This effect, known as the Matthews principle , may represent a self-serving bias in science, which thrives upon high funding, citation rates and attention within specialized scientific groups. As the endocrine disruption field grows and new challenges emerge, researchers and funders may profit from promoting a balance between delving ever further into the effects of known agents and diversifying their goals by casting a wider net that includes less well-known environmental hazards Both approaches could offer the chance for innovation and discovery.
Long-Term Effects of Environmental Endocrine Disruptors on Reproductive Physiology and Behavior
Unwisely limiting our investigations to only a handful of prominent chemicals may inadvertently undermine the overall goal of addressing the greatest threats to human health. Another worthy lesson lays in the roles the public and the medical community have played in the development and acceptance of the EDC field.
For instance, BPA was phased out of baby bottles in response to shifting consumer preferences and pressure from advocacy groups. As basic research reveals new potential hazards for human health, it is important to continue to translate that research into language and actions that are relevant to society and to medical practice. The dialogue between the scientific and medical communities should lead to greater clarity on the practical implications of basic research for doctors; conversely, having potential practical solutions in sight can help generate support for basic research as well as save on health care costs associated with diseases attributed to EDC exposers Finally, the story of the emergence and evolution of the endocrine disruption field has valuable lessons to offer for researchers, regulators, health care providers, and the public.
Public policy and regulatory decision making have critical roles to play by drawing insight from research findings to advance the ultimate goal of improving health. Rarely is there such a thing as safe, rather, decisions about allowable levels of chemicals must be made based on the level of risk that is deemed acceptable vs that which requires action.
To facilitate science-based decision making, there is a need for a broad-spectrum approach to support more effective communication among scientists, business leaders, regulators, and politicians. This communication should begin in the nation's graduate and business schools and extend throughout the culture and practice of decision making in these diverse fields.
We thank numerous colleagues for their help in preparing this manuscript. In particular we thank Heather Patisaul for her keen insights and Katherine Burns and Sylvia Hewitt for careful review of the manuscript. National Center for Biotechnology Information , U. Published online Jul Schug , Anne F. Johnson , Linda S. Birnbaum , Theo Colborn , Louis J. Crews , Terry Collins , Ana M. Soto , Frederick S. Author information Article notes Copyright and License information Disclaimer. Address all correspondence and requests for reprints to: Received Jun 20; Accepted Jul This article has been cited by other articles in PMC.
Abstract Within the past few decades, the concept of endocrine-disrupting chemicals EDCs has risen from a position of total obscurity to become a focus of dialogue, debate, and concern among scientists, physicians, regulators, and the public. Open in a separate window. The Early Days The field of endocrine disruption is in part a scientific offshoot within the larger context of the environmental movement that swept across the United States in the s and s.
Mounting Evidence Fuels Concern and Debate During the s and into the early s, a series of provocative studies drew into greater focus the unique and troubling properties of EDCs. A Fundamentally Multidisciplinary Endeavor The multidisciplinary nature of endocrine disruptor research, which has been a core element of the field from its earliest inception, is at once its greatest asset and its greatest weakness.
A Goal Coalesces By the early s, concern over endocrine disruptors had spread within the scientific community to chemistry and beyond to physicians, regulators, chemical manufacturers, and members of the public. The Current Outlook It is now clear that some environmental substances contribute to the burden of disease by interfering with the human endocrine system and that they are powerful components of epigenetic modification of the genome 81 , Legacy Endocrine Dispurting Chemicals.
- Annual Update in Intensive Care and Emergency Medicine 2013.
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- Anne of Green Gables (Word Cloud Classics);
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- Long-Term Effects of Environmental Endocrine Disruptors on Reproductive Physiology and Behavior.
Transgenerational Effects and Epigenetics Some chemicals, including some EDCs, have the potential to cause health effects in the offspring of exposed individuals through environmentally induced epigenetic modifications. Top-priority areas of inquiry for future EDC research include the following: Toxicity Testing and Research and Development in the Context of EDCs Ultimately, the overarching goal of EDC research is to protect living things from the adverse effects of anthropogenic chemicals and especially to reduce their burden of disease.
Case Study in Green Chemistry: Lessons From the EDC Experience The development of the endocrine disruptor field offers lessons that can be informative to other fields of science, as well as to future challenges in toxicology and environmental health. Acknowledgments We thank numerous colleagues for their help in preparing this manuscript. The authors have nothing to disclose.
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The sheep and cheetah cases are disquietingly similar to the bird and other wildlife studies of the s which ultimately identified the endocrine disrupting properties of DDT. But even today the question of whether or not DDT can impact human health is controversial, and such is the case with soy phytoestrogens. Is there any reasonably good evidence that phytoestrogens can have long term adverse health effects in humans following developmental exposure?
A pair of studies on Puerto Rican girls associated neonatal phytoestrogen exposure with advanced pubertal onset, but a number of confounding factors including the use of potent estrogens in meat production, make the data problematic and difficult to interpret Freni-Titulaer et al. A more recent, retrospective cohort study found that young women fed soy-based infant formula as part of a controlled, University of Iowa feeding study reported longer menstrual bleeding and menstrual discomfort than those who were fed a non-soy based formula as babies Strom et al. Beyond these epidemiology studies, very little is known about how exposure to soy phytoestrogens, either in the womb or in infancy, impacts female reproductive health or behavior in humans.
Data from animal research is more abundant. Neonatal exposure to genistein advances pubertal onset, increases the length of the estrous menstrual cycle and hastens the onset of persistent estrus in rodents. Female mice treated with 0. This acceleration of reproductive senescence could result from disruption anywhere within the HPG axis including the ovary and brain.
Detailed work in mice by Jefferson and colleagues has revealed that genistein can interfere with ovarian differentiation resulting in ovarian malformations indicative of impaired fecundity such as multi-oocyte follicles, and attenuated oocyte cell death Jefferson et al. Ovarian defects, including the absence of corpora lutea, the presence of large antral-like follicles with degenerating or no oocytes and numerous ovarian cysts have also been observed following neonatal genistein exposure in rats Kouki et al. Frequently observed ovarian malformations in rats following neonatal exposure to endocrine disruptors.
A An ovary from an unexposed adult female contains follicles at all stages of folliculogenesis and numerous corpora lutea CLs , indicative of successful ovulation. CLs are often absent or significantly reduced in number when numerous AFs are present. Recent studies in our laboratory have found that the organization of sexually differentiated neural pathways within the hypothalamus is also vulnerable to neonatal endocrine disruption by genistein. This observation indicates that neonatal genistein exposure has a masculinizing effect on the female HPG axis.
This gene codes for a family of peptides called kisspeptins previously called metastins , and rapidly emerging evidence indicates that kisspeptin neurons are essential for coordinating pubertal onset and steroid feedback on GnRH neurons in many species, including humans Kauffman et al. AVPV kisspeptin neurons are more numerous in females than males and are thought to be essential for steroid positive feedback and the initiation of the preovulatory GnRH surge Clarkson et al. A GEN significantly advanced the timing of pubertal onset as measured by day of vaginal opening compared to control females.
C There was no effect of GEN on sexual receptivity following ovariectomy and hormone priming however D the number of GnRH neurons also immunopositive for Fos was significantly reduced indicating an impaired capacity to display steroid positive feedback. Panels A and D adapted from Bateman and Patisaul, It may also take a longer exposure or higher doses, a possibility which illustrates the important concepts of dose and timing when considering the potential effects of EDCs.
Further work will be needed to clarify this issue. The mechanisms by which genistein and the other phytoestrogens influence sex-specific physiology are likely diverse. Genistein is also a potent inhibitor of tyrosine protein kinases Boutin, ; Piontek et al. A further complication is the observation that effects of genistein administration at low doses are compounded when co-administered with other EDCs Kurzer and Xu, ; You et al. Mixture effects of phytoestrogens, as with most other EDCs, are generally unappreciated.
BPA is somewhat unique among EDCs because, in the early twentieth century, it was being developed as a possible synthetic estrogen a pursuit which was abandoned following the synthesis of DES Dodds and Lawson, Since the s, it has been used primarily in the production of polycarbonate plastic products to improve clarity and increase resilience. It is also a component of epoxy resins used to line the interior of metal cans such as soda and soup cans.
Human exposure to BPA occurs through everyday use of these items because it can migrate from the container into the contents, especially when heated Brede et al. The United States Centers for Disease Control recently estimated that nearly all Americans have detectable levels of BPA in their bodies, with children having higher levels than adults Calafat et al. Infants in neonatal intensive care units have particularly high exposure to BPA, presumably from its use in medical devices and from the migration of BPA into infant formula from the container Calafat et al.
Exposure to BPA is not limited to humans, and effects on wildlife from contaminated water supplies have been documented in both males and females of multiple species Crain et al. The mechanism s of low dose activity remains poorly understood but has long been hypothesized to be most potent in hormone sensitive organs and brain regions when endogenous estrogens are low or absent vom Saal and Moyer, Despite the controversy surrounding the mechanism by which low dose exposure to BPA could affect reproductive physiology, the evidence for widespread effects in animal models is increasing.
BPA can also induce apoptosis and cell arrest in cultured ovarian granulosa cells Xu et al. Prolonged, irregular estrus cycles are also frequently observed by us and others following perinatal exposure to low doses suggesting compromised fertility Adewale et al. Mammary gland development appears to be particularly sensitive to BPA at multiple points in the life span including embryonic development, the perinatal period, puberty and adulthood Markey et al.
Defects include intraductal hyperplasias, increased sensitivity to endogenous estradiol and the development of neoplastic lesions Durando et al. Like genistein, BPA may also compromise sexual differentiation in the brain. Another laboratory subsequently reported decreased numbers of dopaminergic neurons in the AVPV of female mice exposed from gestation through lactation to lower, environmentally relevant doses Rubin et al.
Introduction
Collectively, these studies suggest that each sex may be susceptible to different doses, a hypothesis that is intriguing and merits further exploration as the observed discrepancy could also be due to differences in, route of administration, duration of exposure or species; all of which illustrates the challenge of translating animal data to human risk assessments. Although these data support the hypothesis that sexual differentiation of the brain in general, and within the AVPV specifically, may be vulnerable to endocrine disruption, the physiological and functional consequences of these changes has yet to be convincingly established.
Considerable scientific debate remains about whether or not humans are exposed to truly significant levels of BPA. Human serum levels have generally been found to be in the range of 0. Most rodent studies evaluating potential adverse effects of BPA did not measure serum levels in exposed animals making it difficult to determine if the outcomes can be extrapolated to humans.
Further complicating the issue is that humans and rodents metabolize BPA differently, however both species, along with non-human primates, exhibit comparable levels of the unconjugated estrogenically active form of BPA in fluids and thus perhaps equally susceptible to its effects reviewed in detail by Vandenberg et al.
Like DDT, the fate of BPA may ultimately be decided by politics and public perception, rather than a regulatory action based on a measured evaluation of the scientific evidence. Many other states had similar laws pending. In October of , the Food and Drug Administration reaffirmed its conclusion that BPA use in food containers does not pose a public health threat, a decision that was met with considerable criticism. Endocrine disruption can also happen in males. One of the most notable wildlife cases has been documented by researchers at the University of Florida who discovered numerous genital malformations, poor hatching success, and a sex ratio heavily skewed towards females among alligators living in a polluted central Florida lake.
This lake had become heavily contaminated with DDT, difocol, their metabolites, and other pesticides as the result of an industrial spill Guillette et al. In mammals and birds, gonadal differentiation the development of either an ovary or testis is determined by the sex chromosomes. In non-mammalian vertebrates, including reptiles, incubation temperature during a critical window midway through development, influences which gonad forms and thus the sex of the animal.
Guillette and colleagues discovered that exposure to estrogens or estrogenic EDCs can override or interact with this effect of temperature resulting in intersex individuals, males with abnormally low plasma testosterone levels, genital abnormalities, and malformation of the gonads in both sexes. Reproductive abnormalities within reptiles living on this lake persist, even more than three decades after the initial spill, demonstrating that defects can impact multiple generations, particularly when the compounds are strongly lipophilic and have long half-lives.
In humans, there is growing evidence for, but considerable debate over, whether human male reproductive health is truly declining, and whether EDCs play any role in the perceived decline. In , Carlsen and colleagues conducted a comprehensive review of the literature on human semen quality. This finding was widely publicized in the media and subsequently replicated by other investigators, although there appear to be significant regional differences in the severity of the effect Swan et al. Similarly, the incidence of testicular cancer and congenital abnormalities such as hypospadias and cryptorchidism also appear to be increasing Adami et al.
Doubt over the conclusions from these analyses persist however, because reliance on historical data sets retrospective studies restricts the ability to control for differences in data collection methods. With this caveat in mind, one feature of the semen data that stands out is an apparent birth cohort effect, with younger generations having poorer semen quality than older generations Irvine, This suggests that insult in fetal life could be responsible for the defects that emerge later. This hypothesis is supported by epidemiological data showing that the occurrence of one disorder, such as low sperm count, is a risk factor for the occurrence of another, such as testicular cancer.
The TDS hypothesis proposes that these disorders are all manifestations of disturbed prenatal testicular development resulting from abnormal hormone synthesis or action during reproductive tract development. Androgens, including testosterone, produced by the fetal testes are essential for the differentiation of the epididymis, vas deferens and the seminal vesicles from the Wolffian ducts. For example, administration of the androgen receptor antagonist, flutamide during male reproductive tract development induces multiple abnormalities of the external genitalia including hypospadias and cryptorchidism in both rats and monkeys Herman et al.
Environmental toxicants are also known to interfere with male genital development. One of the earliest animal studies designed to test the hypothesis that chemical agents could interfere with androgen action was conducted in using chickens. Injection of DDT resulted in markedly undersized testes and inhibited the development of the comb and wattle. It was later determined that DDT and its metabolites function as anti-androgens as well as estrogen mimics and compete with endogenous androgens for access to the androgen receptor. One class of compounds that has recently received considerable attention for potentially contributing to TDS is the phthalates.
DBP is used in many personal care products such as lotions, cosmetics, nail polish, and perfume. DEHP is primarily used as a plasticizer in the production of flexible products including vinyl, medical tubing and toys. Infants in neonatal intensive care units have some of the highest urinary phthalate levels observed to date, presumably a result of exposure through medical tubing and devices Calafat et al.
A series of studies conducted in rats in the late s was the first to demonstrate that phthalates could interfere with the ability of testosterone to masculinize the male reproductive tract. Exposure in utero , when the genitals are being formed, resulted in a number of genital malformations including hypospadias and hemorrhagic testes Gray et al. Thus it is plausible that neonatal exposure to phthalates could induce TDS.
Interestingly, the phthalates do not produce their effects by antagonizing the androgen receptor, but rather by interfering with the production of androgens in the fetal testis David, Exposure to phthalates during human pregnancy has now been associated with smaller feminized anogenital distance in infant boys Swan et al.
Epidemiological evidence has also positively correlated higher urinary phthalate levels with lower sperm counts and an increased likelihood of sperm with damaged DNA in adult men Duty et al. Although it is important to keep in mind that correlation does not prove causation, these newly emerging epidemiology studies are the best evidence to data that phthalates have the potential to affect male reproductive health in humans.
Intriguingly, exposure to EDCs can also enhance the masculinization of some traits but this many not translate to improved reproductive fitness. A good example of this occurred in song birds exposed to a mixture of compounds including phthalates. In song birds, song production is controlled by discrete neural pathways which develop and operate under the influence of steroid hormones.
Estrogens, as well as androgens to some degree, are essential for proper sex specific organization of the song system. According to sexual selection theory, male secondary sex characteristics, including the production of elaborate songs, have evolved as indicators of male quality and in response to female preferences. Thus, modification of the song system by exposure to estrogenic contaminants could affect song quality and, as a result, how attractive exposed males are to potential mates. A recent experiment by Markman and colleagues tested this hypothesis using European starlings Sturnus vulgaris Markman et al.
The research group first observed the foraging habits of wild starlings at 20 sewage treatment sites and determined that earthworms were a primary prey species. A daily exposure for each compound was then estimated. The birds were exposed from October to April, when foraging on sewage beds is common, prior to the onset of the breeding season in the spring.
Males exposed to the mixture had significantly enhanced song production including a more complex song repertoire, an increased number of song bouts, and longer songs. This was accompanied by enlargement of an important song nucleus, the HVC, in the males fed the mixture compared to control males. Females preferred the song of males fed the mixture to males fed either the vehicle or the E2 alone. Enhanced song production, however, in this case appears to be a false indicator of male quality because subsequent analysis found that, even though circulating androgen levels were comparable to controls, the males fed the mixture were immunocompromised.
Thus, although EDCs enhanced the masculinization of the song system, by misleading females into choosing less fit males the effect could subsequently decrease the overall fitness of the population. Interestingly, males fed only E2 did not show enhanced song production or larger song nuclei demonstrating that this component of the mixture was insufficient on its own to influence this estrogen sensitive behavior.
This finding emphasizes the concern that although some estrogenic compounds may not produce effects at low levels on their own, they may ultimately contribute to disruption when contained within a mixture of compounds with similar mechanisms of action. This concern is potentially considerable for a number of reasons.
Perhaps one of the most worrisome is that, because most laboratory animal diets are derived from soy and therefore contain relatively high levels of genistein and other phytoestrogens actual amounts vary from batch to batch this background of EDC exposure could impact endocrine disruption research Brown and Setchell, ; Degen et al.
Exposure to Environmental Endocrine Disruptors and Child Development
Could this be a significant potential confound? A research group at Washington State University recently reported that they could not replicate previously published BPA effects in the mouse ovary. The concept of mixture effects is an evolving area of endocrine disruption research, the results of which could have profound implications for other disciplines including neuroendocrinology and behavioral biology. It is now becoming evident that the effects of EDC exposure are not necessarily limited to the exposed individual.
Many of these compounds are now recognized to have transgenerational effects and in some cases the effects within subsequent generations are more profound than those seen in the first generation Jirtle and Skinner, ; Steinberg et al. For example, there is emerging concern that the children of DES daughters referred to as DES granddaughters might also experience reproductive problems.
For these girls, their exposure occurred when they were germ cells in their mother's developing ovary, within the womb of their grandmother. If true, it would be the first instance in humans which conclusively demonstrates that persistent, generational effects can result from an in utero exposure to a potent estrogen Newbold et al.
This concern for DES granddaughters arose from data obtained in laboratory animal studies which indicated that the offspring of females exposed in utero were more likely to develop reproductive tract lesions than unexposed control animals Newbold et al. Other studies have produced evidence that DES effects across generations can be transmitted through the paternal line as well Walker and Haven, So far, there is not enough human data to indicate a trend for deleterious effects in DES granddaughters, largely because this cohort is so young.
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Continued monitoring of these women as they age will ultimately be required to determine if there are transgenerational effects of prenatal DES exposure in humans. The precise mechanisms through which endocrine disrupting effects transmit to subsequent generations are not well understood but emerging evidence indicates alteration of chromosomal structure or other epigenetic mechanisms might be the primary method. Epigenetic inheritance involves changes in gene expression patterns without changes in gene sequence. Such effects include DNA methylation and histone modifications, among others.
In most cases, methylation of gene promoter regions abrogates gene transcription while acetylation of the histone tail enhances it Dolinoy et al. These processes can be influenced by environmental factors and if these modifications occur within the germ cell lines then transmission to subsequent generations is possible Giusti et al. This newly discovered and evolving area of research has once again transformed the field of toxicology and introduced a novel method by which endocrine disruptors and other toxicants can affect vertebrate physiology and behavior.
A well characterized animal model demonstrating the potential for epigenetic modifications to impact future generations involves the manipulation of the murine agouti gene in a specialized mouse strain Duhl et al. In this strain, the degree of methylation on an inserted transposable element can vary dramatically and correlates with a wide distribution in coat color that ranges from yellow unmethylated to brown methylated as well as the occurrence of diabetes, obesity and tumorigenesis.
Maternal dietary supplementation of methyl-donors folic acid, vitamin B 12 , choline and betaine during pregnancy can shift the coat color of offspring towards the brown pseudoagouti phenotype Duhl et al. Even more intriguing is the observation that maternal exposure to genistein induces hypermethylation, again shifting the coat color of the offspring to brown Dolinoy et al.
These results illustrate the potential for genistein and perhaps other EDCs to epigenetically alter the phenotype of subsequent generations through in utero exposure. Other compounds, including polychlorinated biphenyls PCBs Aubrecht et al. When a pregnant animal is exposed to an EDC, it is important to keep in mind that the mother F 0 , the embryo F 1 and the F 2 generation as germ cells are all directly exposed. While the majority of studies concerning transgenerational epigenetic effects of EDCs have not been carried past the F 2 generation it is important to note that, to rule out direct exposure effects, the F 3 generation should also be examined for abnormalities.
It is also critical to appreciate that epigenetic effects can also occur outside of the germ line. Thus these mechanisms may underlie many observed EDC effects and could explain how compounds which are only weakly estrogenic, like BPA, can produce appreciable, lasting results at such low levels Jirtle and Skinner, The ability of most estrogenic EDCs, such as DES, genistein and BPA, to pass from mother to offspring through placental blood flow or lactational transfer makes the possibility for epigenetic, transgenerational effects likely Crews and McLachlan, ; Franke and Custer, ; Mably et al.
Although the specific mechanisms underlying the observed transgenerational effects of DES in animals have proven difficult to elucidate, emerging research implicates epigenetic modifications as a significant component Gore, ; Li et al. Newbold and colleagues have recently shown that alterations in gene methylation patterns of estrogen-responsive genes following DES exposure can be passed on to the next generation Li et al.
Although clear indicators of illness occurred early in some individuals, most carcinogenic and reproductive tract abnormalities in DES daughters did not occur until at least middle age and it will be another decade before most of the DES granddaughters reach that age as well. Thus, many transgenerational effects in these individuals have likely not yet emerged Giusti et al. While it appears clear, in both animals and humans, that exposure to EDCs can have adverse effects on reproductive physiology and behavior, controversies surrounding this topic remain.
Importantly, recognition of the prevalence of these compounds in the environment and their potential to adversely affect both wildlife and human populations is increasing among scientists, policy makers, and the general public. Further efforts to understand the mechanisms underlying EDC effects, particularly those seen at environmentally relevant doses by compounds with low hormonal potency, are necessary to adequately develop a public health strategy for preventing or combating their effects.
The ability of these compounds to permanently affect the epigenome could be potentially catastrophic to the welfare of future generations and requires further attention by both toxicologists and endocrinologists. While research surrounding this topic is not conclusive, particularly in humans, there is certainly sufficient evidence to warrant concern about potential long term effects in both wildlife and humans. Obtaining absolute proof of endocrine disruption by BPA, phthalates, and other compounds with weak hormonal activity in humans is likely impossible because it would obviously be unethical to conduct a double-blind study where one group is exposed to a suspected toxicant.
Research in animals, however, is robust and indicates that disruption of sex specific behavior, neuroendocrine circuitry and physiology is possible and, in some cases, transgenerational. Unfortunately, it is extraordinarily difficult for individuals to make informed choices about how to reduce their potential exposure because chemicals in the US are not routinely screened or tested for endocrine disrupting properties. A list of compounds to be screened was not compiled until April of and only 67 chemicals were included, a tiny fraction of the thousands of compounds now suspected of having endocrine disrupting properties.
Moreover, it is often impossible to determine which plastics, cosmetics, toys, or other household items contain any of these compounds so consumers have no adequate way to avoid them if desired. The thought that the mixture of chemicals a pregnant woman is exposed to during her pregnancy could affect not only her daughter's fecundity but also her granddaughter's is alarming and a major reason why the topic of endocrine disruption continues to receive global attention by scientists and the general public.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors are grateful to the editors for providing us the opportunity to summarize this research in this special issue.
Exposure to Environmental Endocrine Disruptors and Child Development
We also thank Karina Todd and Jillian Mickens for their critical reading of this manuscript and assistance with some of the research described in the text. National Center for Biotechnology Information , U. Journal List Front Behav Neurosci v. Published online Jun Prepublished online May Author information Article notes Copyright and License information Disclaimer.
Received May 1; Accepted Jun This is an open-access article subject to an exclusive license agreement between the authors and the Frontiers Research Foundation, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited. This article has been cited by other articles in PMC. Abstract It is well established that, over the course of development, hormones shape the vertebrate brain such that sex specific physiology and behaviors emerge. Introduction Growing awareness of the prevalence of environmental compounds, both synthetic and naturally occurring, with endocrine disrupting properties has generated considerable debate among scientists, regulatory agencies, and the general public about the potential long-term risks they pose for human and wildlife reproductive health.
Open in a separate window. The First Known Endocrine Disruptor The discovery that chemicals could interfere with the endocrine system in non-target species was first made by wildlife biologists who noted rapid population declines and abnormal reproductive physiology and behavior in multiple species.
Key Concepts of Endocrine Disruption: Timing, Dose and Nonlinear Effects The impact of the DES tragedy on the field of toxicology was transformative and three key principles of endocrine disruption emerged. Organization of Reproductive Neuroendocrine Circuits During early development gestation in humans, gestation and early neonatal life in rodents , the neuroendocrine feedback loops which regulate sex-specific reproductive physiology and behavior are sexually differentiated and organized.
Health Risk or Hype? Genistein and Female Reproductive Physiology The endocrine disrupting potential of phytoestrogens was first noticed in Australia in the s when abnormally high rates of infertility, abortion, and reproductive abnormalities in newborn lambs were observed in ewes grazing on clover rich pastures Bennetts and Underwood, ; Bennetts et al. A Dynamic and ongoing Controversy BPA is somewhat unique among EDCs because, in the early twentieth century, it was being developed as a possible synthetic estrogen a pursuit which was abandoned following the synthesis of DES Dodds and Lawson, Transgenerational Effects and the Emerging Field of Epigenetics It is now becoming evident that the effects of EDC exposure are not necessarily limited to the exposed individual.
Conclusions While it appears clear, in both animals and humans, that exposure to EDCs can have adverse effects on reproductive physiology and behavior, controversies surrounding this topic remain. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments The authors are grateful to the editors for providing us the opportunity to summarize this research in this special issue. Testicular cancer in nine northern European countries. Detection of the effects of phytoestrogens on sheep and cattle. Organizational and activational effects of phytoestrogens on the reproductive tract of the ewe. Neonatal bisphenol-a exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin releasing hormone neurons.
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Laying the Groundwork: The Early Days
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