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Bisphenol A (BPA) is an oestrogenic endocrine disruptor widely used in the production of certain plastics, e.g., polycarbonate, hard and clear plastics, and epoxy resins that act as protective coating for food and beverage cans. Human exposure to this chemical is thought to be ubiquitous. BPA alters endocrine function, thereby causing many diseases in human and animals. In the last few decades, studies exploring the mechanism of BPA activity revealed a direct link between BPA-induced oxidative stress and disease pathogenesis. Antioxidants, reducing agents that prevent cellular oxidation reactions, can protect BPA toxicity. Although the important role of antioxidants in minimizing BPA stress has been demonstrated in many studies, a clear consensus on the associated mechanisms is needed, as well as the directives on their efficacy and safety. Herein, considering the distinct biochemical properties of BPA and antioxidants, we provide a framework for understanding how antioxidants alleviate BPA-associated stress. We summarize the current knowledge on the biological function of enzymatic and non-enzymatic antioxidants, and discuss their practical potential as BPA-detoxifying agents.

For many endocrine-disrupting chemicals (EDCs) including Bisphenol A (BPA), animal studies show that environmentally relevant exposures cause harm; human studies are consistent with these findings. Yet, regulatory agencies charged with protecting public health continue to conclude that human exposures to these EDCs pose no risk. One reason for the disconnect between the scientific consensus on EDCs in the endocrinology community and the failure to act in the regulatory community is the dependence of the latter on so-called "guideline studies" to evaluate hazards, and the inability to incorporate independent scientific studies in risk assessment. The Consortium Linking Academic and Regulatory Insights on Toxicity (CLARITY) study was intended to bridge this gap, combining a "guideline" study with independent hypothesis-driven studies designed to be more appropriate to evaluate EDCs. Here we examined an aspect of "guideline" studies, the use of so-called "historical controls," which are essentially control data borrowed from prior studies to aid in the interpretation of current findings. The US Food and Drug Administration authors used historical controls to question the plausibility of statistically significant BPA-related effects in the CLARITY study. We examined the use of historical controls on 5 outcomes in the CLARITY "guideline" study: mammary neoplasms, pituitary neoplasms, kidney nephropathy, prostate inflammation and adenomas, and body weight. Using US Food and Drug Administration-proposed historical control data, our evaluation revealed that endpoints used in "guideline" studies are not as reproducible as previously held. Combined with other data comparing the effects of ethinyl estradiol in 2 "guideline" studies including CLARITY-BPA, we conclude that near-exclusive reliance on "guideline" studies can result in scientifically invalid conclusions., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies.

Endocrine disrupting chemicals (EDCs) are ubiquitous, and pregnancy is a sensitive window for toxicant exposure. EDCs may disrupt the maternal immune system, which may lead to poor pregnancy outcomes. Most studies investigate single EDCs, even though "real life" exposures do not occur in isolation. We tested the hypothesis that uniquely weighted mixtures of early pregnancy exposures are associated with distinct changes in the maternal and neonatal inflammasome. First trimester urine samples were tested for 12 phthalates, 12 phenols, and 17 metals in 56 women. Twelve cytokines were measured in first trimester and term maternal plasma, and in cord blood after delivery. Spearman correlations and linear regression were used to relate individual exposures with inflammatory cytokines. Linear regression was used to relate cytokine levels with gestational age and birth weight. Principal component analysis was used to assess the effect of weighted EDC mixtures on maternal and neonatal inflammation. Our results demonstrated that maternal and cord blood cytokines were differentially associated with (1) individual EDCs and (2) EDC mixtures. Several individual cytokines were positively associated with gestational age and birth weight. These observed associations between EDC mixtures and the pregnancy inflammasome may have clinical and public health implications for women of childbearing age.

Objective: Studies have documented disparities in exposure to endocrine-disrupting chemicals (EDC), but no studies have investigated potential implications for racial/ethnic disparities in chronic disease and associated costs. Our objective was to examine EDC levels in the US population according to race/ethnicity and to quantify disease burden and associated costs., Study Design and Setting: EDC exposure levels in 2007-2010 were obtained from the National Health and Nutrition Examination Surveys. The associated disease burden and costs for 12 exposure-response relationships were determined for non-Hispanic Whites, non-Hispanic Blacks, Mexican Americans, Other Hispanics, and Other/Multicultural., Results: EDC exposure levels and associated burden of disease and costs were higher in non-Hispanic Blacks ($56.8 billion; 16.5% of total costs) and Mexican Americans ($50.1 billion; 14.6%) compared with their proportion of the total population (12.6% and 13.5%, respectively). Associated costs among non-Hispanic whites comprised 52.3% of total costs ($179.8 billion) although they comprise 66.1% of the US population. These disparities are driven by generally higher exposure to persistent pesticides and flame retardants among non-Hispanic blacks and Mexican Americans., Conclusion: Our estimates suggest that racial/ethnic disparities in chronic diseases in the US may be because of chemical exposures and are an important tool to inform policies that address such disparities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study investigated selected steroidal and phenolic endocrine disrupting compounds (EDCs) in the surface water of the Bahe River (China) using gas chromatography mass spectrometry (GC-MS). Their effect on the wild sharpbelly Hemiculter leucisculus was investigated. The concentrations of 4-t-octylphenol, nonylphenol, bisphenol-A, estrone, 17 β-estradiol, 17 α-Ethinylestradiol, and estriol were up to 126.0, 634.8, 1573.1, 55.9, 23.9, 31.5, and 5.2 ng L -1 in the surface water, and up to 26.4, 103.5, 146.9, 14.2, 9.3, 13.8, and 1.3 ng g -1 in the fish muscle tissue, respectively. High estrogen equivalent levels and hazard quotients were found in the middle and lower reaches of the river, and the pollution in these regions caused enhanced growth conditions, inhibition of gonad growth, and suppression of spermatogenesis in H. leucisculus. The up-regulation of Vitellogenin mRNA expression in male fish, collected from relatively heavily EDCs contaminated areas, indicates a potential estrogenic effect. The differential expression profiles of genes related to steroidogenesis at all sampling sites suggests that these endpoints may play an important role for the pollution monitoring of estrogenic EDCs in the Bahe River., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Endocrine disruptive chemicals (EDCs) cause adverse health effects through interaction with endocrine systems. They are classified by chemical structure, effects on specific endocrine systems, bioaccumulation, persistence in the environment, or clinically observable effects. For research of the complex mechanisms of action in the human body, only in vitro model systems have so far been available, that have insufficient high-throughput capacity, which makes risk evaluation more difficult. In addition, in industrial nations, living people are often exposed to mixtures of substances, with various effects. The clinical importance of epigenetic changes caused by the action of EDCs during vulnerable phases of development is currently unclear. Epidemiological studies are criticized because reproducibility is not always guaranteed. Nevertheless, they remain the method of choice for the development and analysis of suitable model systems. Positive associations, in spite of sometimes conflicting results, are key in the selection of factors that can then be analysed in model systems in an unbiased way. This article depicts the mainly positive epidemiological findings for EDC-caused effects in the fields of growth and metabolism, neurocognitive development and sexual development and reproduction. As a result, there is a need for closer linkage between epidemiological studies and mechanistic research into model systems, especially focusing on the interaction of different EDCs and the consequences of prenatal and early life exposure.

Background: Elevated blood or urinary concentrations of endocrine-disrupting chemicals (EDCs) may be related to increased risk of type 2 diabetes (T2D). The aim of the present study was to assess the role of EDCs in affecting risk of T2D and related metabolic traits., Methods: MEDLINE was searched for cross-sectional and prospective studies published before 8 March 2014 into the association between EDCs (dioxin, polychlorinated biphenyl [PCB], chlorinated pesticide, bisphenol A [BPA], phthalate) and T2D and related metabolic traits. Three investigators independently extracted information on study design, participant characteristics, EDC types and concentrations, and association measures., Results: Forty-one cross-sectional and eight prospective studies from ethnically diverse populations were included in the analysis. Serum concentrations of dioxins, PCBs, and chlorinated pesticides were significantly associated with T2D risk; comparing the highest to lowest concentration category, the pooled relative risks (RR) were 1.91 (95% confidence interval [CI] 1.44-2.54) for dioxins, 2.39 (95% CI 1.86-3.08) for total PCBs, and 2.30 (95% CI 1.81-2.93) for chlorinated pesticides. Urinary concentrations of BPA and phthalates were also associated with T2D risk; comparing the highest to lowest concentration categories, the pooled RR were 1.45 (95% CI 1.13-1.87) for BPA and 1.48 (95% CI 0.98-2.25) for phthalates. Further, EDC concentrations were associated with indicators of impaired fasting glucose and insulin resistance., Conclusions: Persistent and non-persistent EDCs may affect the risk of T2D. There is an urgent need for further investigation of EDCs, especially non-persistent ones, and T2D risk in large prospective studies., (© 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Incidence rates of lymphoma are usually higher in men than in women, and oestrogens may protect against lymphoma., Methods: We evaluated occupational exposure to endocrine disrupting chemicals (EDCs) among 2457 controls and 2178 incident lymphoma cases and subtypes from the European Epilymph study., Results: Over 30 years of exposure to EDCs compared to no exposure was associated with a 24% increased risk of mature B-cell neoplasms (P-trend=0.02). Associations were observed among men, but not women., Conclusions: Prolonged occupational exposure to endocrine disruptors seems to be moderately associated with some lymphoma subtypes.

Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ~100kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high levels of the sum (Σ) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. Σphthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with Σdi(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A large variety of anthropogenic chemicals present in the aquatic environment have been shown to be able to alter the endocrine system of exposed organisms, potentially impacting their reproductive function. The aim of this study was to assess the effects of environmental pollution on the reproductive system of wild female roach (Rutilus rutilus) from the Seine River (Normandy, France). A suite of biomarkers of endocrine disruption including gonado-somatic index, plasmatic vitellogenin, gonadal aromatase activity and histological parameters (oocyte diameter and gonad maturation) were studied. Female fish from the polluted sites showed a number of reproductive alterations, including inhibited gonad maturation, reduced oocyte growth, reduced levels of plasmatic vitellogenin and 3-fold lower gonadal aromatase activity than females collected in the reference site. Overall, these results highlight the presence of endocrine disruption in female roach from the Seine River., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Decreasing male fertility has been observed for the past fifty years. Examples of affected reproductive parameters include decreases in sperm count and sperm quality and increases in testicular cancer, cryptorchidism and hypospadias. Exposures to environmental toxicants during fetal development and early postnatal life have been shown to promote infertility. Environmental exposures inducing epigenetic changes related to male infertility range from life style, occupational exposures, environmental toxicants and nutrition. Exposures during fetal gonadal sex determination have been shown to alter the epigenetic programming of the germline that then can transmit this altered epigenetic information to subsequent generations in the absence of any exposures. This environmentally induced epigenetic transgenerational inheritance of disease will be a component of the etiology of male infertility., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Differences exist among fish species in their sensitivity to endocrine disruptors such as 17-α-ethynylestradiol (EE2). We examined whether there were corresponding differences in EE2 uptake rates and short-term internal distribution patterns. Six freshwater species: Japanese ricefish (medaka, Oryzias latipes), goldfish (Carassius auratus), zebrafish (Danio rerio), fathead minnow (Pimephales promelas), Atlantic killifish (Fundulus heteroclitus) and rainbow trout (Oncorhynchus mykiss) were exposed to waterborne radiolabelled EE2 (100ng/L) for 2-h measurements of uptake, tissue accumulation and oxygen consumption rates (MO2). EE2 uptake rate and MO2 were relatively consistent among species (2.5-3.0 fold variation), with the only significant differences being a lower EE2 uptake rate in medaka, and lower MO2 in medaka, goldfish, and zebrafish relative to the other species. EE2 accumulation, however, exhibited two distinct patterns, suggesting differences in metabolic processing. In killifish and medaka, the highest accumulation (~50%) occurred in the liver and gallbladder, whereas in minnow, goldfish, zebrafish and trout, >50% accumulated in the carcass. No significant sex differences were found in killifish or minnow, apart from lower gill tissue EE2 accumulation in minnow females. This study demonstrated that metabolic processing of EE2 may be species-specific and tissue specific EE2 distribution profiles vary. These could be indicative of differences in overall EE2 sensitivity among species., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Polycystic ovary syndrome (PCOS) is the most common and the most heterogeneous endocrine disorder in premenopausal women. Apart from signs of hyperandrogenism such as acne, hirsutism and hair loss, women with PCOS usually present with menstrual irregularities and fertility problems.Additionally, they are often characterized by impaired glucose tolerance, which usually leads to the development of type 2 diabetes mellitus (T2DM). This review article describes current and novel approach to the pathomechanisms of PCOS and the potential role of an endocrine disrupting chemical ("endocrine disruptor" - ED) - bisphenol A (BPA), which is commonly used as a plasticizer and due to its molecular structure can interact with estrogen receptors (ERs). Recent observations point to the higher levels of BPA in biological fluids of women with PCOS and its role in the pathogenesis of hyperandrogenism and hyperinsulinemia. It seems that mother's exposure to BPA during pregnancy may also lead to the development of PCOS in the female offspring.

Nonylphenol (NP), identified as an environmental endocrine disruptor, used as important raw materials for detergents, emulsifiers, and wetting agents in industry and is also found in paints, pesticides, and household toiletries. NP has been reported to have deleterious effects on central nervous system (CNS) other than reproductive and immune systems including disrupting neuroendocrine homeostasis, altering cognitive function, and neurotoxicity of tissues, etc., particularly when NP's disruption occurs during critical developmental window of brain. This review will discuss the evidence for environmental endocrine disruption of NP and the sequelae on endocrine, reproductive and nerve functions, as well as causal relationships between endocrine disruption and cognitive behavior effects.

"Weight of Evidence" (WoE) approaches are often used to critically examine, prioritize, and integrate results from different types of studies to reach general conclusions. For assessing hormonally active agents, WoE evaluations are necessary to assess screening assays that identify potential interactions with components of the endocrine system, long-term reproductive and developmental toxicity tests that define adverse effects, mode of action studies aimed at identifying toxicological pathways underlying adverse effects, and toxicity, exposure and pharmacokinetic data to characterize potential risks. We describe a hypothesis-driven WoE approach for hormonally active agents and illustrate the approach by constructing hypotheses for testing the premise that a substance interacts as an agonist or antagonist with components of estrogen, androgen, or thyroid pathways or with components of the aromatase or steroidogenic enzyme systems for evaluating data within the US EPA's Endocrine Disruptor Screening Program. Published recommendations are used to evaluate data validity for testing each hypothesis and quantitative weightings are proposed to reflect two data parameters. Relevance weightings should be derived for each endpoint to reflect the degree to which it probes each specific hypothesis. Response weightings should be derived based on assay results from the test substance compared to the range of responses produced in the assay by the appropriate prototype hormone and positive and negative controls. Overall WoE scores should be derived based on response and relevance weightings and a WoE narrative developed to clearly describe the final determinations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

There is increasing concern about chemical pollutants that are able to mimic hormones, the so-called endocrine-disrupting compounds (EDCs), because of their structural similarity to endogenous hormones, their ability to interact with hormone transport proteins or because of their potential to disrupt hormone metabolic pathways. Thus, the effects of endogenous hormones can be mimicked or, in some cases, completely blocked. A substantial number of environmental pollutants, such as polychlorinated biphenyls, dioxins, polycyclic aromatic hydrocarbons, phthalates, bisphenol A, pesticides, alkylphenols and heavy metals (arsenic, cadmium, lead, mercury), have been shown to disrupt endocrine function. These compounds can cause reproductive problems by decreasing sperm count and quality, increasing the number of testicular germ cells and causing male breast cancer, cryptorchidism, hypospadias, miscarriages, endometriosis, impaired fertility, irregularities of the menstrual cycle, and infertility. Although EDCs may be released into the environment in different ways, the main sources is industrial waste water. The present paper critically reviews the current knowledge of the impact of EDCs on reproductive disorders in humans.

Breast cancer affects Iranian women one decade younger than their counterparts in other countries and the underlying risk factors have remained controversial. The aryl hydrocarbon receptor (AhR) mediates the effects of many environmental endocrine disruptors and contributes to the many other genes and Gd is an endocrine-regulated glycoprotein which may induce by AhR ligands in endometrium. This study has aimed to compare the interactions between Gd and AhR and other fundamental genes (p53, K-Ras, ER, PgR, AR) between pre and post menopausal Iranian breast cancer patients. To conduct immunohistochemical studies with appropriate monoclonal antibodies, 25 premenopausal invasive ductal carcinomas and 29 postmenopausal invasive ductal carcinomas were selected retrospectively in 2008-2010 from the pathology department of Imam Khomeini hospital complex of Tehran. Higher levels of AhR in epithelial cells of premenopausal patients and breast fibroadenoma emphasized the susceptibility of these cells to environmental induced tumors. Current study demonstrated a significant association between tumoral levels of Gd and AhR (p=0.002) in breast cancers which confirms the preliminary hypothesis about the role of TCDD exposure on Gd biosynthesis and secretion in TCDD-treated endometrial epithelial cells. In summary this study showed the dual prognostic role of Gd especially in premenopausal breast cancer which could be induced by AhR overexpression. Further studies are necessary to find the direct role of breast carcinogens as well as endocrine disrupting chemicals on the differential levels of Gd in breast tumors.

Imposex expression in prosobranch gastropods has been widely used as a biomarker of tributyltin (TBT) pollution. Estuaries have been described as the most affected areas by this problem since they usually enclose the main TBT sources--ports, dockyards and marinas--resulting from the compound's application as a biocide in antifouling paints on ships. Using Hydrobia ulvae as a bioindicator, the current work addresses the most reliable methods to reduce the influence of critical variables, such as the animals' size, on imposex levels assessment for TBT pollution monitoring and presents its temporal trends from 1998 to 2007 in Ria de Aveiro (NW Portugal) to evaluate the effectiveness of recent legislation applied to reduce TBT environmental levels. H. ulvae imposex levels did not decrease in this estuarine system during the last decade despite the implementation of the EU Regulation No. 782/2003. Instead, there was a global significant increase in the percentage of females affected by imposex and a slight increase of the vas deferens sequence index (VDSI), contrasting with what has been described for other bioindicators in the same study area. These results show that different biology/ecology traits determine distinct routes of TBT uptake and/or bioaccumulation, pointing the importance of choosing the bioindicator depending on the compartment that is being monitored (sediment vs. water). Sediment ingestion as feeding habit is discussed and pointed as a reason to choose H. ulvae as a bioindicator of TBT pollution persistence in sediment. It is therefore predicted that the response of different prosobranch species around the world may diverge according to the compartment that is being monitored and that female masculinisation may not be completely eradicated in the near future due to TBT persistence in sediments.

Endocrine disruption refers to the ability of chemicals to interfere with hormonal systems, and has raised considerable concern in recent years. Endocrine disruptive chemicals (EDCs) pose a documented risk to wildlife and have the potential to negatively influence human health. This review focuses on the molecular mechanisms of endocrine disruption and the possible involvement of EDCs in metabolic disorders. The first part describes the role of aryl hydrocarbon receptor (AhR) and nuclear receptors (NRs) in mediating effects of EDCs, in particular, how cross-talk between AhR and NR pathways can lead to endocrine disruption. The second part deals with how these receptors are involved in metabolic functions and how their targeting by EDCs can lead to disturbances in glucose and fat metabolism. The article illustrates that, although there is accumulating data on molecular mechanisms of EDC action as well as on EDC involvement in metabolic disorders, there is still a great demand for data that can unite the mechanistic and the toxicological/epidemiological observations.

There is increasing evidence both from epidemiology studies and animal models that specific endocrine-disrupting compounds may influence the development or progression of prostate cancer. In large part, these effects appear to be linked to interference with estrogen signaling, either through interacting with ERs or by influencing steroid metabolism and altering estrogen levels within the body. In humans, epidemiologic evidence links specific pesticides, PCBs and inorganic arsenic exposures to elevated prostate cancer risk. Studies in animal models also show augmentation of prostate carcinogenesis with several other environmental estrogenic compounds including cadmium, UV filters and BPA. Importantly, there appears to be heightened sensitivity of the prostate to these endocrine disruptors during the critical developmental windows including in utero and neonatal time points as well as during puberty. Thus infants and children may be considered a highly susceptible population for ED exposures and increased risk of prostate cancers with aging.

Androgens, anti-Müllerian hormone, and insulin-like factor 3 are testis-derived hormones that regulate male sexual differentiation. Correct timing of secretion and action of these hormones is critical for normal development. Endocrine disrupters are exogenous substances that cause adverse effects in the endocrine system. They can impair the synthesis, distribution, metabolism, excretion, and action of hormones. Male sexual differentiation can be disrupted by antiandrogens and synthetic estrogens such as diethylstilbestrol. The number of identified environmental antiandrogens keeps growing and these compounds show clear dose-additive effects causing worry that a mixture of these chemicals can cause adverse effects even when each compound is present at a low concentration. This is also a demanding research task for endocrinologists working with disorders of sex differentiation., ((c) 2008 S. Karger AG, Basel.)

Female mosquitofish exposed to pulp and paper mill effluent (PME) in the Fenholloway River, Florida, USA have masculinized secondary sex characteristics and altered aromatase enzyme activity. We and others have shown that the Fenholloway River PME contains androgenic and progestogenic substance(s). The present study was designed to test the hypothesis that the development and reproductive health of PME-exposed Fenholloway River mosquitofish are altered compared to mosquitofish living in Econfina River, which is the reference site. Fish were collected on a single day from both sites in June and August 1999 and January and June 2000. We compared standard length, anal fin length and segment number; body, liver, and gonad mass; and number of eggs and embryos from Fenholloway and Econfina River mosquitofish. The data were analyzed collectively for generalized site effect, for site effects during reproductive and nonreproductive seasons, and for repeatability of site effects between years. Mosquitofish exposed to PME in the Fenholloway River were generally smaller in length and mass, anal fin segment number was greater, and the number of embryos, but not oocytes, was significantly decreased compared to the reference site fish. Anal fin length and segment number and liver and testis masses were generally greater in Fenholloway compared to the Econfina River males. The importance of this study is that we have documented masculinized development and decreased embryo production in PME-exposed mosquitofish and that these site effects are generally consistent across seasons and between years.

Objective: To investigate environmental risk factors associated with polycystic ovary syndrome (PCOS)., Methods: A retrospective study was carried out from Feb 2005 to Apr 2006. A total of 108 cases with PCOS and 108 patients without PCOS (control group) were interviewed using a designed questionnaire., Results: Univariate analysis of environmental factors indicated that risk factors related to PCOS were: occupation, education, disposable plastic cup for drinking, cooking oil fume and indoor decoration, all of which were significantly related to PCOS (P < 0.05). Multi-variate analysis confirmed that the risk factors associated with PCOS were disposable plastic cup for drinking, cooking oil fume and indoor decoration (P value: 0.011, 0.012, 0.026, 0.011, OR value: 2.800, 3.027, 2.370, 2.478)., Conclusions: PCOS is related to environmental endocrine-disrupting chemicals.

On-site, continuous-flow experiments were conducted during August and October 2002 at a major metropolitan wastewater treatment plant (WWTP) to determine if effluent exposure induced endocrine disruption as manifested in the reproductive competence of sexually mature male fathead minnows (Pimephales promelas). The fathead minnows were exposed in parallel experiments to WWTP effluent and WWTP effluent treated with XAD8 macroreticular resin to remove the hydrophobic-neutral fraction which contained steroidal hormones, alkylphenolethoxylates (APEs), and other potential endocrine disrupting compounds (EDCs). The effluent composition varied on a temporal scale and the continuous-flow experiments captured the range of chemical variability that occurred during normal WWTP operations. Exposure to WWTP effluent resulted in vitellogenin induction in male fathead minnows, with greater response in October than in August. Concentrations of ammonia, APEs, 17beta-estradiol, and other EDCs also were greater in October than in August, reflecting a change in effluent composition. In the October experiment, XAD8 treatment significantly reduced vitellogenin induction in the male fathead minnows relative to the untreated effluent, whereas in August, XAD8 treatment had little effect. During both experiments, XAD8 treatment removed greater than 90% of the APEs. Exposure of fish to a mixture of APEs similar in composition and concentration to the WWTP effluent, but prepared in groundwater and conducted at a separate facility, elicited vitellogenin induction during both experiments. There was a positive relation between vitellogenin induction and hepatosomatic index (HSI), but not gonadosomatic index (GSI), secondary sexual characteristics index (SSCI), or reproductive competency. In contrast to expectations, the GSI and SSCI increased in males exposed to WWTP effluent compared to groundwater controls. The GSI, SSCI, and reproductive competency were positively affected by XAD8 treatment of the WWTP effluent.

Female reproductive function depends upon the exquisite control of ovarian steroidogenesis that enables folliculogenesis, ovulation, and pregnancy. These mechanisms are set during fetal and/or neonatal development and undergo phases of differentiation throughout pre- and post-pubescent life. Ovarian development and function are collectively regulated by a host of endogenous growth factors, cytokines, gonadotropins, and steroid hormones as well as exogenous factors such as nutrients and environmental agents. Endocrine disruptors represent one class of environmental agent that can impact female fertility by altering ovarian development and function, purportedly through estrogenic, anti-estrogenic, and/or anti-androgenic effects. This review discusses ovarian development and function and how these processes are affected by some of the known estrogenic and anti-androgenic endocrine disruptors. Recent information suggests not only that exposure to endocrine disruptors during the developmental period causes reproductive abnormalities in adult life but also that these abnormalities are transgenerational. This latter finding adds another level of importance for identifying and understanding the mechanisms of action of these agents.

Demasculinization by environmental endocrine-disrupting chemicals (EDCs) is observed in many animal species but less evident in humans. Rodent studies with gestational exposure to either the fungicide vinclozolin or the insecticide methoxychlor demonstrate impaired male fertility with abnormal DNA methylation patterns in spermatozoa. Once established, these epigenetic changes may be permanent and thus paternally passed to subsequent generations. Conclusive evidence of a similar phenomenon in humans has not been established, but several observations bring up the possibility. Some, but not all, studies show an increase in male genital abnormalities after prenatal EDC exposure. Other studies demonstrate sperm abnormalities in males with EDC contact, although it is unclear as to whether this is due to prenatal or postnatal exposure. Although not examined in males with EDC exposure, one study shows gamete DNA methylation abnormalities in males with severe oligospermia. A subsequent study failed to corroborate these findings. The use of assisted reproductive techniques including intracytoplasmic sperm injection has removed natural selection barriers thus enabling reproduction in males that would otherwise be sterile. This review explores the hypothesis that prenatal EDC exposure results in transgenerational male reproductive abnormalities propagated by the use of assisted reproductive technologies.

Xenobiotic and dietary compounds with hormone-like activity can disrupt endocrine signaling pathways that play important roles during perinatal differentiation and result in alterations that are not apparent until later in life. Evidence implicates developmental exposure to environmental hormone-mimics with a growing list of health problems. Obesity is currently receiving needed attention since it has potential to overwhelm health systems worldwide with associated illnesses such as diabetes and cardiovascular disease. Here, we review the literature that proposes an association of exposure to environmental endocrine disrupting chemicals with the development of obesity. We describe an animal model of developmental exposure to diethylstilbestrol (DES), a potent perinatal endocrine disruptor with estrogenic activity, to study mechanisms involved in programming an organism for obesity. This experimental animal model provides an example of the growing scientific field termed "the developmental origins of adult disease" and suggests new targets of abnormal programming by endocrine disrupting chemicals.

Reproductive organs from 55 male and 44 female East Greenland polar bears were examined to investigate the potential negative impact from organohalogen pollutants (OHCs). Multiple regressions normalizing for age showed a significant inverse relationship between OHCs and testis length and baculum length and weight, respectively, and was found in both subadults (dichlorodiphenyl trichloroethanes, dieldrin, chlordanes, hexacyclohexanes, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs)) and adults (hexachlorobenzene [HCB]) (all p < 0.05). Baculum bone mineral densities decreased with increasing chlordanes, DDTs, and HCB in subadults and adults, respectively (all p < 0.05). In females, a significant inverse relationship was found between ovary length and sigma PCB (p = 0.03) and sigma CHL (p < 0.01), respectively, and between ovary weight and sigma PBDE (p < 0.01) and uterine horn length and HCB (p = 0.02). The study suggests thatthere is an impact from xenoendocrine pollutants on the size of East Greenland polar bear genitalia. This may pose a riskto this polar bear subpopulation in the future because of reduced sperm and egg quality/quantity and uterus and penis size/robustness.

Organochlorine compounds (OCCs), such as pesticides and polychlorinated biphenyls (PCBs), are persistent lipophilic chemicals identified as endocrine disruptors, mainly with estrogen-like effects. Northeastern Argentina, near the Paraná River, is characterized by intensive farming and agricultural activities and industrial development, and is therefore prone to high incidences of environmental and dietary exposure to OCCs. Hence, we conducted a study to (1) estimate the organochlorine residues present in mammary fat tissue in a population of women from this littoral region and (2) identify potential sources of exposure to OCCs. Our subjects were 76 women (residing in and around Santa Fe city and not occupationally exposed to organochlorines) who underwent excision biopsy of a breast lesion or had plastic surgery. Both frequency of occurrence and levels of organochlorine residues were high in breast adipose tissue of all the participants. The organochlorine residues most frequently found were p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) in all the subjects analyzed, hexachlorobenzene (HCB) in 86.8%, and beta-hexachlorocyclohexane (beta-HCH) in 75.0%. The incidence of PCB congeners was very low. p,p'-DDE and beta-HCH residues reached the highest levels, 4794 and 1780 ppb, respectively. The diet was a relevant source of exposure, consumption of animal fat and freshwater fish playing a significant role. Bioaccumulation was evidenced by the significant positive association between organochlorine levels and body mass index (p = 0.0003) and the age of the patient (p = 0.0002). The frequency and levels of OCCs found in our study population raise concerns regarding Argentinean exposure to these endocrine disruptors.

Background, Aims and Scope: Man-made Endocrine Disruptors (EDs) range across all continents and oceans. Some geographic areas are potentially more threatened than others: one of these is the Mediterranean Sea. Levels of some xenobiotics are much higher here than in other seas and oceans. In this paper we review the final results of a project in which the hypothesis that Mediterranean top predator species (such as large pelagic fish and marine mammals) are potentially at risk due to EDs was investigated., Methods: In a four-year survey on the Mediterranean population of swordfish (Xiphias gladius), the potential toxicological effects of organochlorine compounds (OCs) on specimens of swordfish and tuna fish (Thunnus thynnus thynnus), caught in the spawning seasons from 1999 to 2002 in the Straits of Messina, Sicily (Italy), were investigated using vitellogenin (Vtg), Zona radiata proteins (Zrp), and cytochrome P4501A (CYP1A) activities (EROD, BPMO). Tissues (skin and blubber) were obtained from Stenella coeruleoalba, Tursiops truncatus, Delphinus delphis and Balaenoptera physalus from the western Ligurian Sea, between Corsica and the French-Italian coast, and Ionic Sea using biopsy darts launched with a crossbow. Benzo(alpha)pyrene monoxigenase (BPMO) activity was mesured in biopsies and cholrinated hydrocarbon levels were detected., Results and Discussion: We illustrate the need to develop and apply sensitive methodological tools, such as biomarkers (Vitellogenin, Zona Radiata proteins and CYP1A activities) for evaluation of toxicological risk in Xiphias gladius and Thunnus thynnus thynnus), and nondestructive biomarkers (CYP1A activities and fibroblast cell culture in skin biopsy), for the hazard assessment of threatened marine mammals species (Stenella coeruleoalba, Tursiops truncatus, Delphinus delphis and Balaenoptera physalus) exposed to EDs., Conclusion: The present research shows that: a) Vtg and Zrp can be used as diagnostic tools for fish stocks hazard assessment in the Mediterranean Sea; b) that CYP1A1 (BPMO) induction in cetaceans skin biopsy may be an early sign of exposure to EDs such as OCs and a potential alert for transgenerational effects., Recommendation and Outlook: This research represents a warning signal of the potential reproductive alterations in marine top predators and suggest the need for continuous monitoring to avoid reductions in population and biodiversity in the Mediterranean Sea.

Black turtle plasmatic vitellogenin (VTG) was purified from 17beta-estradiol-induced males using ion-exchange chromatography. The isolated protein was identified as VTG by its glycolipoprotein nature and amino acid sequence homology with other vertebrate VTG. It was characterized as a 500-kDa dimer composed of two identical, 200- to 240-kDa monomers. Polyclonal antibodies raised against black turtle VTG showed high titer and specificity, as demonstrated by enzyme-linked immunosorbent assay and Western blot analysis, respectively. The range of the assay was estimated to be between 15 ng/ml and 2 microg/ml, and the inter- and intra-assay coefficients of variation were 9.4 and 7.3%, respectively. Black turtle antibody cross-reacted with VTG of two other sea turtle species, Caretta caretta (loggerhead) and Eretmochelys imbricata (hawksbill), extending the applicability of the assay as part of a sea turtle health assessment program.

Man does not come into the world pre-determined. The lifetime set of environmental conditions impinging on a given individual has been termed the ambiome, which together with the genome and the proteome determines each individual's development and construction. Among the most important elements making up the ambiome are endocrine disruptors. An endocrine disruptor is a chemical substance that has adverse effects on an organism or its progeny, through the endocrine system. The number of known endocrine disruptors is large and continuously increasing, and includes both naturally occurring and synthetic substances. We are convinced that they entail genuine problems; although it is difficult to assess their magnitude and real significance, and we will certainly need some time, probably several decades, to obtain conclusive results; but even so, we consider that the existing body of evidence about effects of endocrine disruptors on human health is sufficiently worrying to justify precautionary measures.