some ligands binding other receptors including glucocorticoid receptors (Mittelman-Smith et al. 2017).

Figure 2
Figure 2

Examples of canonical and non-canonical estrogen receptor (ER) signaling pathways. The two major nuclear forms of ER are ERα and ERβ. Via the classical direct genomic pathway estrogen-bound ERs dimerize, change confirmation, are shuttled to the nucleus, bind estrogen response elements (ERE) on the DNA, and recruit coactivators and that promote transcription (denoted by arrow 1). Most regulatory screening in vitro ER assays for EDC activity probe only this mechanism of estrogen signaling. Non-classical genomic signaling (denoted by arrow 2) is also possible via binding with transcription factors (TF) like AP-1 and others to promote transcription through transcription factor response elements (TFRF). ER transcriptional activity can also be activated by kinases via their receptors and is thus estrogen-independent. Finally, GPER and membrane ERs (mER) including membrane forms of ERα and ERβ confer many of the rapid effects of estrogen and influence transcription and other cell processes, including ion channel activity, via kinases and other intracellular signaling cascades. This diagram is by no means exhaustive and illustrates that there are myriad ways EDCs can act as ER agonists or antagonists, some of which are just beginning to be elucidated. (E2, estradiol; EGFR, epidermal growth factorEGF receptor; ERK, extracellular signal-related kinases; IGFR, insulin-like growth factor receptor; MAPK, mitogen-activated protein kinase; NFKB, nuclear factor kappa-light-chain-enhancer of activated B cells; P13K, phosphoinositide 3-kinase).

Citation: Reproduction 162, 5; 10.1530/REP-20-0596

EDCs are now also recognized as being able to induce epigenetic changes, and this is particularly alarming because it provides a mechanistic path to transgenerational effects. When a pregnant woman is exposed to a chemical, she, her unborn child, and the germ cells in that unborn child are all simultaneously exposed. Thus, exposure is to three generations at once and considered multi-generational. The fourth generation, (called F4) or the great-grandchild, is the first to be born not directly exposed. Effects in this F4 generation are considered transgenerational. There is growing evidence that a multitude of EDCs has transgenerational effects on reproductive endpoints including age at puberty, fertility and fecundity, reproductive behavior, and parental behavior (Rissman & Adli 2014, Ho et al. 2017, Viluksela & Pohjanvirta 2019). These can occur via a variety of epigenetic mechanisms, most of which are only beginning to be fully understood (Walker & Gore 2011) but include DNA methylation, histone modifications, and long and micro RNAs among others (Perera et al. 2020). Although the evidence remains sparse and inconsistent, particularly in humans (Van Cauwenbergh et al. 2020), there is pressing interest in the possibility of transgenerational outcomes, particularly in the face of other life challenges, such as prenatal stress or poor nutrition, which could augment adverse generational effects (Sobolewski et al. 2020). As such, epigenetic effects and, consequently, the potential for transgenerational inheritance are some of the most intense areas of reproductive EDC research.

The reproductive neuroendocrine system

The neuroendocrine system is essentially the master control system of the body and the primary system responsive to environmental signals. The nervous system component mediates the most immediate and rapid effects, and the endocrine level acts to maintain, modulate, and prolong the response. For example, when frightened, the sympathetic nervous system drives the immediate response (e.g. increased heart rate, sweating and goosebumps) while the endocrine system acts to maintain a stress response (via glucocorticoids and other hormones). The neuroendocrine system, especially the reproductive neuroendocrine system, is exquisitely sensitive to steroids and other hormones throughout life. Itself an endocrine organ, the hypothalamus is the apical coordinator of the neuroendocrine system. This diencephalic, heterogeneous, and sexually dimorphic structure communicates with the rest of the brain, the pituitary and, ultimately, all the endocrine glands including the gonads. The placenta also shapes and controls many neuroendocrine functions in the developing fetus, including the organization of the fetal brain, across pregnancy, beginning well before the hypothalamus is even formed (Behura et al. 2019). Thus, it is an ephemeral but critical piece of the neuroendocrine system.

The vertebrate reproductive system is coordinated by the hypothalamic-pituitary-gonadal (HPG) axis, which comprises a complex network of neuronal and endocrine signaling pathways that ultimately centers on the precise control of steroid hormone secretion by gonadotropins (McCarthy et al. 2009, Schulz et al. 2009, Kaprara & Huhtaniemi 2018). HPG steroid hormone action can be organizational or activational depending on the developmental stage (McCarthy et al. 2009, Schulz et al. 2009), and over the pubertal transition, there is a little bit of both (Schulz & Sisk 2016). The neural components of the HPG axis span multiple hypothalamic and other brain nuclei, most importantly regions housing discrete populations of kisspeptin-secreting neurons that regulate gonadotropin-releasing hormone (GnRH) secretion. In humans, a preoptic population coordinates ovulation and steroid positive feedback in females, while the more caudal arcuate (ARC; also called the infundibular nucleus) population regulates pubertal onset and steroid negative feedback in both sexes (Livadas & Chrousos 2016, Barroso et al. 2019, Garcia et al. 2019). Females have more preoptic kisspeptin neurons than males and estrogen upregulates kisspeptin expression in this region via ERα in both sexes which then, in turn, triggers the pre-ovulatory surge of GnRH release in females (Beltramo et al. 2014, Herbison 2020). The ARC population of kisspeptin neurons co-synthesize neurokinin B (NKB) and dynorphin and have thus come to be termed 'KNDy neurons' (Moore et al. 2018). Estrogens suppress the kisspeptin expression in KNDy neurons via membrane ERα, and neuron numbers are not sexually dimorphic (Micevych et al. 2015). KNDy neurons are also critical for metabolic control and are considered key integrators of reproductive and metabolic signaling pathways (Dudek et al. 2018). The network of regulatory inputs from other neural and glial cells in the brain projecting to these kisspeptin populations or to GnRH neurons themselves is diverse, and in many cases, highly sexually dimorphic. Described in detail elsewhere, these pathways are differentiated largely by endogenous gonadal hormones through a series of well-defined, and sometimes very short, gestational, pre- and perinatal critical periods (Simerly 2002, Clarkson et al. 2014, Clarkson & Herbison 2016, McCarthy et al. 2018) spanning gestation through pre-puberty (Simerly 2002, Schulz et al. 2009).

Endocrine disruption of HPG axis sexual differentiation

In humans and other mammals, the fetal testis is steroidogenically active and the secreted testosterone and its metabolites are required to masculinize the brain, genitalia and reproductive tract. Androgens, most significantly dihydrotestosterone, via their action on androgen receptors, are essential for masculinizing the male reproductive organs. By contrast, in rats, mice and some other non-primate species, the masculinizing effect of perinatal androgens in the brain is predominantly conferred by estrogens, derived locally via aromatization, and precisely expressed estrogen receptors (McCarthy 2008, Cao & Patisaul 2011, 2013). Thus, in rodents, estrogen is the 'masculinizing' gonadal hormone of the perinatal brain. In humans, although aromatization occurs, androgen receptors play a far more direct role in brain masculinization, a process that continues after birth (Gooren 2006, Alexander 2014, Savic et al. 2017, Puts & Motta-Mena 2018). This is critically important to keep in mind when interpreting and translating effects on rodent hypothalamic sexual differentiation to humans. Estrogenic action in the perinatal brain will be masculinizing in rodents but not humans or other primates. It is also important to note that the neuroendocrinology of sexual orientation and gender identity remain largely unknown (Roselli 2018).

In many species, the sex-specific organization of GnRH function and feedback can be hormonally manipulated and induce long-term functional consequences. During the perinatal critical period, gonadal steroid hormone exposure can masculinize the female rodent GnRH axis, while neonatal castration can effectively prevent defeminization of the male GnRH axis (Baum 1979, Simerly 2002, Bakker & Baum 2008). Thus, in males castrated as neonates, the potential for estrogen to evoke a GnRH surge is preserved while, conversely, in females neonatally exposed to estrogens, this capacity is diminished or lost. While this critical window is perinatal in rats and mice, it is thought to be entirely prenatal in humans.

Because steroid hormones are essential for the proper organization and sexual differentiation of the perinatal reproductive neuroendocrine system, this process has proven particularly vulnerable to endocrine disruption, especially in males (Kern et al. 2017, Graceli et al. 2020). For example, in rats, fetal exposure to some phthalates particularly di-(2-ethylhexyl phthalate (DEHP), genistein, coumestrol and other phytoestrogens, PCBs, as well as BPA and likely other bisphenols perturb programming in multiple hypothalamic and related nuclei including the ARC, anteroventral periventricular nucleus (AVPV) and medial preoptic nucleus (MPN) (Dickerson et al. 2011, Jefferson et al. 2012, Bell 2014, Gao et al. 2018, Patisaul 2020). These disruptions include changes in nuclear volume, expression of steroid hormone and other receptors, the density of projections between brain nuclei, and density of dopaminergic neurons in regions critical for reproductive function (Frye et al. 2012, Gao et al. 2018, Neubert da Silva et al. 2019, Patisaul 2020). EDCs including genistein, BPA and PCBs can be disruptive to the organization and to the function of the GnRH-kisspeptin system (Tena-Sempere 2010, Patisaul 2013). Neonatal genistein, for example, can masculinize the female rat GnRH axis such that capacity for steroid positive feedback is compromised (Bateman & Patisaul 2008). Rat females exposed for only the first 3 days of life have fewer kisspeptin immunopositive fibers in both the AVPV and ARC across the pubertal transition, an effect accompanied by evidence of disrupted ovarian maturation (Losa et al. 2011). Genistein and BPA exposure over only the first 48 h after birth is sufficient to alter other aspects of AVPV sexual differentiation including the number of dopaminergic neurons (Patisaul et al. 2006). This finding is significant because GnRH neurons express dopamine receptors, and dopamine is a potent modulator of pre- and postsynaptic actions on GnRH neurons (Liu & Herbison 2013, Spergel 2019). Similarly, female mice perinatally exposed to BPA have an early vaginal opening (a marker of rodent puberty), lower circulating levels of LH, and significantly altered numbers of AVPV and ARC kisspeptin neurons (Ruiz-Pino et al. 2019). Perinatal BPA exposure has also been shown to dysregulate the GnRH axis, including kisspeptin neuron numbers, in rats (Bai et al. 2011).

In addition to the HPG axis, some EDCs can disrupt the sexual differentiation of other hypothalamic systems. For example, in mice, prenatal exposure to a mixture of common OPEs used as plasticizers and flame retardants eliminates the sex difference in postnatal Npy (neuropeptide Y) expression in the mediobasal hypothalamus (MBH) and increases the postnatal expression of ERα and other genes related to sexual differentiation, including Pparg (peroxisome proliferator-activated receptor gamma), Tac2 (tachykinin 2), and Pdyn (prodynorphin) in females (Adams et al. 2020). Exposed males were also heavier by the second week of life and had higher levels of Agrp (agouti-related neuropeptide) in the MBH at birth, supporting other studies identifying them as metabolic disruptors (Farhat et al. 2014, Boyle et al. 2019). OPEs have also been found to disrupt HPG function and impair reproduction in fish (Liu et al. 2013, Saunders et al. 2015, Wang et al. 2015). There is also evidence from multiple species including quail and monogamous rodent models that BPA, PCBs and some phthalates alter sexually dimorphic aspects of the oxytocin/vasopressin system and their interface with the mesolimbic dopamine system (Sullivan et al. 2014, Patisaul 2017b, Gore et al. 2019).

In humans, evidence of disrupted hypothalamic sexual differentiation is extremely difficult to detect, but anogenital distance (AGD) has emerged as a potentially useful biomarker of fetal androgen exposure and, consequently, potentially altered the brain defeminization/masculinization (Schwartz et al. 2019). Due to prenatal virilization by androgens, AGD is longer in males than females. Although links to specific brain outcomes are not yet well-defined, shorter male AGD is associated with reduced fertility, sperm quality and circulating androgen levels as well as fewer male-typical play patterns (Thankamony et al. 2016, Priskorn et al. 2019). In addition to shortened AGD, fetal phthalate exposure results in male genital and reproductive organ abnormalities and higher testicular cancer risk in rodent models and humans (Hlisníková et al. 2020) which is sometimes termed 'testicular dysgenesis syndrome' (Sharpe & Skakkebaek 2008, Toppari et al. 2010). Fetal exposure to acetaminophen (Paracetamol or Tylenol), BPA, DDT and its primary metabolites, dioxins, phthalates, some OPEs, and the dicarboximide fungicides such as vinclozolin can also result in shortening AGD and, consequently, are thought to impair HPG masculinization (Schwartz et al. 2019, Adams et al. 2020). Similarly, longer AGD in females is considered an indicator of masculinization, the long-term reproductive consequences of which are not entirely clear. Notably, ectopic fetal activation of the progesterone receptor (PR) can masculinize female genitalia, as can super-physiological doses of potent estrogens, so there are likely multiple modes of action for disrupted AGD length in females. Some EDCs including BPA, paracetamol and a few phthalates have been shown to shorten female rodent AGD, the functional significance of which is unknown. Thus, the relationship between AGD length and HPG sexual differentiation in females has yet to be established. Significantly, AGD measurements have been added to several OECD test guidelines and other regulatory testing strategies for developmental and reproductive toxicity for detecting endocrine-disrupting effects. Its utility for predicting adverse reproductive outcomes in humans is less well-accepted but gaining traction.

Disruption of HPG maturation and adult function

In experimental animals, it is well-established that the administration of steroid hormones during adolescence can accelerate puberty including the premature onset of GnRH pulsatility (Rasier et al. 2006, Mueller & Heger 2014, Lucaccioni et al. 2020). Disruption of HPG axis maturation and pubertal onset has been observed in rodents following exposure to BPA, phthalates, atrazine, DDT and its metabolites, TCDD, and PCBs (Gore et al. 2015). In most cases, female puberty is advanced but high doses of potently estrogenic compounds can also induce a delay. For example, in female rats, parabens administered during peripuberty delayed puberty and resulted in numerous uterine and ovarian histological changes including decreased corpora lutea, increased incidence of cystic follicles and myometrial hypertrophy (Vo et al. 2010).

A far longer list of EDCs including genistein, coumestrol and other phytoestrogens, DDT, atrazine, BPA and other bisphenols, and some PCBs are known to interfere with the activity of the mature HPG axis and thus disrupt GnRH and LH secretion (Gore et al. 2015, Rattan et al. 2017, Graceli et al. 2020). This can occur via direct action on GnRH neurons or other hypothalamic targets but disruption at the level of the pituitary or gonad is more common. In most cases, normal HPG function resumes once exposure is eliminated. For example, a 2009 meta-analysis concluded that isoflavone intake moderately increases cycle length and suppresses luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in adult women (Hooper et al. 2009). A 2008 clinical case report described three women (aged 35 to 56) experiencing a suite of symptoms related to excessive soy intake (estimated to exceed 40 g per day) including abnormal uterine bleeding, endometrial pathology and dysmenorrhea, all of which resolved when soy intake was discontinued or reduced (Chandrareddy et al. 2008). For couples experiencing fertility challenges, it can be difficult to establish if developmental or current exposures (or both) may have adversely contributed, but assisted reproductive technologies are compromised in women with high blood levels of BPA, phthalates, and other EDCs (Karwacka et al. 2019, Mínguez-Alarcón et al. 2019).

Finally, only limited data exist on the impact of EDCs on reproductive senescence and disorders of the aging reproductive system. Estrogenic EDCs including PCBs and phytoestrogens are associated with a higher risk of uterine fibroids, a condition that impacts up to 80% of women in their lifetime and is highly dependent on estrogen and progesterone (Katz et al. 2016). Higher blood levels of DDT and its metabolites are associated with an early age at menopause (Akkina et al. 2004) while other pesticides have been associated with later age at menopause (Farr et al. 2006). There is also some evidence that TCDD and PCBs can advance female reproductive aging (Rattan et al. 2017) and BPA heightens the risk of prostate cancer (Prins et al. 2014, Gore et al. 2015). Effects of phytoestrogens are mixed with conflicting evidence that they are possibly cancer-inducing or protective, most likely depending on dose, the timing of exposure, and other factors (Patisaul & Jefferson 2010). Impacts on other aspects of reproductive aging, including premature depletion of ovarian follicle reserves, are also likely but underexplored (Weiss 2007, Grossman 2014, Johansson et al. 2016, Barakat et al. 2017).

The placenta

There continues to be growing recognition that the placenta is not an impenetrable barrier but, rather, may be a particularly vulnerable target for endocrine disruption (Wang et al. 2016, Gingrich et al. 2020). It is now clear that the bulk of EDCs likely reach the developing fetus (Aylward et al. 2014). For example, maternal estrogens are effectively sequestered by α-fetoprotein but most structurally similar compounds only weakly or fail to bind to α-fetoprotein and can, therefore, enter fetal circulation relatively unimpeded (Milligan et al. 1998, Ikezuki et al. 2002, Vandenberg et al. 2007). Environmental contaminants known to cross the placenta and reach the fetus include BPA and other phenols, phthalates, heavy metals, pesticides, PFAS, and numerous flame retardants (Leazer & Klaassen 2003, D’Aloisio et al. 2013). Some pollutants can accumulate in placental tissue (Esteban-Vasallo et al. 2012, Vizcaino et al. 2014, Leonetti et al. 2016a,b, Phillips et al. 2016, Baldwin et al. 2017) and appear at higher levels in fetal cord blood than maternal blood (e.g. some metals, brominated flame retardants including TBBPA and many PBDE congeners, and polyaromatic hydrocarbons) (Aylward et al. 2014), demonstrating that fetally derived placental tissues and the fetus itself can experience greater exposures than the mother. In the case of some flame retardants, this placental accumulation appears to differ by sex with placentas associated with the male offspring obtaining higher levels, raising the possibility that fetal exposure may differ by sex (Phillips et al. 2016, Rock et al. 2018).

The placenta is the site of nutrient exchange between mother and fetus, but it also provides critical support for fetal growth through hormone and neurotransmitter production. Not surprisingly, the placenta has been found to play a unique and critical role in neurodevelopment, and, consequently, dysfunction of the placenta can severely impact neurodevelopment (Myatt 2006, Konkel 2016). There are many examples of situations where stress-induced inflammation can lead to placental dysfunction and altered neurodevelopment (Bronson & Bale 2014, 2016), however, comparatively few studies have tested whether this type of response can occur from exposure to exogenous chemicals (Gingrich et al. 2020, Mao et al. 2020). Thyroid hormone regulation and transfer are also vital for proper neurodevelopment and highly susceptible to EDCs such as PBDEs and PCBs (Demeneix 2014). Therefore, during the gestational window, neurodevelopment can not only be impacted by direct toxicity to the developing brain, through placental transfer, but can also be impacted indirectly through placental disruption.

Other routes of reproductive endocrine disruption

Endocrine disruption does not have to be direct. Because the neuroendocrine pathways that coordinate reproductive physiology intersect with other organ systems and pathways, even indirect environmental insults can have reproductive consequences. For example, chronic stress including prolonged isolation, parental neglect, starvation, or extreme exercise can itself suppress ovulation, induce miscarriage, reduce sperm count, result in preterm birth, and shift the timing of pubertal maturation. Additionally, dysregulation of the stress axis can contribute to other chronic health conditions including metabolic syndrome, impaired immune function, cardiovascular disease, and cognitive decline (Dirven et al. 2017, Joseph & Golden 2017) highlighting the multi-organ system impacts of neuroendocrine disruption. Similarly, the endocrine and immune systems reciprocally influence each other, and hyperinflammation can suppress fertility and reproduction (Belloni et al. 2014). Reproductive maturation and function are also under strong metabolic control and highly sensitive to body condition (Bellefontaine & Elias 2014). In combination with stress, chronic illness and other bodily insults, the severity and breadth of EDC-related health effects can be compounded. For accelerated female puberty, for example, commonly ascribed causal factors such as father absence and obesity have turned out to play less of a singular role than once believed (Li et al. 2017, Sohn 2017, Reinehr & Roth 2019, Sear et al. 2019). However, in combination with other exogenous insults including chemical exposures, the risk of precocious puberty and other reproductive challenges increase. The degree to which EDCs factor into this complex landscape and influence reproductive outcomes in humans remains difficult to quantify with certainty, but experimental evidence strongly implicates that their impact is likely underestimated and growing.

Finally, many EDCs have the potential to elicit their effects through modes of action that impact other organ systems. The endocrine system has been shown to interact with the immune system, for example, by mediating gene transcription of pro-inflammatory cytokines, and mediators of the innate immune system can feedback on the brain and regulate endocrine signaling (Irwin & Cole 2011, Merrheim et al. 2020). PBDEs and PFAS have been associated with inflammation during pregnancy and the postpartum period in women (Zota et al. 2018). Additionally, uterine remodeling, driven by immune cells, is critical for preparing the uterus for pregnancy, a process that may be vulnerable to EDCs (Meyer & Zenclussen 2020). In the brain, microglia play an essential role in the execution of sexually dimorphic hypothalamic development (Lenz & McCarthy 2015). Consequently, during development, their densities can be sexually dimorphic in hypothalamic nuclei (Schwarz et al. 2012) and environmental exposures, including exposure to air pollution or BPA, can sex-specifically alter their numbers or morphology, particularly in combination with other stressors (Bolton et al. 2013, Hanamsagar & Bilbo 2016, Rebuli et al. 2016, Bolton et al. 2017). Interest in the capacity for EDCs to disrupt the microbiome and the brain-gut axis is also increasing (Roman et al. 2019, Kaur et al. 2020).

Take-home messages: key concepts of endocrine disruption in the reproductive system

The DES disaster illustrates three core principles of endocrine disruption. First, latency between exposure and effect can be extremely long, even decades. DES-exposed babies were born healthy by all appearance, with no evidence of the reproductive consequences that would ultimately befall them. Pioneering work by Drs Beach, Young, Goy and others exploring the mechanisms by which fetal hormone exposure alters sex behavior and sex-specific neuroendocrine feedback systems (Gorski 1963, Young et al. 1964, Goy & Resko 1972, Swaab & Hofman 1984, Balthazart et al. 1996, Marler 2005) identified the primary mechanisms underlying this phenomenon in the reproductive system. As such, neuroendocrinologists laid critical groundwork for conceptually understanding how reproductive development and function could be vulnerable to endocrine disruption. This long latency concept is now a cornerstone of the 'developmental origins of health and disease (DoHAD)' framework; a concept born from the Barker hypothesis stating that metabolic adaptations made during early-life scarcity could later heighten the risk of morbidity in an environment of plenty (Barker 2007, Heindel et al. 2015).

The second key principle is that the timing of exposure, perhaps even more than dose, drives the potential and severity of adverse outcomes. In vertebrates, there are critical moments, both for the reproductive organs and the brain, when sensitivity to endogenous hormones and, consequently, EDCs is especially high. Additionally, there are phases in the life trajectory, particularly in prenatal development, where hormones play an organizational role in the formation of reproductive systems. Because interference with those organizational events can result in irreversible injury, they are considered particularly critical windows of EDC vulnerability. For example, the type and severity of disorders common to DES sons and daughters vary substantially depending on the timing of the mother’s first exposure, total dose, and length of exposure (Robboy et al. 1981, 1984, Faber et al. 1990). The vast majority of experimental EDC research on reproduction has used prenatal or early-life exposure paradigms and exposure later in life assessment. By contrast, exposures during puberty, which is an additional, but not as well-characterized period of organizational hormone action, are not as well-studied (Ahmed et al. 2008, Schulz et al. 2009, Sisk 2016, Herting & Sowell 2017). Also underexplored is the possibility that EDC exposure changes the timing of when and for how long critical windows are open. Thyroid hormones have long been known to open the window for filial imprinting in birds and can reopen that window in some circumstances (Yamaguchi et al. 2012). Embryonic exposure to BPA and BPS has been shown to shift the timing of neurogenesis in the zebrafish brain (Kinch et al. 2015). Almost nothing is known about how windows of HPG organization can be shifted in the mammalian brain by EDCs.

The third key principle of endocrine disruption is that the dose-response of many hormones and EDCs appears to be non-linear, and adverse outcomes might be different at low vs high doses (Vandenberg et al. 2012). The best example of this is thyroid hormone because the effects of abnormally high or low levels are completely different. In adults, symptoms of hyperthyroidism include bulging eyes, weight loss, tachycardia, arrhythmias, goiter, heat intolerance, and anxiety or nervousness, while hypothyroidism can result in weight gain, fatigue, cold intolerance, muscle and joint pain, hair loss, dry skin, depression and menstrual irregularity. This paradigm is anathema to the fundamental toxicological axiom that 'the dose makes the poison' which posits that effects intensify with dose but do not fundamentally change, nor manifest differently, below a certain threshold. Homeostatic adaptation can also produce non-linear dose responses. Our neuroendocrine system evolved to be responsive to environmental signals, both chemical and perceived, including naturally occurring hormonally active compounds. Consequently, we have adaptive responses to some environmental insults and can make imperceptible adjustments to maintain homeostasis, but only up to a point. For example, the neural components of the HPG axis are constantly responding to numerous external signals simultaneously including day length, hormones, infection, olfactory cues, and glucose levels, among others. Complex feedback loops on the HPG axis maintain physiologically appropriate levels of steroid hormones and rhythmic GnRH pulses. These feedback systems are likely one reason why many EDC dose responses more closely approximate a U-shaped or inverted U-shaped curve (Vandenberg et al. 2012, Lagarde et al. 2015, Zoeller & Vandenberg 2015). U-shaped dose effects might also reflect an integration of two different mechanisms of action, each of which occurs at a different dose range. For example, DDT interferes with estrogen and androgen action at low doses but is a potent neurotoxin at higher levels (Toppari et al. 1996). It should be noted that although some toxicologists have expressed concern that non-linear dose responses are underappreciated, others doubt their existence entirely, and the concept remains highly controversial for some, primarily because it would necessitate changing the way regulatory toxicity testing is conducted (Melnick et al. 2002, Vandenberg et al. 2012, Lagarde et al. 2015, Solecki et al. 2017, Demeneix et al. 2020). Others have also perturbed this concept and labeled it 'hormesis', a largely debunked hypothesis which purports that low doses of some toxic compounds can actually be beneficial even if high doses are harmful (Thayer et al. 2006, Kendig et al. 2010).

Concluding thoughts

Human evolution will now occur in a complex chemical landscape of our own making. It is readily evident that exposure to EDCs is already adversely affecting reproductive physiology and behavior in ourselves and our planetary co-occupants and will continue to do so for generations to come. Growing evidence that some EDCs can induce epigenetic reprogramming that may be inherited and impact future generations emphasizes the pressing need to understand how the chemical cocktail inside of us is impacting our reproductive future (Ho et al. 2017). Some of the most obvious and potent compounds such as DDT, PCBs, PBDEs and DES, have been phased out of use and, fortunately, global exposure is consequently declining. For others such as BPA and the phthalates, despite an enormous literature documenting their adverse reproductive effects, regulatory inaction persists. The introduction of new chemicals is rapidly outpacing the capacity to understand their potential health effects or the totality of our exposure (Tweedale 2017). Additionally, even perceived successes are often failures because all too often problematic compounds are replaced by equally problematic cousins, a phenomenon called 'regrettable substitution' (Scherer et al. 2014, Trasande 2017, Blum et al. 2019). Collectively, blood levels of many hormonally active compounds can be several fold higher than endogenous estrogen levels, particularly during pregnancy and neonatal development, and are almost always present in both the environment and in tissues as mixtures (Wang et al. 2016). Yet, regulatory processes overwhelmingly consider their potential harm in isolation, one chemical at a time. Further efforts to understand the mechanisms underlying EDC effects, particularly complex mixtures of ubiquitous compounds with low hormonal potency, are necessary to adequately develop a public health strategy for preventing or combating their reproductive effects (Bopp et al. 2018). That every pregnant woman on the planet is currently carrying a mixture of chemicals during her pregnancy that could affect not only her daughter’s reproductive health but also her granddaughter’s is a major reason why the topic of endocrine disruption must continue to receive global attention from scientists, governments, and the general public.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/REP-20-0596.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by a Department of Defense Autism Research Program, Idea Development Award to H B Patisaul (AR160055), a NIEHS center grant P30ES025128 to R C Smart, and an NIEHS R01ES031419 to H Stapleton (H B Patisaul is a co-PI).

Acknowledgments

This paper forms part of a special section on Reproductive toxicology. The guest editors for this section were Dr Adam Watkins (The University of Nottingham, UK) and Dr Aileen Keating (Iowa State University, IA, USA).

References

  • Adams S, Wiersielis K, Yasrebi A, Conde K, Armstrong L, Guo GL & Roepke TA 2020 Sex- and age-dependent effects of maternal organophosphate flame-retardant exposure on neonatal hypothalamic and hepatic gene expression. Reproductive Toxicology 94 6574. (https://doi.org/10.1016/j.reprotox.2020.04.001)

    • Search Google Scholar
    • Export Citation
  • Ahmed EI, Zehr JL, Schulz KM, Lorenz BH, DonCarlos LL & Sisk CL 2008 Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions. Nature Neuroscience 11 995997. (https://doi.org/10.1038/nn.2178)

    • Search Google Scholar
    • Export Citation
  • Akkina J, Reif J, Keefe T & Bachand A 2004 Age at natural menopause and exposure to organochlorine pesticides in Hispanic women. Journal of Toxicology and Environmental Health: Part A 67 14071422. (https://doi.org/10.1080/15287390490483845)

    • Search Google Scholar
    • Export Citation
  • Aksglaede L, Sorensen K, Petersen JH, Skakkebaek NE & Juul A 2009 Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 123 e932e939. (https://doi.org/10.1542/peds.2008-2491)

    • Search Google Scholar
    • Export Citation
  • Al-Saleh I, Coskun S, Al-Doush I, Abduljabbar M, Al-Rouqi R, Al-Rajudi T & Al-Hassan S 2019 Couples exposure to phthalates and its influence on in vitro fertilization outcomes. Chemosphere 226 597606. (https://doi.org/10.1016/j.chemosphere.2019.03.146)

    • Search Google Scholar
    • Export Citation
  • Alexander GM 2014 Postnatal testosterone concentrations and male social development. Frontiers in Endocrinology 5 15. (https://doi.org/10.3389/fendo.2014.00015)

    • Search Google Scholar
    • Export Citation
  • Aylward LL, Hays SM, Kirman CR, Marchitti SA, Kenneke JF, English C, Mattison DR & Becker RA 2014 Relationships of chemical concentrations in maternal and cord blood: a review of available data. Journal of Toxicology and Environmental Health: Part B, Critical Reviews 17 175203. (https://doi.org/10.1080/10937404.2014.884956)

    • Search Google Scholar
    • Export Citation
  • Bai Y, Chang F, Zhou R, Jin PP, Matsumoto H, Sokabe M & Chen L 2011 Increase of anteroventral periventricular kisspeptin neurons and generation of E2-induced LH-surge system in male rats exposed perinatally to environmental dose of bisphenol-A. Endocrinology 152 15621571. (https://doi.org/10.1210/en.2010-1042)

    • Search Google Scholar
    • Export Citation
  • Bakker J & Baum MJ 2008 Role for estradiol in female-typical brain and behavioral sexual differentiation. Frontiers in Neuroendocrinology 29 116. (https://doi.org/10.1016/j.yfrne.2007.06.001)

    • Search Google Scholar
    • Export Citation
  • Baldwin KR, Phillips AL, Horman B, Arambula SE, Rebuli ME, Stapleton HM & Patisaul HB 2017 Sex specific placental accumulation and behavioral effects of developmental firemaster 550 exposure in Wistar rats. Scientific Reports 7 7118. (https://doi.org/10.1038/s41598-017-07216-6)

    • Search Google Scholar
    • Export Citation
  • Balthazart J, Tlemcani O & Ball GF 1996 Do sex differences in the brain explain sex differences in the hormonal induction of reproductive behavior? What 25 years of research on the Japanese quail tells us. Hormones and Behavior 30 627661. (https://doi.org/10.1006/hbeh.1996.0066)

    • Search Google Scholar
    • Export Citation
  • Barakat R, Oakley O, Kim H, Jin J & Ko CJ 2016 Extra-gonadal sites of estrogen biosynthesis and function. BMB Reports 49 488496. (https://doi.org/10.5483/bmbrep.2016.49.9.141)

    • Search Google Scholar
    • Export Citation
  • Barakat R, Lin PP, Rattan S, Brehm E, Canisso IF, Abosalum ME, Flaws JA, Hess R & Ko C 2017 Prenatal exposure to DEHP induces premature reproductive senescence in male mice. Toxicological Sciences 156 96108. (https://doi.org/10.1093/toxsci/kfw248)

    • Search Google Scholar
    • Export Citation
  • Barker DJ 2007 The origins of the developmental origins theory. Journal of Internal Medicine 261 412417. (https://doi.org/10.1111/j.1365-2796.2007.01809.x)

    • Search Google Scholar
    • Export Citation
  • Barroso A, Roa J & Tena-Sempere M 2019 Neuropeptide control of puberty: beyond kisspeptins. Seminars in Reproductive Medicine 37 155165. (https://doi.org/10.1055/s-0039-3400967)

    • Search Google Scholar
    • Export Citation
  • Bateman HL & Patisaul HB 2008 Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus. Neurotoxicology 29 988997. (https://doi.org/10.1016/j.neuro.2008.06.008)

    • Search Google Scholar
    • Export Citation
  • Baum MJ 1979 Differentiation of coital behavior in mammals: a comparative analysis. Neuroscience and Biobehavioral Reviews 3 265284. (https://doi.org/10.1016/0149-7634(7990013-7)

    • Search Google Scholar
    • Export Citation
  • Beans BE 1997 Eagle’s Plume: The Struggle to Preserve the Life and Haunts of America’s Bald Eagle. Nebraska: University of Nebraska Press.

    • Search Google Scholar
    • Export Citation
  • Behura SK, Dhakal P, Kelleher AM, Balboula A, Patterson A & Spencer TE 2019 The brain-placental axis: therapeutic and pharmacological relevancy to pregnancy. Pharmacological Research 149 104468. (https://doi.org/10.1016/j.phrs.2019.104468)

    • Search Google Scholar
    • Export Citation
  • Bell MR 2014 Endocrine-disrupting actions of PCbs on brain development and social and reproductive behaviors. Current Opinion in Pharmacology 19 134144. (https://doi.org/10.1016/j.coph.2014.09.020)

    • Search Google Scholar
    • Export Citation
  • Bellanger M, Demeneix B, Grandjean P, Zoeller RT & Trasande L 2015 Neurobehavioral deficits, diseases, and associated costs of exposure to endocrine-disrupting chemicals in the European Union. Journal of Clinical Endocrinology and Metabolism 100 12561266. (https://doi.org/10.1210/jc.2014-4323)

    • Search Google Scholar
    • Export Citation
  • Bellefontaine N & Elias CF 2014 Minireview: metabolic control of the reproductive physiology: insights from genetic mouse models. Hormones and Behavior 66 714. (https://doi.org/10.1016/j.yhbeh.2014.04.007)

    • Search Google Scholar
    • Export Citation
  • Belloni V, Sorci G, Paccagnini E, Guerreiro R, Bellenger J & Faivre B 2014 Disrupting immune regulation incurs transient costs in male reproductive function. PLoS ONE 9 e84606. (https://doi.org/10.1371/journal.pone.0084606)

    • Search Google Scholar
    • Export Citation
  • Beltramo M, Dardente H, Cayla X & Caraty A 2014 Cellular mechanisms and integrative timing of neuroendocrine control of GnRH secretion by kisspeptin. Molecular and Cellular Endocrinology 382 387399. (https://doi.org/10.1016/j.mce.2013.10.015)

    • Search Google Scholar
    • Export Citation
  • Bennetts HW, Underwood EJ & Shier FL 1946 A specific breeding problem of sheep on subterranean clover pastures in Western Australia. Australian Veterinary Journal 22 2–12. (https://doi.org/10.1111/j.1751-0813.1946.tb15473.x)

    • Search Google Scholar
    • Export Citation
  • Bishop GJ & Koncz C 2002 Brassinosteroids and plant steroid hormone signaling. Plant Cell 14 (Supplement) S97S110. (https://doi.org/10.1105/tpc.001461)

    • Search Google Scholar
    • Export Citation
  • Blum A, Behl M, Birnbaum L, Diamond ML, Phillips A, Singla V, Sipes NS, Stapleton HM & Venier M 2019 Organophosphate ester flame retardants: are they a regrettable substitution for polybrominated diphenyl ethers? Environmental Science and Technology Letters 6 638649. (https://doi.org/10.1021/acs.estlett.9b00582)

    • Search Google Scholar
    • Export Citation
  • Boeyer ME, Sherwood RJ, Deroche CB & Duren DL 2018 Early maturity as the new normal: a century-long study of bone age. Clinical Orthopaedics and Related Research 476 21122122. (https://doi.org/10.1097/CORR.0000000000000446)

    • Search Google Scholar
    • Export Citation
  • Bolton JL, Huff NC, Smith SH, Mason SN, Foster WM, Auten RL & Bilbo SD 2013 Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice. Environmental Health Perspectives 121 10751082. (https://doi.org/10.1289/ehp.1306560)

    • Search Google Scholar
    • Export Citation
  • Bolton JL, Marinero S, Hassanzadeh T, Natesan D, Le D, Belliveau C, Mason SN, Auten RL & Bilbo SD 2017 Gestational exposure to air pollution alters cortical volume, microglial morphology, and microglia-neuron interactions in a sex-specific manner. Frontiers in Synaptic Neuroscience 9 10. (https://doi.org/10.3389/fnsyn.2017.00010)

    • Search Google Scholar
    • Export Citation
  • Bopp SK, Barouki R, Brack W, Dalla Costa S, Dorne JCM, Drakvik PE, Faust M, Karjalainen TK, Kephalopoulos S & van Klaveren J et al.2018 Current EU research activities on combined exposure to multiple chemicals. Environment International 120 544562. (https://doi.org/10.1016/j.envint.2018.07.037)

    • Search Google Scholar
    • Export Citation
  • Bourguignon JP, Juul A, Franssen D, Fudvoye J, Pinson A & Parent AS 2016 Contribution of the endocrine perspective in the evaluation of endocrine disrupting chemical effects: the case study of pubertal timing. Hormone Research in Paediatrics 86 221232. (https://doi.org/10.1159/000442748)

    • Search Google Scholar
    • Export Citation
  • Boyle M, Buckley JP & Quiros-Alcala L 2019 Associations between urinary organophosphate ester metabolites and measures of adiposity among U.S. children and adults: NHANES 2013–2014. Environment International 127 754763. (https://doi.org/10.1016/j.envint.2019.03.055)

    • Search Google Scholar
    • Export Citation
  • Bronson SL & Bale TL 2014 Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment. Endocrinology 155 26352646. (https://doi.org/10.1210/en.2014-1040)

    • Search Google Scholar
    • Export Citation
  • Bronson SL & Bale TL 2016 The placenta as a mediator of stress effects on neurodevelopmental reprogramming. Neuropsychopharmacology 41 207218. (https://doi.org/10.1038/npp.2015.231)

    • Search Google Scholar
    • Export Citation
  • Buck Louis GM 2014 Persistent environmental pollutants and couple fecundity: an overview. Reproduction 147 R97R104. (https://doi.org/10.1530/REP-13-0472)

    • Search Google Scholar
    • Export Citation
  • Burris HH & Hacker MR 2017 Birth outcome racial disparities: a result of intersecting social and environmental factors. Seminars in Perinatology 41 360366. (https://doi.org/10.1053/j.semperi.2017.07.002)

    • Search Google Scholar
    • Export Citation
  • Calaf GM, Ponce-Cusi R, Aguayo F, Muñoz JP & Bleak TC 2020 Endocrine disruptors from the environment affecting breast cancer. Oncology Letters 20 1932. (https://doi.org/10.3892/ol.2020.11566)

    • Search Google Scholar
    • Export Citation
  • Cao J & Patisaul HB 2011 Sexually dimorphic expression of hypothalamic estrogen receptors alpha and beta and kiss1 in neonatal male and female rats. Journal of Comparative Neurology 519 29542977. (https://doi.org/10.1002/cne.22648)

    • Search Google Scholar
    • Export Citation
  • Cao J & Patisaul HB 2013 Sex specific expression of estrogen receptors alpha and beta and kiss1 in the postnatal rat amygdala. Journal of Comparative Neurology 521 465478. (https://doi.org/10.1002/cne.23185)

    • Search Google Scholar
    • Export Citation
  • Carlsen E, Giwercman A, Keiding N & Skakkebaek NE 1992 Evidence for decreasing quality of semen during past 50 years. BMJ 305 609613. (https://doi.org/10.1136/bmj.305.6854.609)

    • Search Google Scholar
    • Export Citation
  • Catenza CJ, Farooq A, Shubear NS & Donkor KK 2021 A targeted review on fate, occurrence, risk and health implications of bisphenol analogues. Chemosphere 268 129273. (https://doi.org/10.1016/j.chemosphere.2020.129273)

    • Search Google Scholar
    • Export Citation
  • Chandrareddy A, Muneyyirci-Delale O, McFarlane SI & Murad OM 2008 Adverse effects of phytoestrogens on reproductive health: a report of three cases. Complementary Therapies in Clinical Practice 14 132135. (https://doi.org/10.1016/j.ctcp.2008.01.002)

    • Search Google Scholar
    • Export Citation
  • Clarkson J & Herbison AE 2016 Hypothalamic control of the male neonatal testosterone surge. Philosophical Transactions of the Royal Society of London: Series B, Biological Sciences 371 20150115. (https://doi.org/10.1098/rstb.2015.0115)

    • Search Google Scholar
    • Export Citation
  • Clarkson J, Busby ER, Kirilov M, Schütz G, Sherwood NM & Herbison AE 2014 Sexual differentiation of the brain requires perinatal kisspeptin-GnRH neuron signaling. Journal of Neuroscience 34 1529715305. (https://doi.org/10.1523/JNEUROSCI.3061-14.2014)

    • Search Google Scholar
    • Export Citation
  • Cohn BA, La Merrill M, Krigbaum NY, Yeh G, Park JS, Zimmermann L & Cirillo PM 2015 DDT exposure in utero and breast cancer. Journal of Clinical Endocrinology and Metabolism 100 28652872. (https://doi.org/10.1210/jc.2015-1841)

    • Search Google Scholar
    • Export Citation
  • Curtis LR 2001 Organophosphate antagonism of the androgen receptor. Toxicological Sciences 60 12. (https://doi.org/10.1093/toxsci/60.1.1)

  • D’Aloisio AA, DeRoo LA, Baird DD, Weinberg CR & Sandler DP 2013 Prenatal and infant exposures and age at menarche. Epidemiology 24 277284. (https://doi.org/10.1097/EDE.0b013e31828062b7)

    • Search Google Scholar
    • Export Citation
  • Davis DL, Bradlow HL, Wolff M, Woodruff T, Hoel DG & Anton-Culver H 1993 Medical hypothesis: xenoestrogens as preventable causes of breast cancer. Environmental Health Perspectives 101 372377. (https://doi.org/10.1289/ehp.93101372)

    • Search Google Scholar
    • Export Citation
  • Demeneix B 2014 Losing Our Minds: How Environmental Pollution Impairs Human Intelligence and Mental Health. Oxford, New York: Oxford University Press.

    • Search Google Scholar
    • Export Citation
  • Demeneix B, Vandenberg LN, Ivell R & Zoeller RT 2020 Thresholds and endocrine disruptors: an Endocrine Society policy perspective. Journal of the Endocrine Society 4 bvaa085. (https://doi.org/10.1210/jendso/bvaa085)

    • Search Google Scholar
    • Export Citation
  • Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT & Gore AC 2009 Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocrine Reviews 30 293342. (https://doi.org/10.1210/er.2009-0002)

    • Search Google Scholar
    • Export Citation
  • Dickerson SM, Cunningham SL & Gore AC 2011 Prenatal PCbs disrupt early neuroendocrine development of the rat hypothalamus. Toxicology and Applied Pharmacology 252 3646. (https://doi.org/10.1016/j.taap.2011.01.012)

    • Search Google Scholar
    • Export Citation
  • Dirven BCJ, Homberg JR, Kozicz T & Henckens MJAG 2017 Epigenetic programming of the neuroendocrine stress response by adult life stress. Journal of Molecular Endocrinology 59 R11–R31. (https://doi.org/10.1530/JME-17-0019)

    • Search Google Scholar
    • Export Citation
  • Dudek M, Ziarniak K & Sliwowska JH 2018 Kisspeptin and metabolism: the brain and beyond. Frontiers in Endocrinology 9 145. (https://doi.org/10.3389/fendo.2018.00145)

    • Search Google Scholar
    • Export Citation
  • EDSTAC 1998 Endocrine Disruptor Screening and Testing Advisory Committee Final Report: Executive Summary, Vol I and Vol. II. Washington, DC: United States Environmental Protection Agency. (available at: https://www.epa.gov/sites/production/files/2015-08/documents/exesum14.pdf)

    • Search Google Scholar
    • Export Citation
  • Eskenazi B, Warner M, Marks AR, Samuels S, Needham L, Brambilla P & Mocarelli P 2010 Serum dioxin concentrations and time to pregnancy. Epidemiology 21 224231. (https://doi.org/10.1097/EDE.0b013e3181cb8b95)

    • Search Google Scholar
    • Export Citation
  • Esteban-Vasallo MD, Aragones N, Pollan M, Lopez-Abente G & Perez-Gomez B 2012 Mercury, cadmium, and lead levels in human placenta: a systematic review. Environmental Health Perspectives 120 13691377. (https://doi.org/10.1289/ehp.1204952)

    • Search Google Scholar
    • Export Citation
  • European Workshop on the Impact of Endocrine Disrupters on Human Health and Wildlife 1996 Report of Proceedings 1996, Environment and Climate Research Programme of DG XII of the European Commission (Report EUR 17549) 2–4 December 1996, Weybridge, UK.

    • Search Google Scholar
    • Export Citation
  • Faber K, Jones M & Tarraza HM 1990 Invasive squamous cell carcinoma of the vagina in a diethylstilbestrol-exposed woman. Gynecologic Oncology 37 125128. (https://doi.org/10.1016/0090-8258(9090320-k)

    • Search Google Scholar
    • Export Citation
  • Farhat A, Buick JK, Williams A, Yauk CL, O’Brien JM, Crump D, Williams KL, Chiu S & Kennedy SW 2014 Tris(1,3-dichloro-2-propyl) phosphate perturbs the expression of genes involved in immune response and lipid and steroid metabolism in chicken embryos. Toxicology and Applied Pharmacology 275 104112. (https://doi.org/10.1016/j.taap.2013.12.020)

    • Search Google Scholar
    • Export Citation
  • Farr SL, Cai J, Savitz DA, Sandler DP, Hoppin JA & Cooper GS 2006 Pesticide exposure and timing of menopause: the Agricultural Health Study. American Journal of Epidemiology 163 731742. (https://doi.org/10.1093/aje/kwj099)

    • Search Google Scholar
    • Export Citation
  • Filardo EJ & Thomas P 2012 Minireview: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology. Endocrinology 153 29532962. (https://doi.org/10.1210/en.2012-1061)

    • Search Google Scholar
    • Export Citation
  • Fritsche E, Grandjean P, Crofton KM, Aschner M, Goldberg A, Heinonen T, Hessel EVS, Hogberg HT, Bennekou SH & Lein PJ et al.2018 Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes. Toxicology and Applied Pharmacology 354 36. (https://doi.org/10.1016/j.taap.2018.02.004)

    • Search Google Scholar
    • Export Citation
  • Frye CA, Bo E, Calamandrei G, Calza L, Dessi-Fulgheri F, Fernandez M, Fusani L, Kah O, Kajta M & Le Page Y et al.2012 Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems. Journal of Neuroendocrinology 24 144159. (https://doi.org/10.1111/j.1365-2826.2011.02229.x)

    • Search Google Scholar
    • Export Citation
  • Fucic A, Gamulin M, Ferencic Z, Katic J, Krayer von Krauss M, Bartonova A & Merlo DF 2012 Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system, breast, lung, kidney, pancreas, and brain. Environmental Health: A Global Access Science Source 11 (Supplement 1) S8. (https://doi.org/10.1186/1476-069X-11-S1-S8)

    • Search Google Scholar
    • Export Citation
  • Fudvoye J, Lopez-Rodriguez D, Franssen D & Parent AS 2019 Endocrine disrupters and possible contribution to pubertal changes. Best Practice and Research: Clinical Endocrinology and Metabolism 33 101300. (https://doi.org/10.1016/j.beem.2019.101300)

    • Search Google Scholar
    • Export Citation
  • Gangolli SD 1982 Testicular effects of phthalate esters. Environmental Health Perspectives 45 7784. (https://doi.org/10.1289/ehp.824577)

  • Gao N, Hu R, Huang Y, Dao L, Zhang C, Liu Y, Wu L, Wang X, Yin W & Gore AC 2018 Specific effects of prenatal DEHP exposure on neuroendocrine gene expression in the developing hypothalamus of male rats. Archives of Toxicology 92 501512. (https://doi.org/10.1007/s00204-017-2049-z)

    • Search Google Scholar
    • Export Citation
  • Garcia JP, Keen KL, Seminara SB & Terasawa E 2019 Role of kisspeptin and NKB in puberty in nonhuman primates: sex differences. Seminars in Reproductive Medicine 37 4755. (https://doi.org/10.1055/s-0039-3400253)

    • Search Google Scholar
    • Export Citation
  • Geoffroy-Siraudin C, Loundou AD, Romain F, Achard V, Courbiere B, Perrard MH, Durand P & Guichaoua MR 2012 Decline of semen quality among 10 932 males consulting for couple infertility over a 20-year period in Marseille, France. Asian Journal of Andrology 14 584590. (https://doi.org/10.1038/aja.2011.173)

    • Search Google Scholar
    • Export Citation
  • Gill WB, Schumacher GF & Bibbo M 1976 Structural and functional abnormalities in the sex organs of male offspring of mothers treated with diethylstilbestrol (DES). Journal of Reproductive Medicine 16 147153.

    • Search Google Scholar
    • Export Citation
  • Gingrich J, Ticiani E & Veiga-Lopez A 2020 Placenta disrupted: endocrine disrupting chemicals and pregnancy. Trends in Endocrinology and Metabolism 31 508524. (https://doi.org/10.1016/j.tem.2020.03.003)

    • Search Google Scholar
    • Export Citation
  • Gonzalez FJ & Nebert DW 1990 Evolution of the P450 gene superfamily: animal-plant ‘warfare’, molecular drive and human genetic differences in drug oxidation. Trends in Genetics 6 182186. (https://doi.org/10.1016/0168-9525(9090174-5)

    • Search Google Scholar
    • Export Citation
  • Gonzalez TL, Moos RK, Gersch CL, Johnson MD, Richardson RJ, Koch HM & Rae JM 2018 Metabolites of n-butylparaben and iso-butylparaben exhibit estrogenic properties in MCF-7 and T47D human breast cancer cell lines. Toxicological Sciences 164 5059. (https://doi.org/10.1093/toxsci/kfy063)

    • Search Google Scholar
    • Export Citation
  • Gooren L 2006 The biology of human psychosexual differentiation. Hormones and Behavior 50 589601. (https://doi.org/10.1016/j.yhbeh.2006.06.011)

    • Search Google Scholar
    • Export Citation
  • Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, Toppari J & Zoeller RT 2015 EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocrine Reviews 36 E1E150. (https://doi.org/10.1210/er.2015-1010)

    • Search Google Scholar
    • Export Citation
  • Gore AC, Krishnan K & Reilly MP 2019 Endocrine-disrupting chemicals: effects on neuroendocrine systems and the neurobiology of social behavior. Hormones and Behavior 111 722. (https://doi.org/10.1016/j.yhbeh.2018.11.006)

    • Search Google Scholar
    • Export Citation
  • Gorski RA 1963 Modification of ovulatory mechanisms by postnatal administration of estrogen to the rat. American Journal of Physiology 205 842844. (https://doi.org/10.1152/ajplegacy.1963.205.5.842)

    • Search Google Scholar
    • Export Citation
  • Goy RW & Resko JA 1972 Gonadal hormones and behavior of normal and pseudohermaphroditic nonhuman female primates. Recent Progress in Hormone Research 28 707733.

    • Search Google Scholar
    • Export Citation
  • Graceli JB, Dettogni RS, Merlo E, Niño O, da Costa CS, Zanol JF, Ríos Morris EA, Miranda-Alves L & Denicol AC 2020 The impact of endocrine-disrupting chemical exposure in the mammalian hypothalamic-pituitary axis. Molecular and Cellular Endocrinology 518 110997. (https://doi.org/10.1016/j.mce.2020.110997)

    • Search Google Scholar
    • Export Citation
  • Grossman E 2014 Time after time: environmental influences on the aging brain. Environmental Health Perspectives 122 A238A243. (https://doi.org/10.1289/ehp/122-A238)

    • Search Google Scholar
    • Export Citation
  • Guillette Jr LJ, Gross TS, Masson GR, Matter JM, Percival HF & Woodward AR 1994 Developmental abnormalities of the gonad and abnormal sex hormone concentrations in juvenile alligators from contaminated and control lakes in Florida. Environmental Health Perspectives 102 680688. (https://doi.org/10.1289/ehp.94102680)

    • Search Google Scholar
    • Export Citation
  • Guillette Jr LJ, Crain DA, Rooney AA & Pickford DB 1995 Organization versus activation: the role of endocrine-disrupting contaminants (EDCs) during embryonic development in wildlife. Environmental Health Perspectives 103 (Supplement 7) 157164. (https://doi.org/10.1289/ehp.95103s7157)

    • Search Google Scholar
    • Export Citation
  • Hanamsagar R & Bilbo SD 2016 Sex differences in neurodevelopmental and neurodegenerative disorders: focus on microglial function and neuroinflammation during development. Journal of Steroid Biochemistry and Molecular Biology 160 127133. (https://doi.org/10.1016/j.jsbmb.2015.09.039)

    • Search Google Scholar
    • Export Citation
  • Hannas BR, Furr J, Lambright CS, Wilson VS, Foster PM & Gray Jr LE 2011 Dipentyl phthalate dosing during sexual differentiation disrupts fetal testis function and postnatal development of the male Sprague-Dawley rat with greater relative potency than other phthalates. Toxicological Sciences 120 184193. (https://doi.org/10.1093/toxsci/kfq386)

    • Search Google Scholar
    • Export Citation
  • Hauser R, Skakkebaek NE, Hass U, Toppari J, Juul A, Andersson AM, Kortenkamp A, Heindel JJ & Trasande L 2015 Male reproductive disorders, diseases, and costs of exposure to endocrine-disrupting chemicals in the European Union. Journal of Clinical Endocrinology and Metabolism 100 12671277. (https://doi.org/10.1210/jc.2014-4325)

    • Search Google Scholar
    • Export Citation
  • Heindel JJ, Balbus J, Birnbaum L, Brune-Drisse MN, Grandjean P, Gray K, Landrigan PJ, Sly PD, Suk W & Slechta DC et al.2015 Developmental origins of health and disease: integrating environmental influences. Endocrinology 156 34163421. (https://doi.org/10.1210/EN.2015-1394)

    • Search Google Scholar
    • Export Citation
  • Herbison AE 2020 A simple model of estrous cycle negative and positive feedback regulation of GnRH secretion. Frontiers in Neuroendocrinology 57 100837. (https://doi.org/10.1016/j.yfrne.2020.100837)

    • Search Google Scholar
    • Export Citation
  • Herbst AL, Green Jr TH & Ulfelder H 1970 Primary carcinoma of the vagina: an analysis of 68 cases. American Journal of Obstetrics and Gynecology 106 210218. (https://doi.org/10.1016/0002-9378(7090265-6)

    • Search Google Scholar
    • Export Citation
  • Herbst AL, Ulfelder H & Poskanzer DC 1971 Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. New England Journal of Medicine 284 878881. (https://doi.org/10.1056/NEJM197104222841604)

    • Search Google Scholar
    • Export Citation
  • Herman-Giddens ME 2006 Recent data on pubertal milestones in United States children: the secular trend toward earlier development. International Journal of Andrology 29 241246; discussion 286290. (https://doi.org/10.1111/j.1365-2605.2005.00575.x)

    • Search Google Scholar
    • Export Citation
  • Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG & Hasemeier CM 1997 Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99 505512. (https://doi.org/10.1542/peds.99.4.505)

    • Search Google Scholar
    • Export Citation
  • Herting MM & Sowell ER 2017 Puberty and structural brain development in humans. Frontiers in Neuroendocrinology 44 122137. (https://doi.org/10.1016/j.yfrne.2016.12.003)

    • Search Google Scholar
    • Export Citation
  • Hewitt SC & Korach KS 2018 Estrogen receptors: new directions in the new millennium. Endocrine Reviews 39 664675. (https://doi.org/10.1210/er.2018-00087)

    • Search Google Scholar
    • Export Citation
  • Hlisníková H, Petrovičová I, Kolena B, Šidlovská M & Sirotkin A 2020 Effects and mechanisms of phthalates’ action on reproductive processes and reproductive health: a literature review. International Journal of Environmental Research and Public Health 17 6811. (https://doi.org/10.3390/ijerph17186811)

    • Search Google Scholar
    • Export Citation
  • Ho SM, Cheong A, Adgent MA, Veevers J, Suen AA, Tam NNC, Leung YK, Jefferson WN & Williams CJ 2017 Environmental factors, epigenetics, and developmental origin of reproductive disorders. Reproductive Toxicology 68 85104. (https://doi.org/10.1016/j.reprotox.2016.07.011)

    • Search Google Scholar
    • Export Citation
  • Hodgson E & Rose RL 2007 Human metabolic interactions of environmental chemicals. Journal of Biochemical and Molecular Toxicology 21 182186. (https://doi.org/10.1002/jbt.20175)

    • Search Google Scholar
    • Export Citation
  • Hooper L, Ryder JJ, Kurzer MS, Lampe JW, Messina MJ, Phipps WR & Cassidy A 2009 Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Human Reproduction Update 15 423440. (https://doi.org/10.1093/humupd/dmp010)

    • Search Google Scholar
    • Export Citation
  • Hotchkiss AK, Rider CV, Blystone CR, Wilson VS, Hartig PC, Ankley GT, Foster PM, Gray CL & Gray LE 2008 Fifteen years after ‘Wingspread’ – environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go. Toxicological Sciences 105 235259. (https://doi.org/10.1093/toxsci/kfn030)

    • Search Google Scholar
    • Export Citation
  • Ibitoye M, Choi C, Tai H, Lee G & Sommer M 2017 Early menarche: a systematic review of its effect on sexual and reproductive health in low- and middle-income countries. PLoS ONE 12 e0178884. (https://doi.org/10.1371/journal.pone.0178884)

    • Search Google Scholar
    • Export Citation
  • Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y & Taketani Y 2002 Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. Human Reproduction 17 28392841. (https://doi.org/10.1093/humrep/17.11.2839)

    • Search Google Scholar
    • Export Citation
  • Irwin MR & Cole SW 2011 Reciprocal regulation of the neural and innate immune systems. Nature Reviews: Immunology 11 625632. (https://doi.org/10.1038/nri3042)

    • Search Google Scholar
    • Export Citation
  • Ismail MF & Mohamed HM 2012 Deltamethrin-induced genotoxicity and testicular injury in rats: comparison with biopesticide. Food and Chemical Toxicology 50 34213425. (https://doi.org/10.1016/j.fct.2012.07.060)

    • Search Google Scholar
    • Export Citation
  • Jefferson WN, Patisaul HB & Williams CJ 2012 Reproductive consequences of developmental phytoestrogen exposure. Reproduction 143 247260. (https://doi.org/10.1530/REP-11-0369)

    • Search Google Scholar
    • Export Citation
  • Jin Y, Zhang Q, Pan JX, Wang FF & Qu F 2019 The effects of di(2-ethylhexyl) phthalate exposure in women with polycystic ovary syndrome undergoing in vitro fertilization. Journal of International Medical Research 47 62786293. (https://doi.org/10.1177/0300060519876467)

    • Search Google Scholar
    • Export Citation
  • Johansson HK, Jacobsen PR, Hass U, Svingen T, Vinggaard AM, Isling LK, Axelstad M, Christiansen S & Boberg J 2016 Perinatal exposure to mixtures of endocrine disrupting chemicals reduces female rat follicle reserves and accelerates reproductive aging. Reproductive Toxicology 61 186194. (https://doi.org/10.1016/j.reprotox.2016.03.045)

    • Search Google Scholar
    • Export Citation
  • Joseph JJ & Golden SH 2017 Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus. Annals of the New York Academy of Sciences 1391 2034. (https://doi.org/10.1111/nyas.13217)

    • Search Google Scholar
    • Export Citation
  • Kamatenesi-Mugisha M & Oryem-Origa H 2007 Medicinal plants used to induce labour during childbirth in western Uganda. Journal of Ethnopharmacology 109 19. (https://doi.org/10.1016/j.jep.2006.06.011)

    • Search Google Scholar
    • Export Citation
  • Kaprara A & Huhtaniemi IT 2018 The hypothalamus-pituitary-gonad axis: tales of mice and men. Metabolism: Clinical and Experimental 86 317. (https://doi.org/10.1016/j.metabol.2017.11.018)

    • Search Google Scholar
    • Export Citation
  • Karnaky KJ 1953 Diethylstilbestrol therapy; long period and high dosage Des therapy. Medical Times 81 315317.

  • Karwacka A, Zamkowska D, Radwan M & Jurewicz J 2019 Exposure to modern, widespread environmental endocrine disrupting chemicals and their effect on the reproductive potential of women: an overview of current epidemiological evidence. Human Fertility 22 225. (https://doi.org/10.1080/14647273.2017.1358828)

    • Search Google Scholar
    • Export Citation
  • Katz TA, Yang Q, Trevino LS, Walker CL & Al-Hendy A 2016 Endocrine-disrupting chemicals and uterine fibroids. Fertility and Sterility 106 967977. (https://doi.org/10.1016/j.fertnstert.2016.08.023)

    • Search Google Scholar
    • Export Citation
  • Kaur S, Sarma SJ, Marshall BL, Liu Y, Kinkade JA, Bellamy MM, Mao J, Helferich WG, Schenk AK & Bivens NJ et al.2020 Developmental exposure of California mice to endocrine disrupting chemicals and potential effects on the microbiome-gut-brain axis at adulthood. Scientific Reports 10 10902. (https://doi.org/10.1038/s41598-020-67709-9)

    • Search Google Scholar
    • Export Citation
  • Kavlock RJ & Ankley GT 1996 A perspective on the risk assessment process for endocrine-disruptive effects on wildlife and human health. Risk Analysis 16 731739. (https://doi.org/10.1111/j.1539-6924.1996.tb00824.x)

    • Search Google Scholar
    • Export Citation
  • Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S, Lucier G, Luster M, Mac MJ & Maczka C et al.1996 Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environmental Health Perspectives 104 (Supplement 4) 715740. (https://doi.org/10.1289/ehp.96104s4715)

    • Search Google Scholar
    • Export Citation
  • Kawaguchi M, Morohoshi K, Imai H, Morita M, Kato N & Himi T 2010 Maternal exposure to isobutyl-paraben impairs social recognition in adult female rats. Experimental Animals 59 631635. (https://doi.org/10.1538/expanim.59.631)

    • Search Google Scholar
    • Export Citation
  • Kendig EL, Le HH & Belcher SM 2010 Defining hormesis: evaluation of a complex concentration response phenomenon. International Journal of Toxicology 29 235246. (https://doi.org/10.1177/1091581810363012)

    • Search Google Scholar
    • Export Citation
  • Kern JK, Geier DA, Homme KG, King PG, Bjørklund G, Chirumbolo S & Geier MR 2017 Developmental neurotoxicants and the vulnerable male brain: a systematic review of suspected neurotoxicants that disproportionally affect males. Acta Neurobiologiae Experimentalis 77 269296. (https://doi.org/10.21307/ane-2017-061)

    • Search Google Scholar
    • Export Citation
  • Kim YR, Pacella RE, Harden FA, White N & Toms LL 2019 A systematic review: impact of endocrine disrupting chemicals exposure on fecundity as measured by time to pregnancy. Environmental Research 171 119133. (https://doi.org/10.1016/j.envres.2018.12.065)

    • Search Google Scholar
    • Export Citation
  • Kinch CD, Ibhazehiebo K, Jeong JH, Habibi HR & Kurrasch DM 2015 Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish. PNAS 112 14751480. (https://doi.org/10.1073/pnas.1417731112)

    • Search Google Scholar
    • Export Citation
  • Konkel L 2016 Lasting impact of an ephemeral organ: the role of the placenta in fetal programming. Environmental Health Perspectives 124 A124A129. (https://doi.org/10.1289/ehp.124-A124)

    • Search Google Scholar
    • Export Citation
  • Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesné L, Serrano T, Main KM & Jégou B 2016 Analgesic use – prevalence, biomonitoring and endocrine and reproductive effects. Nature Reviews: Endocrinology 12 381393. (https://doi.org/10.1038/nrendo.2016.55)

    • Search Google Scholar
    • Export Citation
  • Kuchera LK 1971 Postcoital contraception with diethylstilbestrol. JAMA 218 562.

  • La Merrill MA, Vandenberg LN, Smith MT, Goodson W, Browne P, Patisaul HB, Guyton KZ, Kortenkamp A, Cogliano VJ & Woodruff TJ et al.2020 Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nature Reviews: Endocrinology 16 4557. (https://doi.org/10.1038/s41574-019-0273-8)

    • Search Google Scholar
    • Export Citation
  • Lagarde F, Beausoleil C, Belcher SM, Belzunces LP, Emond C, Guerbet M & Rousselle C 2015 Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment. Environmental Health: A Global Access Science Source 14 13. (https://doi.org/10.1186/1476-069X-14-13)

    • Search Google Scholar
    • Export Citation
  • Leatherland J 1992 Endocrine and reproductive function in Great Lakes salmon. In Chemically Induced Alterations in Sexual and Functional Development: The Wildlife/Human Connection, pp. 129145. Eds Colborn T, Clement CPrinceton: Princeton Scientific Publishing.

    • Search Google Scholar
    • Export Citation
  • Leazer TM & Klaassen CD 2003 The presence of xenobiotic transporters in rat placenta. Drug Metabolism and Disposition 31 153167. (https://doi.org/10.1124/dmd.31.2.153)

    • Search Google Scholar
    • Export Citation
  • Lenz KM & McCarthy MM 2015 A starring role for microglia in brain sex differences. Neuroscientist 21 306321. (https://doi.org/10.1177/1073858414536468)

    • Search Google Scholar
    • Export Citation
  • Leonetti C, Butt CM, Hoffman K, Hammel SC, Miranda ML & Stapleton HM 2016a Brominated flame retardants in placental tissues: associations with infant sex and thyroid hormone endpoints. Environmental Health: A Global Access Science Source 15 113. (https://doi.org/10.1186/s12940-016-0199-8)

    • Search Google Scholar
    • Export Citation
  • Leonetti C, Butt CM, Hoffman K, Miranda ML & Stapleton HM 2016b Concentrations of polybrominated diphenyl ethers (PBDEs) and 2,4,6-tribromophenol in human placental tissues. Environment International 88 2329. (https://doi.org/10.1016/j.envint.2015.12.002)

    • Search Google Scholar
    • Export Citation
  • Li W, Liu Q, Deng X, Chen Y, Liu S & Story M 2017 Association between obesity and puberty timing: a systematic review and meta-analysis. International Journal of Environmental Research and Public Health 14 1266. (https://doi.org/10.3390/ijerph14101266)

    • Search Google Scholar
    • Export Citation
  • Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A & Hemminki K 2000 Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland. New England Journal of Medicine 343 7885. (https://doi.org/10.1056/NEJM200007133430201)

    • Search Google Scholar
    • Export Citation
  • Ling C, Liew Z, von Ehrenstein OS, Heck JE, Park AS, Cui X, Cockburn M, Wu J & Ritz B 2018 Prenatal exposure to ambient pesticides and preterm birth and term low birthweight in agricultural regions of California. Toxics 6 41. (https://doi.org/10.3390/toxics6030041)

    • Search Google Scholar
    • Export Citation
  • Liu X & Herbison AE 2013 Dopamine regulation of gonadotropin-releasing hormone neuron excitability in male and female mice. Endocrinology 154 340350. (https://doi.org/10.1210/en.2012-1602)

    • Search Google Scholar
    • Export Citation
  • Liu X, Ji K, Jo A, Moon HB & Choi K 2013 Effects of TDCPP or TPP on gene transcriptions and hormones of HPG axis, and their consequences on reproduction in adult zebrafish (Danio rerio). Aquatic Toxicology 134–135 104111. (https://doi.org/10.1016/j.aquatox.2013.03.013)

    • Search Google Scholar
    • Export Citation
  • Livadas S & Chrousos GP 2016 Control of the onset of puberty. Current Opinion in Pediatrics 28 551558. (https://doi.org/10.1097/MOP.0000000000000386)

    • Search Google Scholar
    • Export Citation
  • Losa SM, Todd KL, Sullivan AW, Cao J, Mickens JA & Patisaul HB 2011 Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat. Reproductive Toxicology 31 280289. (https://doi.org/10.1016/j.reprotox.2010.10.002)

    • Search Google Scholar
    • Export Citation
  • Lucaccioni L, Trevisani V, Marrozzini L, Bertoncelli N, Predieri B, Lugli L, Berardi A & Iughetti L 2020 Endocrine-disrupting chemicals and their effects during female puberty: a review of current evidence. International Journal of Molecular Sciences 21 2078. (https://doi.org/10.3390/ijms21062078)

    • Search Google Scholar
    • Export Citation
  • Manfo FP, Nantia EA & Mathur PP 2014 Effect of environmental contaminants on mammalian testis. Current Molecular Pharmacology 7 119135. (https://doi.org/10.2174/1874467208666150126155420)

    • Search Google Scholar
    • Export Citation
  • Mao J, Jain A, Denslow ND, Nouri MZ, Chen S, Wang T, Zhu N, Koh J, Sarma SJ & Sumner BW et al.2020 Bisphenol A and bisphenol S disruptions of the mouse placenta and potential effects on the placenta-brain axis. PNAS 117 46424652. (https://doi.org/10.1073/pnas.1919563117)

    • Search Google Scholar
    • Export Citation
  • Marler P 2005 Ethology and the origins of behavioral endocrinology. Hormones and Behavior 47 493502. (https://doi.org/10.1016/j.yhbeh.2005.01.002)

    • Search Google Scholar
    • Export Citation
  • Martin JA, Hamilton BE, Osterman MJK & Driscoll AK 2019 Births: final data for 2018. National Vital Statistics Reports 68 147. (PMID:32501202)

  • Mbuni YM, Wang S, Mwangi BN, Mbari NJ, Musili PM, Walter NO, Hu G, Zhou Y & Wang Q 2020 Medicinal plants and their traditional uses in local communities around Cherangani Hills, Western Kenya. Plants 9 331. (https://doi.org/10.3390/plants9030331)

    • Search Google Scholar
    • Export Citation
  • McCarthy MM 2008 Estradiol and the developing brain. Physiological Reviews 88 91124. (https://doi.org/10.1152/physrev.00010.2007)

  • McCarthy MM 2016 Sex differences in the developing brain as a source of inherent risk. Dialogues in Clinical Neuroscience 18 361372. (https://doi.org/10.31887/DCNS.2016.18.4/mmccarthy)

    • Search Google Scholar
    • Export Citation
  • McCarthy MM 2020 A new view of sexual differentiation of mammalian brain. Journal of Comparative Physiology: A, Neuroethology, Sensory, Neural, and Behavioral Physiology 206 369378. (https://doi.org/10.1007/s00359-019-01376-8)

    • Search Google Scholar
    • Export Citation
  • McCarthy MM, Wright CL & Schwarz JM 2009 New tricks by an old dogma: mechanisms of the organizational/activational hypothesis of steroid-mediated sexual differentiation of brain and behavior. Hormones and Behavior 55 655665. (https://doi.org/10.1016/j.yhbeh.2009.02.012)

    • Search Google Scholar
    • Export Citation
  • McCarthy MM, Herold K & Stockman SL 2018 Fast, furious and enduring: sensitive versus critical periods in sexual differentiation of the brain. Physiology and Behavior 187 1319. (https://doi.org/10.1016/j.physbeh.2017.10.030)

    • Search Google Scholar
    • Export Citation
  • McLachlan JA 2016 Environmental signaling: from environmental estrogens to endocrine-disrupting chemicals and beyond. Andrology 4 684694. (https://doi.org/10.1111/andr.12206)

    • Search Google Scholar
    • Export Citation
  • McLachlan JA, Newbold RR, Shah HC, Hogan MD & Dixon RL 1982 Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertility and Sterility 38 364371. (https://doi.org/10.1016/s0015-0282(1646520-9)

    • Search Google Scholar
    • Export Citation
  • Melnick R, Lucier G, Wolfe M, Hall R, Stancel G, Prins G, Gallo M, Reuhl K, Ho SM & Brown T et al.2002 Summary of the National Toxicology Program’s report of the endocrine disruptors low-dose peer review. Environmental Health Perspectives 110 427431. (https://doi.org/10.1289/ehp.02110427)

    • Search Google Scholar
    • Export Citation
  • Merrheim J, Villegas J, Van Wassenhove J, Khansa R, Berrih-Aknin S, le Panse R & Dragin N 2020 Estrogen, estrogen-like molecules and autoimmune diseases. Autoimmunity Reviews 19 102468. (https://doi.org/10.1016/j.autrev.2020.102468)

    • Search Google Scholar
    • Export Citation
  • Meyer N & Zenclussen AC 2020 Immune cells in the uterine remodeling: are they the target of endocrine disrupting chemicals? Frontiers in Immunology 11 246. (https://doi.org/10.3389/fimmu.2020.00246)

    • Search Google Scholar
    • Export Citation
  • Micevych PE, Wong AM & Mittelman-Smith MA 2015 Estradiol membrane-initiated signaling and female reproduction. Comprehensive Physiology 5 12111222. (https://doi.org/10.1002/cphy.c140056)

    • Search Google Scholar
    • Export Citation
  • Milligan SR, Khan O & Nash M 1998 Competitive binding of xenobiotic oestrogens to rat alpha-fetoprotein and to sex steroid binding proteins in human and rainbow trout (Oncorhynchus mykiss) plasma. General and Comparative Endocrinology 112 8995. (https://doi.org/10.1006/gcen.1998.7146)

    • Search Google Scholar
    • Export Citation
  • Mínguez-Alarcón L, Williams PL, Chiu YH, Gaskins AJ, Nassan FL, Dadd R, Petrozza J, Hauser R, Chavarro JEEarth Study Team 2018 Secular trends in semen parameters among men attending a fertility center between 2000 and 2017: identifying potential predictors. Environment International 121 12971303. (https://doi.org/10.1016/j.envint.2018.10.052)

    • Search Google Scholar
    • Export Citation
  • Mínguez-Alarcón L, Messerlian C, Bellavia A, Gaskins AJ, Chiu YH, Ford JB, Azevedo AR, Petrozza JC, Calafat AM & Hauser R et al.2019 Urinary concentrations of bisphenol A, parabens and phthalate metabolite mixtures in relation to reproductive success among women undergoing in vitro fertilization. Environment International 126 355362. (https://doi.org/10.1016/j.envint.2019.02.025)

    • Search Google Scholar
    • Export Citation
  • Mittelman-Smith MA, Rudolph LM, Mohr MA & Micevych PE 2017 Rodent models of non-classical progesterone action regulating ovulation. Frontiers in Endocrinology 8 165. (https://doi.org/10.3389/fendo.2017.00165)

    • Search Google Scholar
    • Export Citation
  • Moore AM, Coolen LM, Porter DT, Goodman RL & Lehman MN 2018 KNDy cells revisited. Endocrinology 159 32193234. (https://doi.org/10.1210/en.2018-00389)

  • Mueller JK & Heger S 2014 Endocrine disrupting chemicals affect the gonadotropin releasing hormone neuronal network. Reproductive Toxicology 44 7384. (https://doi.org/10.1016/j.reprotox.2013.10.011)

    • Search Google Scholar
    • Export Citation
  • Myatt L 2006 Placental adaptive responses and fetal programming. Journal of Physiology 572 2530. (https://doi.org/10.1113/jphysiol.2006.104968)

    • Search Google Scholar
    • Export Citation
  • Neubert da Silva G, Zauer Curi T, Lima Tolouei SE, Tapias Passoni M, Sari Hey GB, Marino Romano R, Martino-Andrade AJ & Dalsenter PR 2019 Effects of diisopentyl phthalate exposure during gestation and lactation on hormone-dependent behaviours and hormone receptor expression in rats. Journal of Neuroendocrinology 31 e12816. (https://doi.org/10.1111/jne.12816)

    • Search Google Scholar
    • Export Citation
  • Newbold RR 2008 Prenatal exposure to diethylstilbestrol (DES). Fertility and Sterility 89 (Supplement) e55e56. (https://doi.org/10.1016/j.fertnstert.2008.01.062)

    • Search Google Scholar
    • Export Citation
  • Newbold RR & McLachlan JA 1982 Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol. Cancer Research 42 20032011.

    • Search Google Scholar
    • Export Citation
  • Ohlsson C, Bygdell M, Celind J, Sondén A, Tidblad A, Sävendahl L & Kindblom JM 2019 Secular trends in pubertal growth acceleration in Swedish boys born from 1947 to 1996. JAMA Pediatrics 173 860865. (https://doi.org/10.1001/jamapediatrics.2019.2315)

    • Search Google Scholar
    • Export Citation
  • Palmer JR, Wise LA, Robboy SJ, Titus-Ernstoff L, Noller KL, Herbst AL, Troisi R & Hoover RN 2005 Hypospadias in sons of women exposed to diethylstilbestrol in utero. Epidemiology 16 583586. (https://doi.org/10.1097/01.ede.0000164789.59728.6d)

    • Search Google Scholar
    • Export Citation
  • Palmlund I 1996 Exposure to a xenoestrogen before birth: the diethylstilbestrol experience. Journal of Psychosomatic Obstetrics and Gynaecology 17 7184. (https://doi.org/10.3109/01674829609025667)

    • Search Google Scholar
    • Export Citation
  • Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J & Bourguignon JP 2003 The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocrine Reviews 24 668693. (https://doi.org/10.1210/er.2002-0019)

    • Search Google Scholar
    • Export Citation
  • Partsch CJ & Sippell WG 2001 Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Human Reproduction Update 7 292302. (https://doi.org/10.1093/humupd/7.3.292)

    • Search Google Scholar
    • Export Citation
  • Patisaul HB 2013 Effects of environmental endocrine disruptors and phytoestrogens on the kisspeptin system. Advances in Experimental Medicine and Biology 784 455479. (https://doi.org/10.1007/978-1-4614-6199-9_21)

    • Search Google Scholar
    • Export Citation
  • Patisaul HB 2017a Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviours. Proceedings of the Nutrition Society 76 130144. (https://doi.org/10.1017/S0029665116000677)

    • Search Google Scholar
    • Export Citation
  • Patisaul HB 2017b Endocrine disruption of vasopressin systems and related behaviors. Frontiers in Endocrinology 8 134. (https://doi.org/10.3389/fendo.2017.00134)

    • Search Google Scholar
    • Export Citation
  • Patisaul HB 2020 Achieving clarity on bisphenol A, brain and behaviour. Journal of Neuroendocrinology 32 e12730. (https://doi.org/10.1111/jne.12730)

    • Search Google Scholar
    • Export Citation
  • Patisaul HB & Jefferson W 2010 The pros and cons of phytoestrogens. Frontiers in Neuroendocrinology 31 400419. (https://doi.org/10.1016/j.yfrne.2010.03.003)

    • Search Google Scholar
    • Export Citation
  • Patisaul HB, Fortino AE & Polston EK 2006 Neonatal genistein or bisphenol-A exposure alters sexual differentiation of the AVPV. Neurotoxicology and Teratology 28 111118. (https://doi.org/10.1016/j.ntt.2005.11.004)

    • Search Google Scholar
    • Export Citation
  • Perera BPU, Faulk C, Svoboda LK, Goodrich JM & Dolinoy DC 2020 The role of environmental exposures and the epigenome in health and disease. Environmental and Molecular Mutagenesis 61 176192. (https://doi.org/10.1002/em.22311)

    • Search Google Scholar
    • Export Citation
  • Phillips AL, Chen A, Rock KD, Horman B, Patisaul HB & Stapleton HM 2016 Editor’s highlight: transplacental and lactational transfer of firemaster(R) 550 components in dosed Wistar rats. Toxicological Sciences 153 246257. (https://doi.org/10.1093/toxsci/kfw122)

    • Search Google Scholar
    • Export Citation
  • Piette PCM 2020 The pharmacodynamics and safety of progesterone. Best Practice and Research: Clinical Obstetrics and Gynaecology 69 1329. (https://doi.org/10.1016/j.bpobgyn.2020.06.002)

    • Search Google Scholar
    • Export Citation
  • Prins GS, Hu WY, Shi GB, Hu DP, Majumdar S, Li G, Huang K, Nelles JL, Ho SM & Walker CL et al.2014 Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium. Endocrinology 155 805817. (https://doi.org/10.1210/en.2013-1955)

    • Search Google Scholar
    • Export Citation
  • Priskorn L, Bang AK, Nordkap L, Krause M, Mendiola J, Jensen TK, Juul A, Skakkebaek NE, Swan SH & Jorgensen N 2019 Anogenital distance is associated with semen quality but not reproductive hormones in 1106 young men from the general population. Human Reproduction 34 1224. (https://doi.org/10.1093/humrep/dey326)

    • Search Google Scholar
    • Export Citation
  • Proos LA, Hofvander Y & Tuvemo T 1991 Menarcheal age and growth pattern of Indian girls adopted in Sweden. I. Menarcheal age. Acta Paediatrica Scandinavica 80 852858. (https://doi.org/10.1111/j.1651-2227.1991.tb11960.x)

    • Search Google Scholar
    • Export Citation
  • Puts D & Motta-Mena NV 2018 Is human brain masculinization estrogen receptor-mediated? Reply to Luoto and Rantala. Hormones and Behavior 97 34. (https://doi.org/10.1016/j.yhbeh.2017.07.018)

    • Search Google Scholar
    • Export Citation
  • Qie Y, Qin W, Zhao K, Liu C, Zhao L & Guo LH 2021 Environmental estrogens and their biological effects through GPER mediated signal pathways. Environmental Pollution 278 116826. (https://doi.org/10.1016/j.envpol.2021.116826)

    • Search Google Scholar
    • Export Citation
  • Ragusa A, Svelato A, Santacroce C, Catalano P, Notarstefano V, Carnevali O, Papa F, Rongioletti MCA, Baiocco F & Draghi S et al.2021 Plasticenta: first evidence of microplastics in human placenta. Environment International 146 106274. (https://doi.org/10.1016/j.envint.2020.106274)

    • Search Google Scholar
    • Export Citation
  • Rahban R, Priskorn L, Senn A, Stettler E, Galli F, Vargas J, Van den Bergh M, Fusconi A, Garlantezec R & Jensen TK et al.2019 Semen quality of young men in Switzerland: a nationwide cross-sectional population-based study. Andrology 7 818826. (https://doi.org/10.1111/andr.12645)

    • Search Google Scholar
    • Export Citation
  • Ramesh SA, Tyerman SD, Xu B, Bose J, Kaur S, Conn V, Domingos P, Ullah S, Wege S & Shabala S et al.2015 GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters. Nature Communications 6 7879. (https://doi.org/10.1038/ncomms8879)

    • Search Google Scholar
    • Export Citation
  • Rasier G, Toppari J, Parent AS & Bourguignon JP 2006 Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data. Molecular and Cellular Endocrinology 254–255 187201. (https://doi.org/10.1016/j.mce.2006.04.002)

    • Search Google Scholar
    • Export Citation
  • Rattan S, Zhou C, Chiang C, Mahalingam S, Brehm E & Flaws JA 2017 Exposure to endocrine disruptors during adulthood: consequences for female fertility. Journal of Endocrinology 233 R109–R129. (https://doi.org/10.1530/JOE-17-0023)

    • Search Google Scholar
    • Export Citation
  • Rebuli ME, Gibson P, Rhodes CL, Cushing BS & Patisaul HB 2016 Sex differences in microglial colonization and vulnerabilities to endocrine disruption in the social brain. General and Comparative Endocrinology 238 3946. (https://doi.org/10.1016/j.ygcen.2016.04.018)

    • Search Google Scholar
    • Export Citation
  • Reed CE & Fenton SE 2013 Exposure to diethylstilbestrol during sensitive life stages: a legacy of heritable health effects. Birth Defects Research: Part C, Embryo Today: Reviews 99 134146. (https://doi.org/10.1002/bdrc.21035)

    • Search Google Scholar
    • Export Citation
  • Reers AR, Eng ML, Williams TD, Elliott JE, Cox ME & Beischlag TV 2016 The flame-retardant Tris(1,3-dichloro-2-propyl) phosphate represses androgen signaling in human prostate cancer cell lines. Journal of Biochemical and Molecular Toxicology 30 249257. (https://doi.org/10.1002/jbt.21786)

    • Search Google Scholar
    • Export Citation
  • Reinehr T & Roth CL 2019 Is there a causal relationship between obesity and puberty? Lancet: Child and Adolescent Health 3 4454. (https://doi.org/10.1016/S2352-4642(1830306-7)

    • Search Google Scholar
    • Export Citation
  • Rissman EF & Adli M 2014 Minireview: transgenerational epigenetic inheritance: focus on endocrine disrupting compounds. Endocrinology 155 27702780. (https://doi.org/10.1210/en.2014-1123)

    • Search Google Scholar
    • Export Citation
  • Robboy SJ, Szyfelbein WM, Goellner JR, Kaufman RH, Taft PD, Richard RM, Gaffey TA, Prat J, Virata R & Hatab PA et al.1981 Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project. American Journal of Obstetrics and Gynecology 140 579586. (https://doi.org/10.1016/0002-9378(8190236-2)

    • Search Google Scholar
    • Export Citation
  • Robboy SJ, Young RH, Welch WR, Truslow GY, Prat J, Herbst AL & Scully RE 1984 Atypical vaginal adenosis and cervical ectropion: association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring. Cancer 54 869875. (https://doi.org/10.1002/1097-0142(19840901)54:5<869::aid-cncr2820540519>3.0.co;2-i)

    • Search Google Scholar
    • Export Citation
  • Rochester JR, Bolden AL, Pelch KE & Kwiatkowski CF 2017 Potential developmental and reproductive impacts of triclocarban: a scoping review. Journal of Toxicology 2017 9679738. (https://doi.org/10.1155/2017/9679738)

    • Search Google Scholar
    • Export Citation
  • Rock KD, Horman B, Phillips AL, McRitchie SL, Watson S, Deese-Spruill J, Jima D, Sumner S, Stapleton HM & Patisaul HB 2018 EDC IMPACT: molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain. Endocrine Connections 7 305324. (https://doi.org/10.1530/EC-17-0373)

    • Search Google Scholar
    • Export Citation
  • Rodgers KM, Udesky JO, Rudel RA & Brody JG 2018 Environmental chemicals and breast cancer: an updated review of epidemiological literature informed by biological mechanisms. Environmental Research 160 152182. (https://doi.org/10.1016/j.envres.2017.08.045)

    • Search Google Scholar
    • Export Citation
  • Roman P, Cardona D, Sempere L & Carvajal F 2019 Microbiota and organophosphates. Neurotoxicology 75 200208. (https://doi.org/10.1016/j.neuro.2019.09.013)

    • Search Google Scholar
    • Export Citation
  • Roselli CE 2018 Neurobiology of gender identity and sexual orientation. Journal of Neuroendocrinology 30 e12562. (https://doi.org/10.1111/jne.12562)

    • Search Google Scholar
    • Export Citation
  • Ruiz-Pino F, Miceli D, Franssen D, Vazquez MJ, Farinetti