Diethylstilbestrol versus estradiol as neonatal disruptors of the hamster (Mesocricetus auratus) cervix

The synthetic estrogen diethylstilbestrol (DES) is an established, estrogenic endocrine disruptor (ED). The Syrian golden hamster (Mesocricetus auratus) offers some unique advantages as an experimental system to investigate the perinatal ED action of DES and other estrogenic EDs. Previous analyses regarding the consequences of neonatal administration (100 microg) of DES versus estradiol-17beta (E2) showed that DES had a more potent disruptive effect on morphogenesis and gene expression in the uterus, oviduct, and ovary as well as in the testis and male accessory organs. The objectives of the present study were to describe the histopathological consequences of the two neonatal treatment regimens in the hamster cervix and to compare them with our previous observations in the hamster uterus. As previously found in the hamster uterus, DES was more potent than E2 as a neonatal disruptor of the hamster cervix in prepubertal animals and in ovarian-intact adult animals. However, the cervix-versus-uterus scenario diverged in animals that were ovariectomized prepubertally and then chronically stimulated with natural estrogen (E2). We confirmed previous observations that neonatal exposure to DES, but not to E2, permanently alters estrogen responsiveness in the adult hamster uterus, but neither neonatal treatment regimen affected estrogen responsiveness in the adult hamster cervix. These results suggest that an unidentified ovarian factor influences the extent of neonatal DES-induced disruption of the cervix, but not of the uterus, in hamsters.     

Gender bent but not in the mind of fish

There is strong evidence that environmental exposure to endocrine disrupting chemicals (EDCs) is resulting in significant alterations to the reproductive system of many wildlife populations. Most of these studies measure chemically induced changes to the endocrine system or reproductive morphology and mostly provide simple markers of exposure. The heightened concern over the effects of EDCs is however primarily driven by the hypothesis that this disruption may have serious deleterious consequences on reproductive success. In extensive laboratory studies on breeding populations of zebrafish, I have shown that multigenerational exposure to environmentally relevant levels of endocrine disruptors cause very significant reductions in reproductive success. Lifetime exposure to 5 ng/l of ethynylestradiol, for example, caused complete reproductive failure. These reproductive failures were not caused by exposure proximate to the timing of spawning but by the disruption of development during earlier embryonic and larval sexual differentiation. Histology revealed that male gonads had not differentiated into functional testes. Significantly, these sterile males still initiated spawning in females and resulted in unfertilized eggs. This differential in the sensitivity of behaviour compared to gonadal disruption raises important issues in understanding the implications of endocrine disruption in wild populations. Moreover, the particular mode of reproduction behaviour that is used by a species fundamentally affects the population level impact of endocrine disruptors. This paper will discuss these results and how a greater understanding of the dynamics of group spawning may help in assessing the potential impact of endocrine disruption     

Neonatal inhalatory anesthetic exposure: reproductive changes in male rats

We investigated the effects of an inhalatory anesthetic (ethyl ether) during the neonatal period of brain sexual differentiation on the later fertility and sexual behavior of male rats. Animals were exposed to ethyl ether immediately after birth. At adulthood, body weight, testes wet weight, and plasma testosterone levels were not affected; however, neonatal exposure to ether showed alterations on male fertility: a decrease in the number of spermatids and spermatozoa, an increase in the transit time of cauda epididymal spermatozoa and a decrease in daily sperm production. An alteration of sexual behavior was also observed: decreased male sexual behavior and appearance of homosexual behavior when the male rats were castrated and pretreated with exogenous estrogen. Probably, the ether delayed or reduced the testosterone peak of the sexual differentiation period, altering the processes of masculinization and defeminization of the hypothalamus. Our results indicate that perinatal exposure to ethyl ether during the critical period of male brain sexual differentiation, acting as endocrine disruptors, has a long-term effect on the fertility and sexual behavior of male rats, suggesting endocrine disruption through incomplete masculinization and defeminization of the central nervous system.     

Integrated decision-tree testing strategies for developmental and reproductive toxicity with respect to the requirements of the EU REACH legislation

Liverpool John Moores University and FRAME conducted a research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.     

Endocrine Disruption and Developmental Abnormalities of Female Reproduction

The developing organism is particularly sensitive to exposureto estrogenic chemicals during a critical period in the inductionof longterm changes in female reproductive organs, and persistentmolecular alterations induced by the perinatal estrogenic agents.The perinatal mouse model can be utilized as an indicator ofpossible longterm consequences of exposure to exogenous estrogeniccompounds including environmental endocrine disruptors. Attentionshould be paid to abnormalities in female genital organs exposedto estrogenic endocrine disruptors during fetal and early postnataldevelopment in mammals including humans.     

Early life exposure to endocrine-disrupting chemicals causes lifelong molecular reprogramming of the hypothalamus and premature reproductive aging

Gestational exposure to the estrogenic endocrine disruptor methoxychlor (MXC) disrupts the female reproductive system at the molecular, physiological, and behavioral levels in adulthood. The current study addressed whether perinatal exposure to endocrine disruptors re-programs expression of a suite of genes expressed in the hypothalamus that control reproductive function and related these molecular changes to premature reproductive aging. Fischer rats were exposed daily for 12 consecutive days to vehicle (dimethylsulfoxide), estradiol benzoate (EB) (1 mg/kg), and MXC (low dose, 20 μg/kg or high dose, 100 mg/kg), beginning on embryonic d 19 through postnatal d 7. The perinatally exposed females were aged to 16-17 months and monitored for reproductive senescence. After euthanasia, hypothalamic regions [preoptic area (POA) and medial basal hypothalamus] were dissected for real-time PCR of gene expression or pyrosequencing to assess DNA methylation of the Esr1 gene. Using a 48-gene PCR platform, two genes (Kiss1 and Esr1) were significantly different in the POA of endocrine-disrupting chemical-exposed rats compared with vehicle-exposed rats after Bonferroni correction. Fifteen POA genes were up-regulated by at least 50% in EB or high-dose MXC compared with vehicle. To understand the epigenetic basis of the increased Esr1 gene expression, we performed bisulfite conversion and pyrosequencing of the Esr1 promoter. EB-treated rats had significantly higher percentage of methylation at three CpG sites in the Esr1 promoter compared with control rats. Together with these molecular effects, perinatal MXC and EB altered estrous cyclicity and advanced reproductive senescence. Thus, early life exposure to endocrine disruptors has lifelong effects on neuroendocrine gene expression and DNA methylation, together with causing the advancement of reproductive senescence.     

Ovarian endocrine disruption underlies premature reproductive senescence following environmentally relevant chronic exposure to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin

The aryl hydrocarbon receptor (AHR) mediates the effects of many endocrine disruptors and contributes to the loss of fertility in polluted environments. While previous work has focused on mechanisms of short-term endocrine disruption and ovotoxicity in response to AHR ligands, we have shown recently that chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces premature reproductive senescence in female rats without depletion of ovarian follicular reserves. In the current study, premature reproductive senescence was induced using a range of low-dose exposure to TCDD (0, 1, 5, 50, and 200 ng kg(-1) wk(-1)) beginning in utero and continuing until the transition to reproductive senescence. Doses of 50 and 200 ng TCDD kg(-1) wk(-1) delayed the age at vaginal opening and accelerated the loss of normal reproductive cyclicity with age without depletion of follicular reserves. Serum estradiol concentrations were decreased in a dose-dependent fashion (>/=5 ng kg(-1) wk(-1)) across the estrous cycle in perisenescent rats still displaying normal cyclic vaginal cytology. Serum FSH, LH, and progesterone profiles were unchanged by TCDD. The loss of reproductive cyclicity following chronic exposure to TCDD was not accompanied by decreased responsiveness to GnRH. Ovarian endocrine disruption is the predominant functional change preceding the premature reproductive senescence induced by chronic exposure to low doses of the AHR-specific ligand TCDD.     

Effets d’une exposition à la Vinclozoline et à la Génistéine de la gestation à l’âge adulte sur la fonction de reproduction du ratWistar mâle: protocole et résultats préliminaires

Current evidence indicates that endocrine disrupters (EDs) can induce adverse effects on the male reproductive tract in various mammalian species. Recent reports indicate deterioration in male reproductive health in several human populations, but the evidence for a causal link with endocrine disruption is still weak. In addition, the experimental conditions of most of the reportedin vivo studies are not representative of environmental exposures (for example, high doses, short-term exposure, a single ED) and the mechanisms by which EDs disrupt the reproductive system are poorly understood. The objective of the present study is to develop an animal model to assess the reproductive effects and study the putative cellular and molecular mechanisms involved after exposure to genistein (phytoestrogen) and vinclozolin (fungicide with a known antiandrogenic potential) alone or in combination. The study will be performed in male Wistar rats, with administration of low and high doses of the compounds from conception to adulthood and a subset of the males in each treatment group will be mated with unexposed females. We plan to assess the level of sperm production, histology of the reproductive organs, motility and morphometry of spermatozoa and hormone levels, as well as DNA fragmentation of spermatozoa and determination of the number of germ cells, Sertoli cells and the diameters of seminiferous tubules. Estrogen, androgen, progesterone and FSH receptors will be detected and quantified and the level of testicular apoptosis and several apoptosis pathways will be studied to determine the putative cellular and molecular mechanisms involved. The preliminary results confirmed the developmental effects previously reported for high doses of vinclozolin. More interestingly, they indicated a number of deleterious effects for male rats exposed to low dosages alone or mixtures of low and high dosages compared to controls and rats exposed to high dosages alone. For example, a number of developmental anomalies of the genitalia were observed and a significant decrease of sperm motility and motion and fertilizing ability were observed. These preliminary results provide evidence that chronic exposure to environmental levels of EDs or mixtures of EDs have a detrimental impact on the male reproductive tract. The next step involves assessment of the anatomical disorders and the study of some of the cellular and molecular mechanisms possibly involved.     

Neuroendocrine and behavioral implications of endocrine disrupting chemicals in quail

Studies in our laboratory have focused on endocrine, neuroendocrine, and behavioral components of reproduction in the Japanese quail. These studies considered various stages in the life cycle, including embryonic development, sexual maturation, adult reproductive function, and aging. A major focus of our research has been the role of neuroendocrine systems that appear to synchronize both endocrine and behavioral responses. These studies provide the basis for our more recent research on the impact of endocrine disrupting chemicals (EDCs) on reproductive function in the Japanese quail. These endocrine active chemicals include pesticides, herbicides, industrial products, and plant phytoestrogens. Many of these chemicals appear to mimic vertebrate steroids, often by interacting with steroid receptors. However, most EDCs have relatively weak biological activity compared to native steroid hormones. Therefore, it becomes important to understand the mode and mechanism of action of classes of these chemicals and sensitive stages in the life history of various species. Precocial birds, such as the Japanese quail, are likely to be sensitive to EDC effects during embryonic development, because sexual differentiation occurs during this period. Accordingly, adult quail may be less impacted by EDC exposure. Because there are a great many data available on normal development and reproductive function in this species, the Japanese quail provides an excellent model for examining the effects of EDCs. Thus, we have begun studies using a Japanese quail model system to study the effects of EDCs on reproductive endocrine and behavioral responses. In this review, we have two goals: first, to provide a summary of reproductive development and sexual differentiation in intact Japanese quail embryos, including ontogenetic patterns in steroid hormones in the embryonic and maturing quail. Second, we discuss some recent data from experiments in our laboratory in which EDCs have been tested in Japanese quail. The Japanese quail provides an excellent avian model for testing EDCs because this species has well-characterized reproductive endocrine and behavioral responses. Considerable research has been conducted in quail in which the effects of embryonic steroid exposure have been studied relative to reproductive behavior. Moreover, developmental processes have been studied extensively and include investigations of the reproductive axis, thyroid system, and stress and immune responses. We have conducted a number of studies, which have considered long-term neuroendocrine consequences as well as behavioral responses to steroids. Some of these studies have specifically tested the effects of embryonic steroid exposure on later reproductive function in a multigenerational context. A multigenerational exposure provides a basis for understanding potential exposure scenarios in the field. In addition, potential routes of exposure to EDCs for avian species are being considered, as well as differential effects due to stage of the life cycle at exposure to an EDC. The studies in our laboratory have used both diet and egg injection as modes of exposure for Japanese quail. In this way, birds were exposed to a specific dose of an EDC at a selected stage in development by injection. Alternatively, dietary exposure appears to be a primary route of exposure; therefore experimental exposure through the diet mimics potential field situations. Thus, experiments should consider a number of aspects of exposure when attempting to replicate field exposures to EDCs.     

Neonatal exposure to endocrine disruptors suppresses juvenile testis weight and steroidogenesis but spermatogenesis is considerably restored during puberty

Neonatal exposure to endocrine disruptors induces developmental abnormalities in the male reproductive system. As to investigate whether neonatal exposure affects spermatogenesis in juvenile and pubertal testes, Sprague-Dawley rat pups were given various endocrine disruptors by a single injection on the day of birth at concentrations ranging between 4 microM and 40 mM and sacrificed on day 21 (juvenile) or 50 (puberty). The testes were weighed and examined histologically at each stage. Further, the metabolites of steroidogenesis were analyzed using normal-phase high performance liquid chromatography. Neonatal exposure significantly reduced testis weights and steroid biosynthesis of juveniles, but they were highly restored at puberty.     

Ectopic testicular xenografts from newborn hamsters (Phodopus sungorus) show better spermatogenic activity in aged compared with young recipients

The mechanisms behind testicular aging are poorly understood. Previous studies suggest that the testicular microenvironment is more affected by age than the male germ cell lineage. Here we analyze male reproductive aging using a unique xenografting approach. By exposing young and aged mice to newborn hamster testicular tissue, we can explore (a) whether the development and endocrine activity of hamster testicular grafts and the initiation of stem cell activity within them are affected by age of the recipients and (b) whether the endocrine response to the xenografted hamster tissue varies with recipient age. Newborn Djungarian hamster (Phodopus sungorus) testes were grafted into young (12 weeks) and aged (1 year) adult castrated nude mice. We also analyzed intact and castrated young and old control groups. After 13 weeks, 100 grafts were recovered from a total of 15 recipients and were histologically analyzed. Anatomical and endocrine parameters were recorded for each recipient as well as for the controls. Xenografted recipients responded with a normalization of their endocrine and anatomical parameters to an extent typical for their age. Although recipient age did not significantly affect graft survival and size, histopathological changes as well as spermatogenic damage within the grafts were more pronounced in the young recipients (56% Sertoli-cell-only tubules vs. 32% in the old recipients). We conclude from our data that the androgen-related changes associated with male reproductive aging are not primarily controlled by the testis. We speculate that the better development of testicular grafts in aged recipients may be owing to immunosenescence.     

Vitamin A prevents the irreversible proliferation of vaginal epithelium induced by neonatal injection of keratinocyte growth factor in mice

Exposure of female mice to estrogen during the perinatal period results in estrogen-independent persistent proliferation and cornification of the vaginal epithelium when the animals become adults. However, the occurrence of such irreversible vaginal changes is blocked by concurrent vitamin A treatment. Neonatal exposure to keratinocyte growth factor (KGF), which is a paracrine mediator of epithelial-mesenchymal interactions, also induces the persistent proliferation and cornification of the vaginal epithelium in adult mice. This study was designed to examine whether concurrent administration of vitamin A inhibits the development of the irreversible vaginal changes in mice exposed neonatally to KGF. The vaginal epithelium in ovariectomized 35-day-old mice given 5 microg of KGF for 3 days after birth possessed a significantly larger number of layers and increased thickness as compared to that in control mice. Concurrent injections of 100 IU of vitamin A acetate inhibited the occurrence of the irreversible proliferation of the vaginal epithelium. These changes were equal to the results observed when 20 micro g of estrogen with or without vitamin A acetate was administered for 5 days after birth. Unlike the case of estrogen treatment, the effect of neonatal treatment with KGF seemed to appear after a latent period, since the vaginal epithelium did not show proliferation soon after the treatment. We discuss the inhibitory effect of VA on the irreversible vaginal changes induced by neonatal KGF treatment with reference to endocrine disruption by neonatal estrogen exposure.     

Alligators and Endocrine Disrupting Contaminants: A Current Perspective

Many xenobiotic compounds introduced into the environment byhuman activity have been shown to adversely affect wildlife.Reproductive disorders in wildlife include altered fertility,reduced viability of offspring, impaired hormone secretion oractivity and modified reproductive anatomy. It has been hypothesizedthat many of these alterations in reproductive function aredue to the endocrine disruptive effects of various environmentalcontaminants. The endocrine system exhibits an organizationaleffect on the developing embryo. Thus, a disruption of the normalhormonal signals can permanently modify the organization andfuture function of the reproductive system. We have examinedthe reproductive and developmental endocrinology of severalpopulations of American alligator (Alligator mississippiensis)living in contaminated and reference lakes and used this speciesas a sentinel species in field studies. We have observed thatneonatal and juvenile alligators living in pesticide-contaminatedlakes have altered plasma hormone concentrations, reproductivetract anatomy and hepatic functioning. Experimental studiesexposing developing embryos to various persistent and nonpersistentpesticides, have produced alterations in gonadal steroidogenesis,secondary sex characteristics and gonadal anatomy. These experimentalstudies have begun to provide the causal relationships betweenembryonic pesticide exposure and reproductive abnormalitiesthat have been lacking in pure field studies of wild populations.An understanding of the developmental consequences of endocrinedisruption in wildlife can lead to new indicators of exposureand a better understanding of the most sensitive life stagesand the consequences of exposure during these periods.     

A treatise on hazards of endocrine disruptors and tool to evaluate them

Hormones mediate a major part of our essential physiological functions. Both endogenous and exogenous compounds and their metabolites are known to act through hormone receptors leading to regulation of endocrine function. The endogenous ligands that control reproductive functions are generally steroids such as 17beta-estradiol, androgens, progesterone, pregnenolone and glucocorticoids. However, exogenous compounds that are structurally and functionally similar gain entry into animals including humans through the diet or by occupational exposures, causing endocrine disruption. In the recent decade, there is a lot of apprehension about the so-called "endocrine disruptors" which are wide spread in the environment, mainly due to unrestricted human activity. These compounds of anthropogenic or natural origin mimic the action of sex hormones and can interfere with the endocrine system. It has been hypothesized that environmental exposure to synthetic estrogenic chemicals and related endocrine active compounds may be responsible for malformations in the male reproductive tract, crytorchidism, hypospadias, decrease in sperm counts, decreased male reproductive capacity and even testicular cancers. The increasing concern in both public and scientific communities about these abnormalities have prompted the initiation of epidemiological studies to not only identify, but to also analyze the short and long term effects of endocrine disruptors. As a result, a number of assays have been developed and are undergoing validation aimed at high throughput screening of chemical agents that disrupt endocrine activity. This review consolidates the findings of epidemiological studies, particularly in relation to male reproductive disorders and brings to light the various types of in vitro and in vivo models that are available for tiered testing of suspected compounds.     

Effects of cadmium on the reproductive axis of Japanese medaka (Oryzias latipes)

Cadmium (Cd) is a ubquitous element and a significant inorganic pollutant that has previously been found to bioaccumulate in reproductive organs of fish and disrupt important endocrine processes, especially those involved in synthesis, release and metabolism of hormones. Clearly, there is potential for reproductive effects in fish populations exposed to Cd, however, few studies have investigated the non-lethal consequences of Cd in fish. To this extent, adult male and female Japanese medaka were exposed to 0-10 ppb Cd for 7 weeks. Reproductive endpoints were monitored during weeks 6 and 7 of exposure and compared to physiological responses along the hypothalamus-pituitary-gonadal (HPG) axis, including plasma vitellogenin (VTG), hepatic estrogen receptor (ER), plasma steroids, gonadal-somatic indices (GSI), and gonadal steroid release. There were no observed effects on VTG and ER by long-term Cd exposure. However, gonadal steroid release was significantly decreased in males and females at all exposure concentrations and female plasma estradiol levels were significantly altered at concentrations higher than 5 ppb Cd. Overall, responses along the HPG axis were more sensitive to Cd exposure than the reproductive and developmental endpoints, which were not affected in this study, indicating that higher level impairment in fish might be relatively protected.     

Altered neonatal development and endocrine function in Alligator mississippiensis associated with a contaminated environment

Reduced reproductive success, altered reproductive tract development, and differences in circulating hormones have been documented in American alligators (Alligator mississippiensis) from Lake Apopka, FL, compared to less contaminated sites, such as the Lake Woodruff National Wildlife Refuge, FL. Comparative studies among alligators of varying size and age suggest that in ovo contaminant-induced alterations of endocrine function are further modified during postembryonic development and/or through environmental exposure. In the present study, we examined developmental and endocrine-related indices in neonatal (age, <1 mo) alligators from Lake Apopka in comparison to those of a reference population (Lake Woodruff), thereby limiting contaminant exposure to that derived via maternal contribution. We compared several reproductive and developmental parameters, including hatching success, primary sex determination, and somatic indices. Furthermore, we examined circulating testosterone concentrations and aromatase activity in an effort to establish relative gonadal endocrine function shortly after hatching. Finally, we compared phallus size among males and oviduct epithelial cell height (ECH) among females (androgen- and estrogen-dependent tissues, respectively). Significant differences between populations were noted for body size and spleen somatic index. Neonatal alligators from Lake Apopka exhibited higher plasma testosterone, but no differences were detected in gonadal aromatase activity compared to Lake Woodruff. Phallus tip length and cuff diameter were smaller in males from Lake Apopka, whereas no differences were noted in oviduct ECH. Our data establish basic indices of development and endocrine function in neonatal alligators before environmental exposure to contaminants. These results should begin to help separate developmental abnormalities resulting from in ovo exposure, presumably of maternal origin, from physiological alterations induced through environmental exposure to contaminants.     

Endocrine disrupting chemicals and disease susceptibility

Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products--including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption.     

Widespread endocrine disruption and reproductive impairment in an estuarine fish population exposed to seasonal hypoxia

The long-term effects on marine fish populations of the recent increase worldwide in the incidence of coastal hypoxia are unknown. Here we show that chronic environmental exposure of Atlantic croaker (Micropogonias undulatus) to hypoxia in a Florida estuary caused marked suppression of ovarian and testicular growth which was accompanied by endocrine disruption. Laboratory hypoxia studies showed that the endocrine disruption was associated with impairment of reproductive neuroendocrine function and decreases in hypothalamic serotonin (5-HT) content and the activity of the 5-HT biosynthetic enzyme, tryptophan hydroxylase. Pharmacological restoration of hypothalamic 5-HT levels also restored neuroendocrine function, indicating that the stimulatory serotonergic neuroendocrine pathway is a major site of hypoxia-induced inhibition. Inhibition of tryptophan hydroxylase activity to downregulate reproductive activity could have evolved as an adaptive mechanism to survive periodic hypoxia, but in view of the recent increased incidence of coastal hypoxia could become maladaptive and potentially affect fish population abundance and threaten valuable fishery resources.     

Endocrine disruptors and female fertility: Focus on (bovine) ovarian follicular physiology

Throughout the previous century, the production, use and, as a result, presence of chemicals in the environment increased enormously. Consequently, humans and animals are exposed to a wide variety of chemical substances of which some possess the ability to disrupt the endocrine system in the body, thereby denominated as “endocrine disrupting chemicals” (EDCs) or “endocrine disruptors”. Because the reproductive system is a target organ for endocrine disruption, EDCs are postulated as one of the possible causes of human subfertility. Within the reproductive system, the ovarian follicle can be considered as an extremely fragile microenvironment where interactions between the oocyte and its surrounding somatic cells are essential to generate a fully competent oocyte. In this review, we explore how EDCs can interfere with the well-balanced conditions in the ovarian follicle. In addition, we highlight the bovine ovarian follicle as an alternative in vitro model for EDC and broader toxicology research.     

The endocrine disruption potential of betamethasone using Japanese medaka as a fish model

The presence of synthetic glucocorticosteroids (GCs) in surface water and their potential endocrine disruption (ED) activity at environmental concentrations has not been fully investigated. Synthetic GCs may interfere with endogenous receptors within the hypothalamic-pituitary-gonadal (HPG) axis and disruptions of this pathway can result in decreased reproduction and/or adverse developmental effects. Betamethasone, a synthetic GC, has been on the market in the United States since the 1980's. The Pharmaceutical Assessment and Transport Evaluation model estimated betamethasone concentrations to be <0.6 ng/L in 95% of all U.S. surface waters. Concentrations of 0.01, 0.1, and 1.0 µg betamethasone/L were used in a two-generation fish full life cycle study with Japanese medaka. Gross endpoints, secondary sexual characteristics, and vitellogenin expression were evaluated. The highest concentration at which ED outcomes are not anticipated was determined to be 0.1 µg/L. The ratio of the predicted environmental concentration to the no effect concentration for ED is less than one, indicating no risk to aquatic life from environmentally relevant concentrations of betamethasone.