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Oestrogen plays a crucial physiological role in both women and men. It regulates reproductive functions and maintains various non-reproductive tissues through its receptors, such as oestrogen receptor 1/oestrogen receptor α (ESR1/Erα), oestrogen receptor 2/oestrogen receptor β (ESR2/Erβ), and G protein-coupled oestrogen receptor 1 (GPER). This hormone is essential for the proper functioning of women's ovaries and uterus. Oestrogen supports testicular function and spermatogenesis in men and contributes to bone density, cardiovascular health, and metabolic processes in both sexes. Nuclear receptors Er-α and Er-β belong to the group of transcription activators that stimulate cell proliferation. In the environment, compounds similar in structure to the oestrogens compete with endogenous hormones for binding sites to receptors and to disrupt homeostasis. The lack of balance in oestrogen levels can lead to infertility, cancer, immunological disorders, and other conditions. Exogenous endocrine-active compounds, such as bisphenol A (BPA), phthalates, and organic phosphoric acid esters, can disrupt signalling pathways responsible for cell division and apoptosis processes. The metabolism of oestrogen and its structurally similar compounds can produce carcinogenic substances. It can also stimulate the growth of cancer cells by regulating genes crucial for cell proliferation and cell cycle progression, with long-term elevated levels linked to hormone-dependent cancers such as breast cancer. Oestrogens can also affect markers of immunological activation and contribute to the development of autoimmune diseases. Hormone replacement therapy, oral contraception, in vitro fertilisation stimulation, and hormonal stimulation of transgender people can increase the risk of breast cancer. Cortisol, similar in structure to oestrogen, can serve as a biomarker associated with the risk of developing breast cancer. The aim of this review is to analyse the sources of oestrogens and their effects on the endogenous and exogenous process of homeostasis. [ABSTRACT FROM AUTHOR]

Oestrogen plays a crucial physiological role in both women and men. It regulates reproductive functions and maintains various non-reproductive tissues through its receptors, such as oestrogen receptor 1/oestrogen receptor α (ESR1/Erα), oestrogen receptor 2/oestrogen receptor β (ESR2/Erβ), and G protein-coupled oestrogen receptor 1 (GPER). This hormone is essential for the proper functioning of women’s ovaries and uterus. Oestrogen supports testicular function and spermatogenesis in men and contributes to bone density, cardiovascular health, and metabolic processes in both sexes. Nuclear receptors Er-α and Er-β belong to the group of transcription activators that stimulate cell proliferation. In the environment, compounds similar in structure to the oestrogens compete with endogenous hormones for binding sites to receptors and to disrupt homeostasis. The lack of balance in oestrogen levels can lead to infertility, cancer, immunological disorders, and other conditions. Exogenous endocrine-active compounds, such as bisphenol A (BPA), phthalates, and organic phosphoric acid esters, can disrupt signalling pathways responsible for cell division and apoptosis processes. The metabolism of oestrogen and its structurally similar compounds can produce carcinogenic substances. It can also stimulate the growth of cancer cells by regulating genes crucial for cell proliferation and cell cycle progression, with long-term elevated levels linked to hormone-dependent cancers such as breast cancer. Oestrogens can also affect markers of immunological activation and contribute to the development of autoimmune diseases. Hormone replacement therapy, oral contraception, in vitro fertilisation stimulation, and hormonal stimulation of transgender people can increase the risk of breast cancer. Cortisol, similar in structure to oestrogen, can serve as a biomarker associated with the risk of developing breast cancer. The aim of this review is to analyse the sources of oestrogens and their effects on the endogenous and exogenous process of homeostasis.

Bisphenols are chemicals extensively used in plastic industries. Bisphenol A (BPA), a member of the bisphenol family, is widely used in manufacturing epoxy resins and polycarbonate plastic. Epoxy resins have applications in manufacturing the inside lining of metal cans to preserve the quality of canned foods. Polycarbonate plastics have a usage in the manufacture of packaging of food and drinks. BPA-containing plastic is also extensively used in the production of dental implants and sales receipts. There is constant leaching of BPA from the plastic items into the edibles stored in them, particularly when these plastic containers get exposed to high temperatures, non-neutral pH and multiple uses. On consuming these contaminated food items, the gut is the first organ exposed to BPA, followed by all other body systems. In most human body fluid samples examined, BPA is present in a detectable amount. BPA belongs to the family of known endocrine-disrupting chemicals with oestrogenic properties. The increasing alarms regarding the adverse effects of BPA on child development compelled prohibiting products that contain BPA from being used in baby care in many countries worldwide. Being a known xeno-oestrogen, BPA may target the oestrogen receptors in the gut and may affect the various actions mediated by oestrogen in the gut. Besides oestrogenic properties, BPA may have many other hormonal and non-hormonal actions that may affect gut functions. The present article reviews the studies reporting the effect of BPA on gut functions. [ABSTRACT FROM AUTHOR]

Bisphenols are chemicals extensively used in plastic industries. Bisphenol A (BPA), a member of the bisphenol family, is widely used in manufacturing epoxy resins and polycarbonate plastic. Epoxy resins have applications in manufacturing the inside lining of metal cans to preserve the quality of canned foods. Polycarbonate plastics have a usage in the manufacture of packaging of food and drinks. BPA-containing plastic is also extensively used in the production of dental implants and sales receipts. There is constant leaching of BPA from the plastic items into the edibles stored in them, particularly when these plastic containers get exposed to high temperatures, non-neutral pH and multiple uses. On consuming these contaminated food items, the gut is the first organ exposed to BPA, followed by all other body systems. In most human body fluid samples examined, BPA is present in a detectable amount. BPA belongs to the family of known endocrine-disrupting chemicals with oestrogenic properties. The increasing alarms regarding the adverse effects of BPA on child development compelled prohibiting products that contain BPA from being used in baby care in many countries worldwide. Being a known xeno-oestrogen, BPA may target the oestrogen receptors in the gut and may affect the various actions mediated by oestrogen in the gut. Besides oestrogenic properties, BPA may have many other hormonal and non-hormonal actions that may affect gut functions. The present article reviews the studies reporting the effect of BPA on gut functions.

Among vertebrates, teleosts display a wide array of sex determination and differentiation mechanisms ranging from chromosomal sex determination on one end of the spectrum to environmental sex determination on the other end. However, the interplay of both these mechanisms is also not uncommon. Several gonochoristic fishes exhibit gonadal plasticity often resulting in sex reversal. The major manipulation of sex differentiation in teleost is affected by sex steroids. In this context, the increasing contamination of aquatic ecosystems by estrogen-like compounds, commonly known as xenoestrogens, is of major concern. This often leads to deleterious effects on the reproductive success of fish and thereby adversely impacts aquatic biodiversity. In the present review, we have focused on impact of xenoestrogen at different levels of the reproductive system influencing not only gonadal differentiation in teleosts but also their reproductive functions. The review would also explore the mitigation strategies and regulations in place for aquatic xenoestrogen management.

Despite significant advances in understanding nephron segment patterning, many questions remain about the underlying genes and signaling pathways that orchestrate renal progenitor cell fate choices and regulate differentiation. In an effort to identify elusive regulators of nephron segmentation, our lab conducted a high-throughput drug screen using a bioactive chemical library and developing zebrafish, which are a conserved vertebrate model and particularly conducive to large-scale screening approaches. 17β-estradiol (E2), which is the dominant form of estrogen in vertebrates, was a particularly interesting hit from this screen. E2 has been extensively studied in the context of gonad development, but roles for E2 in nephron development were unknown. Here, we report that exogenous estrogen treatments affect distal tubule composition, namely, causing an increase in the distal early segment and a decrease in the neighboring distal late. These changes were noted early in development but were not due to changes in cell dynamics. Interestingly, exposure to the xenoestrogens ethinylestradiol and genistein yielded the same changes in distal segments. Further, upon treatment with an estrogen receptor 2 (Esr2) antagonist, PHTPP, we observed the opposite phenotypes. Similarly, genetic deficiency of the Esr2 analog, esr2b, revealed phenotypes consistent with that of PHTPP treatment. Inhibition of E2 signaling also resulted in decreased expression of essential distal transcription factors, irx3b and its target irx1a. These data suggest that estrogenic compounds are essential for distal segment fate during nephrogenesis in the zebrafish pronephros and expand our fundamental understanding of hormone function during kidney organogenesis. [ABSTRACT FROM AUTHOR]

Xenoestrogens are natural or synthetic compounds that mimic the effect of endogenous estrogens and might cause cancer. We aimed to compare the global transcriptomic response to zearalenone (ZEA; mycotoxin) and bisphenol A (BPA; plastic additive) with the effect of physiological estradiol (E2) in the PEO1 human ovarian cell line by mRNA and microRNA sequencing. Estrogen exposure induced remarkable transcriptomic changes: 308, 288 and 63 genes were upregulated (log2FC > 1); 292, 260 and 45 genes were downregulated (log2FC < −1) in response to E2 (10 nM), ZEA (10 nM) and BPA (100 nM), respectively. Furthermore, the expression of 13, 11 and 10 miRNAs changed significantly (log2FC > 1, or log2FC < −1) after exposure to E2, ZEA and BPA, respectively. Functional enrichment analysis of the significantly differentially expressed genes and miRNAs revealed several pathways related to the regulation of cell proliferation and migration. The effect of E2 and ZEA was highly comparable: 407 genes were coregulated by these molecules. We could identify 83 genes that were regulated by all three treatments that might have a significant role in the estrogen response of ovarian cells. Furthermore, the downregulation of several miRNAs (miR-501-5p, let-7a-2-3p, miR-26a-2-3p, miR-197-5p and miR-582-3p) was confirmed by qPCR, which might support the proliferative effect of estrogens in ovarian cells. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate in vitro the possible mechanisms underlying the estrogenic potential of benzalkonium chloride (BAC) as a disinfectant emerging contaminant. Effects of BAC at the environmentally-relevant concentrations on estrogen synthesis and estrogen receptor (ER) signaling were assessed using the H295R steroidogenesis assay and the MCF-7 proliferation assay, respectively. Results showed that exposure to BAC at concentrations of 1.0-1.5 mg/L for 48 h significantly increased estradiol production of H295R cells in a concentration-dependent manner. Transcription of steroidogenic genes 3β‐HSD2, 17β‐HSD1, 17β‐HSD4, and CYP19A were significantly enhanced by BAC. In ER-positive MCF-7 cells, exposure to 0.5-1.5 mg/L BAC for 48 h significantly promoted cell proliferation and increased the expressions of ERα and G-protein coupled estrogen receptor 1. Flow cytometry analysis showed that 0.5-1.5 mg/L BAC significantly decreased the percentage of cells in G0/G1 phase, increased the percentage in S phase, and BAC at concentrations of 1.0 and 1.5 mg/L increased the G2/M phase cells. Findings of the study suggested that BAC at environmentally-relevant concentrations might act as a xenoestrogen through its inhibitory effect on steroidogenesis and ER-mediated mechanism.

In this study, a biochar obtained from poplar wood gasification at a temperature of 850 °C was used to adsorb the xenoestrogens 4-tert-octylphenol (OP) and bisphenol A (BPA) and the herbicide metribuzin from water. Scanning electron microscopy (SEM-EDX) and Fourier-transform infrared (FTIR) spectroscopy were employed to investigate the surface micromorphology and functional groups composition of biochar, respectively. The study of sorption kinetics showed that all compounds achieved the steady state in less than 2 h, according to a pseudo-second order model, which denoted the formation of strong bonds (chemisorption) between biochar and the compounds. Adsorption isotherms data were described by the Henry, Freundlich, Langmuir and Temkin equations. At temperatures of 10 and 30 °C, the equilibrium data of the compounds were generally better described by the Freundlich model, although, in some cases, high correlation coefficients (r ≥ 0.98) were obtained for more than one model. Freundlich constants, KF, for OP, BPA and metribuzin were, respectively, 218, 138 and 4 L g−1 at 10 °C and 295, 243 and 225 L g−1 at 30 °C, indicating a general increase of adsorption at higher temperature. Desorption of all compounds, especially OP and BPA, from biochar was slow and very scarce, denoting an irreversible and hysteretic process. Comparing the results of this study with those reported in the literature, we can conclude that the present biochar has a surprising ability to retain organic compounds almost permanently, thus behaving as an excellent low-cost biosorbent. [ABSTRACT FROM AUTHOR]

A class of chemical with a potentially important perceived future contribution to the net zero carbon goal (as "green" solvents) is the methylimidazolium ionic liquids (MILs). These solvents are used in industrial processes such as biofuel production yet little is known about their environmental stability or toxicity in man although one MIL – 1-octyl-3-methylimidazolium (M8OI) – has been shown to activate the human estrogen receptor alpha (ERα). The stabilities of the chloride unsubstituted methylimidazolium (MI) and MILs possessing increasing alkyl chain lengths (2C, 1-ethyl-3-methylimidazolium (EMI); 4C, 1-butyl-3-methylimidazolium (BMI); 6C; 1-hexyl-3-methylimidazolium (HMI), 8C, M8OI; 10C, 1-decyl-3-methylimidazolium (DMI)) were examined in river water and a human liver model system. The MILs were also screened for their abilities to activate the human ERα in vitro and induce uterine growth in pre-pubertal rats in vivo. Short chain MILs (EMI, BMI and HMI) underwent negligible metabolism and mineralisation in river water; were not metabolised in a model of human liver metabolism; activated the human ERα in vitro and were estrogenic in vivo in rats. A structure-based computational approach predicted short chain MIL binding to both the estrogen binding site and an additional site on the human estrogen receptor alpha. Longer chain MILs (M8OI and DMI) were metabolised in river water and partially mineralised. Based on structure-activity considerations, some of these environmentally-derived metabolites may however, remain a hazard to the population. MILs therefore have the potential to become forever chemicals with adverse effects to both man, other animals and the environment in general. [Display omitted] • Short chain MILs underwent negligible metabolism and mineralisation in river water. • Short chain MILs were not metabolised by human liver. • Short chain MILs activated the human estrogen receptor alpha. • Short chain MILs were estrogenic in vivo in rats. • Longer chain MILs were metabolised and partially mineralised. [ABSTRACT FROM AUTHOR]

It is unclear if complex mycotoxin mixtures produced by Alternaria spp. act estrogenic and/or genotoxic under physiological conditions, particularly considering the co-occurrence with antioxidants in food. Thus, this study focused on enlightening the impact of N-acetyl cysteine (NAC), as a representative anti-oxidative SH-donor, on the mentioned toxicological endpoints of the signature Alternaria toxins alternariol (AOH), altertoxin-II (ATX-II) and a complex extract (CE) of an Alternaria alternata culture.Using Ishikawa cells as an in vitro model, we monitored alterations in toxin concentrations by LC-MS/MS, estrogenicity by alkaline phosphatase assays, cytotoxicity by sulforhodamine B assays, genotoxicity by single-cell gel electrophoresis and the transcription of selected genes of interest by quantitative real-time PCR.The results indicate that the strong genotoxic effects of epoxide-carrying perylene quinones such as ATX-II are erased in the presence of NAC. The cellular effects of ATX-II/AOH mixtures are dominated by the genotoxicity of the perylene chinone. In this mixture, AOH regained its estrogenicity when co-incubated with NAC. In contrast, NAC treatment of an AOH/CE mixture did not result in a recovery of estrogenicity, but in potentiated anti-estrogenic effects. These findings were in line with gene transcription data, that indicated the aryl hydrocarbon receptor (AhR) to be a prime mediator of Alternaria toxin – induced antagonistic effects towards estrogen receptor signaling.Taken together, further studies on potential endocrine-disruptive properties of non-genotoxic perylene quinones should be a future research priority in the field of these emerging contaminants.

Targeted gene lists have been used in clinical settings to specify breast tumor type, and to predict breast cancer prognosis and response to treatment. Separately, panels have been curated to predict systemic toxicity and xenoestrogen activity as a part of chemical screening strategies. However, currently available panels do not specifically target biological processes relevant to breast development and carcinogenesis. We have developed a gene panel called the Breast Carcinogen Screen (BCScreen) as a tool to identify potential breast carcinogens and characterize mechanisms of toxicity. First, we used four seminal reviews to identify 14 key characteristics of breast carcinogenesis, such as apoptosis, immunomodulation, and genotoxicity. Then, using a hybrid data and knowledge-driven framework, we systematically combined information from whole transcriptome data from genomic databases, biomedical literature, the CTD chemical-gene interaction database, and primary literature review to generate a panel of 500 genes relevant to breast carcinogenesis. We used normalized pointwise mutual information (NPMI) to rank genes that frequently co-occurred with key characteristics in biomedical literature. We found that many genes identified for BCScreen were not included in prognostic breast cancer or systemic toxicity panels. For example, more than half of BCScreen genes were not included in the Tox21 S1500+ general toxicity gene list. Of the 230 that did overlap between the two panels, representation varied across characteristics of carcinogenesis ranging from 21% for genes associated with epigenetics to 82% for genes associated with xenobiotic metabolism. Enrichment analysis of BCScreen identified pathways and processes including response to steroid hormones, cancer, cell cycle, apoptosis, DNA damage and breast cancer. The biologically-based systematic approach to gene prioritization demonstrated here provides a flexible framework for creating disease-focused gene panels to support discovery related to etiology. With validation, BCScreen may also be useful for toxicological screening relevant to breast carcinogenesis.

Among vertebrates, teleosts display a wide array of sex determination and differentiation mechanisms ranging from chromosomal sex determination on one end of the spectrum to environmental sex determination on the other end. However, the interplay of both these mechanisms is also not uncommon. Several gonochoristic fishes exhibit gonadal plasticity often resulting in sex reversal. The major manipulation of sex differentiation in teleost is affected by sex steroids. In this context, the increasing contamination of aquatic ecosystems by estrogen-like compounds, commonly known as xenoestrogens, is of major concern. This often leads to deleterious effects on the reproductive success of fish and thereby adversely impacts aquatic biodiversity. In the present review, we have focused on impact of xenoestrogen at different levels of the reproductive system influencing not only gonadal differentiation in teleosts but also their reproductive functions. The review would also explore the mitigation strategies and regulations in place for aquatic xenoestrogen management. [ABSTRACT FROM AUTHOR]

It has been 25 years since the U.S. Congress passed the Food Quality Protection Act of 1996, an amendment to the Food Drug and Cosmetic Act, which mandated that the US Environmental Protection Agency (EPA) test all pesticide chemicals used in food for endocrine disruption. Soon after the law passed, EPA established the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to provide recommendations to the agency on how its Endocrine Disruptor Screening Program (EDSP) should work. Among them, the committee recommended that EDSP screening should 1) evaluate both human and ecological effects; 2) test for disruption of the estrogen, androgen, and thyroid systems; 3) evaluate pesticide and non-pesticide chemicals; and 4) implement a tiered approach. EPA adopted the recommendations and the EDSP was created in 1998. To date, the EPA has yet to fully implement the law; in other words, it has failed to test all pesticide chemicals for endocrine disruption. Of the small number that have been tested, not a single pesticide chemical has been determined to be an endocrine disruptor, and no regulatory actions have been taken. Here, we review the missed opportunities EPA had to make the EDSP a functional and effective program aimed at protecting human health and the environment. Two reports by the EPA’s Office of Inspector General from 2011 to 2021 provide the framework for our discussion.

Mammary stroma is a prominent modulator of epithelial development, and a complex set of interactions between these tissue compartments is essential for normal development, which can be either permissive or restrictive in tumor initiation and progression. During perinatal development, exposures of mice to oxybenzone, a common UV filter, environmental pollutant and endocrine disruptor, induce alterations in mammary epithelium. Our prior research indicates that oxybenzone alters mammary epithelial structures at puberty and in adulthood. We had also previously observed changes in the expression of hormone receptors at puberty (e.g., oxybenzone induced a decrease in the number of epithelial cells positive for progesterone receptor) and in adulthood (e.g., oxybenzone induced a decrease in the number of estrogen receptor-positive epithelial cells), and increased body weight in adulthood. Here, we investigated mammary stromal changes in BALB/c animals exposed during gestation and perinatal development to 0, 30, or 3000 μg oxybenzone/kg/day. In mice exposed to 30 μg/kg/day, we observed morphological changes in adulthood (e.g., a thicker periductal stroma and adipocytes that were considerably larger). We also observed an increased number of mast cells in the mammary stroma at puberty which may represent a transient influence of oxybenzone exposure. These results provide additional evidence that even low doses of oxybenzone can disrupt hormone sensitive outcomes in the mammary gland when exposures occur during critical windows of development, and some of these effects manifest in later life.

Studies suggested that exposure to air pollutants, with endocrine disrupting (ED) properties, have a key role in breast cancer (BC) development. Although the population is exposed simultaneously to a mixture of multiple pollutants and ED pollutants may act via common biological mechanisms leading to synergic effects, epidemiological studies generally evaluate the effect of each pollutant separately. We aimed to assess the complex effect of exposure to a mixture of four xenoestrogen air pollutants (benzo-[a]-pyrene (BaP), cadmium, dioxin (2,3,7,8-Tétrachlorodibenzo-p-dioxin TCDD)), and polychlorinated biphenyl 153 (PCB153)) on the risk of BC, using three recent statistical methods, namely weighted quantile sum (WQS), quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR). The study was conducted on 5222 cases and 5222 matched controls nested within the French prospective E3N cohort initiated in 1990. Annual average exposure estimates to the pollutants were assessed using a chemistry transport model, at the participants' residence address between 1990 and 2011. We found a positive association between the WQS index of the joint effect and the risk of overall BC (adjusted odds ratio (OR) = 1.10, 95% confidence intervals (CI): 1.03–1.19). Similar results were found for QGC (OR = 1.11, 95%CI: 1.03–1.19). Despite the association did not reach statistical significance in the BKMR model, we observed an increasing trend between the joint effect of the four pollutants and the risk of BC, when fixing other chemicals at their median concentrations. BaP, cadmium and PCB153 also showed positive trends in the multi-pollutant mixture, while dioxin showed a modest inverse trend. Despite we found a clear evidence of a positive association between the joint exposure to pollutants and BC risk only from WQS and QGC regression, we observed a similar suggestive trend using BKMR. This study makes a major contribution to the understanding of the joint effects of air pollution. [Display omitted] • We report the joint effect of four xenoestrogens on breast cancer risk. • Weighted quantile sum regression and g-computation show significant mixture effects. • A similar suggestive trend is observed with the Bayesian kernel machine regression. • Benzo [a]pyrene, cadmium and Polychlorinated biphenyl (153) dominate the effect. • Our study greatly improves the understanding of joint effects of air pollutants. [ABSTRACT FROM AUTHOR]

Xenoestrogens are natural or synthetic compounds that mimic the effect of endogenous estrogens and might cause cancer. We aimed to compare the global transcriptomic response to zearalenone (ZEA; mycotoxin) and bisphenol A (BPA; plastic additive) with the effect of physiological estradiol (E2) in the PEO1 human ovarian cell line by mRNA and microRNA sequencing. Estrogen exposure induced remarkable transcriptomic changes: 308, 288 and 63 genes were upregulated (log2FC > 1); 292, 260 and 45 genes were downregulated (log2FC < −1) in response to E2 (10 nM), ZEA (10 nM) and BPA (100 nM), respectively. Furthermore, the expression of 13, 11 and 10 miRNAs changed significantly (log2FC > 1, or log2FC < −1) after exposure to E2, ZEA and BPA, respectively. Functional enrichment analysis of the significantly differentially expressed genes and miRNAs revealed several pathways related to the regulation of cell proliferation and migration. The effect of E2 and ZEA was highly comparable: 407 genes were coregulated by these molecules. We could identify 83 genes that were regulated by all three treatments that might have a significant role in the estrogen response of ovarian cells. Furthermore, the downregulation of several miRNAs (miR-501-5p, let-7a-2-3p, miR-26a-2-3p, miR-197-5p and miR-582-3p) was confirmed by qPCR, which might support the proliferative effect of estrogens in ovarian cells.

Despite significant advances in understanding nephron segment patterning, many questions remain about the underlying genes and signaling pathways that orchestrate renal progenitor cell fate choices and regulate differentiation. In an effort to identify elusive regulators of nephron segmentation, our lab conducted a high-throughput drug screen using a bioactive chemical library and developing zebrafish, which are a conserved vertebrate model and particularly conducive to large-scale screening approaches. 17β-estradiol (E2), which is the dominant form of estrogen in vertebrates, was a particularly interesting hit from this screen. E2 has been extensively studied in the context of gonad development, but roles for E2 in nephron development were unknown. Here, we report that exogenous estrogen treatments affect distal tubule composition, namely, causing an increase in the distal early segment and a decrease in the neighboring distal late. These changes were noted early in development but were not due to changes in cell dynamics. Interestingly, exposure to the xenoestrogens ethinylestradiol and genistein yielded the same changes in distal segments. Further, upon treatment with an estrogen receptor 2 (Esr2) antagonist, PHTPP, we observed the opposite phenotypes. Similarly, genetic deficiency of the Esr2 analog, esr2b, revealed phenotypes consistent with that of PHTPP treatment. Inhibition of E2 signaling also resulted in decreased expression of essential distal transcription factors, irx3b and its target irx1a. These data suggest that estrogenic compounds are essential for distal segment fate during nephrogenesis in the zebrafish pronephros and expand our fundamental understanding of hormone function during kidney organogenesis.

Abstract Background An individual’s response to environmental exposures varies depending on their genotype, which has been termed the gene-environment interaction. The phenotype of cell exposed can also be a key determinant in the response to physiological cues, indicating that a cell-gene-environment interaction may exist. We investigated whether the cellular environment could alter the transcriptional response to environmental chemicals. Publicly available gene expression array data permitted a targeted comparison of the transcriptional response to a unique subclass of environmental chemicals that alter the activity of the estrogen receptor, xenoestrogens. Results Thirty xenoestrogens were included in the analysis, for which 426 human gene expression studies were identified. Comparisons were made for studies that met the predefined criteria for exposure length, concentration, and experimental replicates. The cellular response to the phytoestrogen genistein resulted in remarkably unique transcriptional profiles in breast, liver, and uterine cell-types. Analysis of gene regulatory networks and molecular pathways revealed that the cellular context mediated the activation or repression of functions important to cellular organization and survival, including opposing effects by genistein in breast vs. liver and uterine cell-types. When controlling for cell-type, xenoestrogens regulate unique gene networks and biological functions, despite belonging to the same class of environmental chemicals. Interestingly, the genetic sex of the cell-type also strongly influenced the transcriptional response to xenoestrogens in the liver, with only 22% of the genes significantly regulated by genistein common between male and female cells. Conclusions Our results demonstrate that the transcriptional response to environmental chemicals depends on a variety of factors, including the cellular context, the genetic sex of a cell, and the individual chemical. These findings highlight the importance of evaluating the impact of exposure across cell-types, as the effect is responsive to the cellular environment. These comparative genetic results support the concept of a cell-gene-environment interaction.

In this study, a biochar obtained from poplar wood gasification at a temperature of 850 °C was used to adsorb the xenoestrogens 4-tert-octylphenol (OP) and bisphenol A (BPA) and the herbicide metribuzin from water. Scanning electron microscopy (SEM-EDX) and Fourier-transform infrared (FTIR) spectroscopy were employed to investigate the surface micromorphology and functional groups composition of biochar, respectively. The study of sorption kinetics showed that all compounds achieved the steady state in less than 2 h, according to a pseudo-second order model, which denoted the formation of strong bonds (chemisorption) between biochar and the compounds. Adsorption isotherms data were described by the Henry, Freundlich, Langmuir and Temkin equations. At temperatures of 10 and 30 °C, the equilibrium data of the compounds were generally better described by the Freundlich model, although, in some cases, high correlation coefficients (r ≥ 0.98) were obtained for more than one model. Freundlich constants, KF, for OP, BPA and metribuzin were, respectively, 218, 138 and 4 L g−1 at 10 °C and 295, 243 and 225 L g−1 at 30 °C, indicating a general increase of adsorption at higher temperature. Desorption of all compounds, especially OP and BPA, from biochar was slow and very scarce, denoting an irreversible and hysteretic process. Comparing the results of this study with those reported in the literature, we can conclude that the present biochar has a surprising ability to retain organic compounds almost permanently, thus behaving as an excellent low-cost biosorbent.

Background: Chronic kidney disease (CKD) is a growing concern worldwide. Exposure to xenoestrogens (XEs), such as phthalates, parabens, and phenols, lead to CKD. However, kidney function and its complex relationship with XEs, lifestyle, and dietary habits are not well understood. Methods: In the present cross-sectional community-based cohort study, we enrolled 887 subjects for a questionnaire-based interview and laboratory tests. XE exposure concerning lifestyle/dietary habits were evaluated using questionnaires. Urinary levels of 17XE metabolites were measured in 60 subjects with high exposure risk scores and 60 subjects with low exposure risk scores. Results: Univariate and multivariate linear regression showed that a high exposure score (β ± SE: 4.226 ± 1.830, P = 0.021) was independently negatively associated with eGFR in 887 subjects. Univariate and multivariate linear regression to urinary XEs and urine albumin creatinine excretion ratio (UACR) in 120 subjects indicated that ethylparaben (EP) (β: 1.934, 95% CI: 0.135–3.733, P = 0.035) was significantly associated with increased UACR. Multivariate regression analyses of the CKD subgroup (n = 38), after adjusting for age, showed that higher levels of mono-(2-ethylhexyl) phthalate (MEHP), EP, nonylphenol (NP), and benzophenone-3 (BP-3) were significantly associated with lower estimated glomerular filtration rate (eGFR). Higher urinary levels of MEHP (OR: 3.037, 95% CI: 1.274–7.241) were more likely associated with high exposure scores (>5 points), after adjusting for diabetes, gender, eGFR, age, Na, Ca, albumin, vitamin D, systolic blood pressure (SBP), white blood cell count, total bilirubin, aspartate transaminase, and heart rate. MEHP (β ± SE: 0.033 ± 0.009, P

Some prenylated polyphenols originating from hops, which are thus natural constituents of beer, have been discussed critically for their agonistic potential toward estrogen receptors. So far, little attention has been attributed to the fact that humans are typically not exposed to isolated compounds, but to mixtures which for example might comprise in addition to hop flavonoids further xenoestrogens, e.g., certain pesticides used for plant protection of hops and barley. Thus, we used the alkaline phosphatase assay to assess combinatory estrogenic effects of three signature compounds – xanthohumol, 8-prenylnaringenin and iso-xanthohumol–on Ishikawa cells in a combination that resembled the concentration ratios observable in beer. Moreover, we added this natural flavonoid pattern to a mixture of representative estrogenic pesticides to assess their combined effects. Using state-of-the-art statistical tools, we observed cumulative to slightly synergistic effects between isolated flavonoids as well as the flavonoid and the pesticide mixture. Of potential importance, these effects were found at low nanomolar hop polyphenol concentrations that one can reasonably expect to occur in vivo after the consumption of strongly hopped beer. Taken together, our results imply that cumulative/synergistic estrogenicity should be explored in detail and urgently be incorporated into risk assessment of prenylated chalcones.

The mammary gland is a hormone sensitive organ that is susceptible to endocrine-disrupting chemicals (EDCs) during the vulnerable periods of parous reorganization (ie, pregnancy, lactation, and involution). Pregnancy is believed to have long-term protective effects against breast cancer development; however, it is unknown if EDCs can alter this effect. We examined the long-term effects of propylparaben, a common preservative used in personal care products and foods, with estrogenic properties, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 20, 100, or 10 000 µg/kg/day propylparaben throughout pregnancy and lactation. Unexposed nulliparous females were also evaluated. Five weeks post-involution, mammary glands were collected and assessed for changes in histomorphology, hormone receptor expression, immune cell number, and gene expression. For several parameters of mammary gland morphology, propylparaben reduced the effects of parity. Propylparaben also increased proliferation, but not stem cell number, and induced modest alterations to expression of ERα-mediated genes. Finally, propylparaben altered the effect of parity on the number of several immune cell types in the mammary gland. These results suggest that propylparaben, at levels relevant to human exposure, can interfere with the effects of parity on the mouse mammary gland and induce long-term alterations to mammary gland structure. Future studies should address if propylparaben exposures negate the protective effects of pregnancy on mammary cancer development. [ABSTRACT FROM AUTHOR]

The multifactorial etiology of autoimmune diseases has been studied at large. Genetic risk factors and environmental agents play an integral role in the pathogenesis of autoimmune processes. In recent decades, Bisphenol A (BPA), an exogenous compound found in polycarbonate plastic, has gained attention for its harmful multifocal effects on a diverse subset of systemic pathways, potentially contributing to disease onset and exacerbation. BPA is a xenoestrogen used globally in the manufacture of daily use products including plastic storage containers, water and infant bottles, and food and drink packaging. BPA exhibits immune stimulatory activity bringing into question the association between its greater global presence and the increased prevalence of autoimmune diseases. The purpose of this multi-study analysis is to assess recent research investigating the underlying role of BPA in autoreactive mechanisms. Although research at present does not directly link BPA exposure to the development of autoimmune diseases, a large body of evidence supports the pro-inflammatory effects of BPA on the immune system. Further studies are required to elucidate the role of BPA in autoimmune pathogenesis, however caution should be taken in the use of BPA containing products by those affected or genetically susceptible to developing autoimmune diseases.

Background: An individual's response to environmental exposures varies depending on their genotype, which has been termed the gene-environment interaction. The phenotype of cell exposed can also be a key determinant in the response to physiological cues, indicating that a cell-gene-environment interaction may exist. We investigated whether the cellular environment could alter the transcriptional response to environmental chemicals. Publicly available gene expression array data permitted a targeted comparison of the transcriptional response to a unique subclass of environmental chemicals that alter the activity of the estrogen receptor, xenoestrogens. Results: Thirty xenoestrogens were included in the analysis, for which 426 human gene expression studies were identified. Comparisons were made for studies that met the predefined criteria for exposure length, concentration, and experimental replicates. The cellular response to the phytoestrogen genistein resulted in remarkably unique transcriptional profiles in breast, liver, and uterine cell-types. Analysis of gene regulatory networks and molecular pathways revealed that the cellular context mediated the activation or repression of functions important to cellular organization and survival, including opposing effects by genistein in breast vs. liver and uterine cell-types. When controlling for cell-type, xenoestrogens regulate unique gene networks and biological functions, despite belonging to the same class of environmental chemicals. Interestingly, the genetic sex of the cell-type also strongly influenced the transcriptional response to xenoestrogens in the liver, with only 22% of the genes significantly regulated by genistein common between male and female cells. Conclusions: Our results demonstrate that the transcriptional response to environmental chemicals depends on a variety of factors, including the cellular context, the genetic sex of a cell, and the individual chemical. These findings highlight the importance of evaluating the impact of exposure across cell-types, as the effect is responsive to the cellular environment. These comparative genetic results support the concept of a cell-gene-environment interaction. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a typical environmental endocrine disruptor that exhibits estrogen-mimicking, hormone-like properties and can cause the collapse of bone homeostasis by an imbalance between osteoblasts and osteoclasts. Various BPA substitutes, structurally similar to BPA, have been used to manufacture ‘BPA-free’ products; however, the regulatory role of BPA alternatives in osteoclast differentiation still remains unelucidated. This study aimed to investigate the effects of these chemicals on osteoclast differentiation using the mouse osteoclast precursor cell line RAW 264.7. Results confirmed that both BPA and its alternatives, bisphenol F and tetramethyl bisphenol F (TMBPF), were nontoxic to RAW 264.7 cells. In particular, tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cell staining and activity calculation assays revealed that TMBPF enhanced osteoclast differentiation upon stimulation of the receptor activator of nuclear factor-kappa B ligand (RANKL). Additionally, TMBPF activated the mRNA expression of osteoclast-related target genes, such as the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CtsK). Western blotting analysis indicated activation of the mitogen-activated protein kinase signaling pathway, including phosphorylation of c-Jun N-terminal kinase and p38. Together, the results suggest that TMBPF enhances osteoclast differentiation, and it is critical for bone homeostasis and skeletal health.

Ethinyl estradiol (EE) is a synthetic estrogen used in pharmaceutical contraceptives. In many studies evaluating estrogenic endocrine disruptors, EE is used as a positive control for estrogenicity. However, the effects of EE often differ from the effects of other xenoestrogens, suggesting that these other compounds might act via distinct mechanisms. Reported here are data describing the effect of low doses of EE during pregnancy and lactation on the morphology of the lactating mammary gland in CD-1 mice. The data suggest that these low doses have few if any discernable effects on mammary gland morphology. Alterations to cell proliferation and the expression of estrogen receptor (ER)α were also not observed. These companion data were collected from the same females analyzed for effects of EE on maternal behavior and brain recently published in Reproductive Toxicology (Catanese & Vandenberg, 2017).

Xenoestrogens (XEs) are substances that imitate endogenous estrogens to affect the physiologic functions of humans or other animals. As endocrine disruptors, they can be either synthetic or natural chemical compounds derived from diet, pesticides, cosmetics, plastics, plants, industrial byproducts, metals, and medications. By mimicking the chemical structure that is naturally occurring estrogen compounds, synthetic XEs, such as polychlorinated biphenyls (PCBs), bisphenol A (BPA), and diethylstilbestrol (DES), are considered the focus of a group of exogenous chemical. On the other hand, nature phytoestrogens in soybeans can also serve as XEs to exert estrogenic activities. In contrast, some XEs are not similar to estrogens in structure and can affect the physiologic functions in ways other than ER-ERE ligand routes. Studies have confirmed that even the weakly active compounds could interfere with the hormonal balance with persistency or high concentrations of XEs, thus possibly being associated with the occurrence of the reproductive tract or neuroendocrine disorders and congenital malformations. However, XEs are most likely to exert tissue-specific and non-genomic actions when estrogen concentrations are relatively low. Current research has reported that there is not only one factor affected by XEs, but opposite directions are also found on several occasions, or even different components stem from the identical endocrine pathway; thus, it is more challenging and unpredictable of the physical health. This review provides a summary of the identification, detection, metabolism, and action of XEs. However, many details of the underlying mechanisms remain unknown and warrant further investigation.

Highlights • NP and E2 exposure and sex specific increase in expression of ERs in goldfish macrophages. • Effect of NP on expression of ERs was different in in vitro and in vivo. • Stimulating apoptosis in the macrophages by NP and E2 were dose depend manner and sex specific. Abstract The expression of estrogen receptors (ERs) and their roles in important cell processes such as apoptosis in the macrophages exposed to estrogen/xenoestrogen have remained a complex secret. This study focused on the expression of estrogen receptors (ERs) and the stimulation of apoptosis in the macrophages from the two sexes of goldfish (Carassius auratus) exposed to 17-βestradiol (E2) and nonylphenol (NP) under in vivo and in vitro conditions. For the in vivo experiment, fish were exposed to NP (10−6 M and 10−7 M) and E2 (10−6 M) for 24 days. Then, the head kidney macrophages from the male and the female goldfish were isolated and assayed. For the in vitro experiments, the macrophages derived from the two sexes were cultured in L-15 medium and exposed to E2 (150 nM) and NP (10 nM and 150 nM) for 3 days. The results showed that the three isoforms of ERs (ERα, ERβ 1 , ERβ 2) were expressed in the goldfish macrophages. After the exposure of macrophages to NP and E2, sex-specific increase of ERs expression and apoptosis were observed (P < 0.05). The expression of ERα after NP treatment showed the highest alteration, with the response being concentration-dependent. The most alteration of ERs expression were observed in the in vivo experiment. This study provides insight to understand how exposure of the goldfish macrophages to E2 and NP can up-regulate the transcript levels of estrogen receptor subtypes and stimulate apoptosis. [ABSTRACT FROM AUTHOR]

Abstract Endocrine disrupting compounds (EDCs) are becoming an increasing concern regarding bioaccumulation in aquatic biota. However, the effects of regional pollution levels and specific feeding habits on the bioaccumulation of EDCs in fish are rarely reported. 4-Nonylphenol (4-NP), bisphenol A (BPA), 4-tert-octylphenol (4-t-OP), triclocarban (TCC) and triclosan (TCS) were determined in abiotic compartments [water, sediment, suspended particulate matter (SPM)] and fish with different feeding habits along the Pearl River, China. EDCs in abiotic compartments exhibited significant (p < 0.05) spatial variations, forming five zones clustered based on site-specific EDC concentrations. 4-NP was the dominant compound, contributing 58–98% of the EDCs in fish, followed by BPA (<41%), 4-t-OP (<13%), and TCC and TCS (<4.7%). The concentrations of 4-NP and 4-t-OP, BPA, and TCC and TCS were the highest in brackish carnivorous, planktivorous, and detritivorous fish, respectively. The bioaccumulation factors (BAFs) showed that 4-NP accumulated (BAF > 5000) in all fish except for suck-feeding detritivores, while 4-t-OP and TCC accumulated in filter-feeding planktivores. The concentration of 4-NP in carnivores was significantly higher than that in detritivores, indicating the potential biomagnification of 4-NP along food chains. EDCs in sediment and SPM and those in water were most positively correlated with those in detritivores and planktivores, respectively, suggesting the potential of fish with these two feeding habits to act as bioindicators of EDC pollutants. Graphical abstract Image 1 Highlights • Endocrine disrupting compounds (EDCs) in fish varied greatly across spatial zones. • EDCs in fish followed 4-nonylphenol > bisphenol A >4-tert-octylphenol > two biocides. • Xenoestrogen in carnivores/planktivores and biocide in detritivores accumulated most. • 4-Nonylphenol with bioaccumulation factors > 5000 in fish exhibited biomagnification. • EDCs in detritivores and planktivores could indicate those in environmental media. Endocrine disrupting compounds in fish varied significantly across feeding habits and spatial zones, with the greatest 4-nonylphenol accumulation in brackish carnivores near the Pearl River Estuary. [ABSTRACT FROM AUTHOR]

Optimal manure treatment aimed at usage as agricultural soil fertilizers is a prerequisite ecological pollution control strategy. In this work, livestock manure-based fertilizers were collected from 71 animal farms across 14 provinces in China. The contamination levels and potential ecotoxicological risks of residual steroid estrogens (SEs): estrone (E1), estriol (E3), 17α-estradiol (17α-E2), 17β-estradiol (17β-E2) and xenoestrogen (XE) bisphenol A (BPA), were investigated. The results showed that the occurrence frequencies for SEs and XE ranged from 66.67% to 100%, and the mean concentration varied considerably across the study locations. The total content of SEs and XE in Hebei province was the highest, and swine manure-based fertilizers concentrations were higher than the levels reported in other animal fertilizers. Compared with farm level manure, manure-based fertilizers are processed by composting, and the micropollutants quantities are significantly reduced (mean: 87.65 – 534.02 μg/kg). The total estradiol equivalent quantity (EEQ) that might migrate to the soil was estimated to be 1.23 μg/kg. Based on the estimated application rate of manure, 38% of the fertilizers risk quotients exceeded 0.1, indicating medium to high risks pressure on terrestrial organisms. Nonetheless, the estrogenic risk was lower in manure-based fertilizers than in manure. This study highlights the significance of proper treatment of livestock manure and designing an optimal manure fertilization strategy to mitigate the risks posed by SEs and XEs to the agroecosystems. [Display omitted] • SEs and XE were widely detected in manure-based fertilizers across China. • 17β-estradiol was the dominant steroid estrogens in manure-based fertilizers. • SEs and XE levels decreased in manure-based fertilizers by manure composting process. • SEs/XE have lower risk in manure-based fertilizers than in manure for ecological environment. [ABSTRACT FROM AUTHOR]

Exposure to the xenoestrogen nonylphenol (NP) during critical windows of development leads to metabolic abnormalities in adult life. However, less is known about NP exposure outside the developmental period on metabolic outcomes. We investigated the effect of prolonged exposure to NP after sexual maturity and at environmentally relevant concentrations below the 'no observable adverse effects level' (0.5 and 2.5 mg/kg/d). Male Swiss mice fed a normal-fat diet exposed to 2.5 mg/kg/d NP showed reduced weight gain and hepatic fat content. In male and female C57BL/6 mice fed a high-fat diet, NP exposure modified the mRNA levels of estrogen receptor α (Esr1) and adipose lineage markers in a sexually dimorphic and adipose depot-dependent pattern. Moreover, in primary female but not male stromal vascular cells from C57BL/6 mouse inguinal WAT induced to differentiate into adipocytes, NP upregulated Fabp4 expression. Low-level exposure to NP outside critical developmental windows may affect the metabolic phenotype distinctly. All data not included in the manuscript, such as raw results, are available upon request and should be addressed to AAA. • Exposure to nonylphenol reduces weight and hepatic fat in male Swiss mice. • Exposure to nonylphenol modifies adipose tissue gene expression in C57BL/6 mice. • Nonylphenol modifies adipose tissue gene expression in a sexually dimorphic fashion. • NP has adipogenic action on primary female but not male cells from C57BL/6 mice. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) and zearalenone (ZEA) are two widespread xenoestrogens involved in male reproductive disorders. Few studies investigated the effects of these compounds on the prepubertal testis, which is highly sensitive to endocrine disruptors such as xenoestrogens. An ex vivo approach was performed to evaluate the effects of BPA or ZEA (10−11, 10−9, 10−6 M) on the testes of 20 and 25 d pp rats. To investigate the involvement of classical nuclear ER-mediated estrogen signaling in these effects, pre-incubation with an antagonist (ICI 182.780 10−6 M) was performed. BPA and ZEA have similar effects on spermatogenesis- and steroidogenesis-related endpoints in the immature testis, but our study highlights different age-dependent patterns of sensitivity to each compound during the prepubertal period. Moreover, our results indicate that the effects of BPA are likely to be induced by nuclear ER, whereas those of ZEA appear to involve other mechanisms. • BPA and ZEA disrupt steroidogenesis and spermatogenesis in prepubertal rat testes. • BPA and ZEA exhibit different age-related patterns of disruption within this period. • BPA's effects in prepubertal rat testes seem to involve the nuclear ER. • ZEA's effects in prepubertal rat testes seem to involve alternative mechanisms. • The prepubertal stage constitutes a critical window of sensitivity to BPA and ZEA. [ABSTRACT FROM AUTHOR]

Aims of the study: Endometriosis is a prevalent gynecologic disorder in young women at reproductive age but the underlying risk factors have not identified yet in Iran and other neighboring countries. Persistent exposure to environmental endocrine disrupting chemicals (EDCs) in particular dioxins, PAHs and polychlorinated biphenyls (PCBs) with xenoestrogenic potentials have been hypothesized in the etiopathogenesis of endometriosis .We aimed in the present study to investigate the joint effects of endogenous and exogenous sources of estrogens on the incidence of endometriosis in Iranian women who born and lived in Tehran .Methods: The age matched study population consisted of 34 women with endometriosis and 100 healthy women who underwent surgery from March 2009 to March 2012 . Results: Out of evaluated exogenous sources of estrogen exposure, living near xenoestrogen producing factories (p

The Fusarium toxin zearalenone (ZEN) and its reductive metabolite α-zearalenol (α-ZEL) are well-documented endocrine disruptors that are frequently found to contaminate cereal products, including beer. But also hop is known to represent a source for endocrine active compounds, containing amongst others xanthohumol (XAN), which might be converted to the potent phytoestrogen 8-prenylnaringenin (8-PN). In the present study, we investigated the interaction of these xenoestrogens in mixtures which might occur in beer. Estrogenicity was measured as induction of alkaline phosphatase (AlP) expression in estrogen-sensitive Ishikawa cells. In binary combinations, XAN was found to act as a potent antagonist of mycotoxin-induced estrogenicity, significantly suppressing the AlP-inducing impact of both ZEN and α-ZEL at nanomolar concentrations. Also 8-PN antagonized the estrogenic stimulus of the two fungal metabolites, although less pronounced. These effects also manifested in combinations of three or four test compounds, and at the level of cell proliferation, that was assessed via an E-screen-like approach in Ishikawa cells. Of note, co-exposure to the investigated myco- and phyto-estrogens did not result in additive or overadditive/synergistic estrogenic effects in the applied test system. Being aware that the actual study is still limited to the in vitro situation, our results even suggest that prenylated chalkones from hops might protect against Fusarium toxin–induced endocrine disruptive activities at concentrations that can be reached by moderate beer consumption.

Background: The neurochemistry of hepatic nerve fibres was investigated in large animal models after dietary exposure to the endocrine disrupting compound known as bisphenol A (BPA).Materials and Methods: Antibodies against neuronal peptides were used to study changes in hepatic nerve fibres after exposure to BPA at varying concentrations using standard immunofluorescence techniques. The neuropeptides investigated were substance P (SP), galanin (GAL), pituitary adenylate cyclase activating polypeptide (PACAP), calcitonin gene regulated peptide (CGRP) and cocaine and amphetamine regulated transcript (CART). Immunoreactive nerve fibres were counted in multiple sections of the liver and among multiple animals at varying exposure levels. The data was pooled and presented as mean ± standard error of the mean.Results: It was found that all of the nerve fibres investigated showed upregulation of these neural markers after BPA exposure, even at exposure levels currently considered to be safe. These results show very dramatic increases in nerve fibres containing the above-mentioned neuropeptides and the altered neurochemical levels may be causing a range of pathophysiological states if the trend of over-expression is extrapolated to developing humans.Conclusions: This may have serious implications for children and young adults who are exposed to this very common plastic polymer, if the same trends are occurring in humans. [ABSTRACT FROM AUTHOR]

The apparent increase in hormone-induced cancers and disorders of the reproductive tract has led to a growing demand for new technologies capable of screening xenoestrogens. We reported an estrogen receptor (ER)-based reusable fiber biosensor for facile screening estrogenic compounds in environment. The bioassay is based on the competition of xenoestrogens with 17β-estradiol (E 2 ) for binding to the recombinant receptor of human estrogen receptor α (hERα) protein, leaving E 2 free to bind to fluorophore-labeled anti–E 2 monoclonal antibody. Unbound anti–E 2 antibody then binds to the immobilized E 2 –protein conjugate on the fiber surface, and is detected by fluorescence emission induced by evanescent field. As expected, the stronger estrogenic activity of xenoestrogen would result in the weaker fluorescent signal. Three estrogen-agonist compounds, diethylstilbestrol (DES), 4-n-nonylphenol (NP) and 4-n-octylphenol (OP), were chosen as a paradigm for validation of this assay. The rank order of estrogenic potency determined by this biosensor was DES>OP>NP, which were consistent with the published results in numerous studies. Moreover, the E 2 –protein conjugate modified optical fiber was robust enough for over 300 sensing cycles with the signal recoveries ranging from 90% to 100%. In conclusion, the biosensor is reusable, reliable, portable and amenable to on-line operation, providing a facile, efficient and economical alternative to screen potential xenoestrogens in environment. [ABSTRACT FROM AUTHOR]

Many environmental matrices contaminated with organic pollutants derived from crude oil or degraded petroleum contain mixtures so complex that they are typically unresolved by conventional analytical techniques such as gas chromatography. The resulting chromatographic features have become known as ‘humps’ or unresolved complex mixtures (UCMs). These UCMs often dominate the organic contaminants of polluted environmental samples: for example, in oil sands produced water up to 150 mg L −1 of ‘naphthenic acids’ appear as UCMs when examined by gas chromatography as the esters. In oil-contaminated mussels, aromatic hydrocarbon UCMs may comprise almost all of the total toxic hydrocarbons, with over 7000 μg g −1 dry weight reported in some samples. Over the last 25 years, efforts to resolve and thus identify, or at least to produce average structures, for some UCM components, have proved fruitful. Numerous non-polar UCM hydrocarbons and more polar UCM acids have been identified, then synthesised or purchased from commercial suppliers. As UCMs have been proposed to represent a risk to aquatic organisms, the need for assessment of the ecotoxicological effects and characterisation of the mode of action (MoA) of these environmental pollutants has arisen. In the present study, several chemicals with structures typical of those found in some UCMs, were assessed for their potential to disrupt membrane integrity, inhibit metabolic activity, activate the aryl hydrocarbon receptor (AhR), and activate the estrogen receptor (ER) in primary rainbow trout hepatocytes ( Oncorhynchus mykiss ). These endpoints were determined in order to screen for common toxic modes of action (MoA) in this diverse group of chemicals. The results from the in vitro screening indicated that of the endpoints tested, the predominant toxic MoA was cytotoxicity. EC 50 values for cytotoxicity were obtained for 16 compounds and ranged from 77 μM–24 mM, whereof aliphatic monocyclic acids, monoaromatic acids, polycyclic monoaromatic acids and alkylnaphthalenes were the most toxic. The observed cytotoxicity of the chemicals correlated well with the hydrophobicity (LogK OW ) suggesting that the toxicity was predominantly due to a non-specific MoA. Interestingly, two compounds induced the ER-mediated production of vitellogenin (Vtg) and six compounds induced the AhR-mediated Ethoxyresorufin-O-deethylase (EROD) enzymatic activity to >20% of the positive control; by doing so suggesting that they may act as ER or AhR agonists in fish. The heterogeneous group of ‘UCM compounds’ tested exhibited multiple MoA that may potentially cause adverse effects in fish. Additional studies to determine if these compounds may cause adverse effects in vivo at environmentally relevant concentrations, are warranted to identify if such compounds are indeed of potential environmental concern. [ABSTRACT FROM AUTHOR]

Sex hormone levels and timing of sexual maturation are considered important markers for health status of adolescents in puberty, and previous research suggests they might be influenced by metal exposure. In three campaigns of the Flemish Environment and Health Study (FLEHS I 2002–2006; FLEHS II 2007–2011 and FLEHS III 2012–2015), data were collected on internal exposure to metals (Cd, Cu, Pb, Cr, Mn, Tl, Ni, Sb, Hg, As and As species) and sexual maturation in 2671 14–15 years old adolescents. All metals were measured in blood and/or urine, except total- and methylmercury which were measured in hair samples. Sex hormone levels were measured in blood serum of adolescent males of the cohorts of FLEHS I and FLESH II. The use of a uniform methodology in successive campaigns allows to confirm associations between exposure and health in different cohorts and over time. Furthermore, mathematical and statistical density correction methods using creatinine or specific gravity were tested for urinary markers. Significant associations between sex hormones and maturity markers were observed in the FLEHS I and II campaigns, when both were assessed together. Regardless of the applied correction method, creatinine correction systematically introduced bias due to associations of creatinine with sex hormones and maturation markers, especially in adolescent males, while this is not the case for specific gravity. A series of exposure-response associations were found, but several involving Cd, Pb, As, Tl and Cu persisted in different FLEHS campaigns. The effects of Pb and Cu on luteinizing hormone, (free) testosterone, (free) oestradiol and maturation support a xenoestrogenic agonistic action on the feedback of oestradiol to the hypothalamus-pituitary-gonadal axis. Our results suggest that specific care should be taken when selecting urine density correction for investigating associations with hormonal and maturation markers in adolescent males. Furthermore, the possibility of xenoestrogenic effects of certain metals in environmentally exposed adolescents warrants further investigation. [ABSTRACT FROM AUTHOR]

Abstract Environmental change can increase the likelihood of interspecific hybridization by altering properties of mate recognition and discrimination between sympatric congeners. We examined how exposure to an environmentally widespread endocrine‐disrupting chemical (EDC), bisphenol A (BPA), affected visual communication signals and behavioral isolation between an introduced freshwater fish and a native congener (genus: Cyprinella). Exposure to BPA induced changes in the expression of male secondary traits as well as male and female mate choice, leading to an overall reduction in prezygotic isolation between congeners. Changes in female mate discrimination were not tightly linked to changes in male phenotypic traits, suggesting that EDC exposure may alter female choice thresholds independently of the effects of exposure on males. These findings indicate that environmental exposure to EDCs can lead to population declines via the erosion of species boundaries and by promoting the establishment and spread of non‐native species via hybridization.

OBJECTIVES: We investigated the association between occupational exposure to endocrine-disrupting chemicals (EDC) and the risk of uveal melanoma using international data of a case–control study from nine European countries. METHODS: After exclusion of proxy interviews, 280 cases and 3084 control subjects were included in the final analysis. Information on possible exposure to EDC was derived from 27 job-specific questionnaires (JSQ), which solicited detailed questions on occupational tasks. Relative risk estimates were based on the JSQ and potential exposure to a group of endocrine-disrupting agents. We constructed several exposure scores, taking into account intensity of exposure, use of personal protective equipment, and exposure duration. We calculated unconditional logistic regression analyses, adjusting for country, age, sex, eye color and a history of ocular damage due to intense ultraviolet (UV) exposure. RESULTS: The overall exposure prevalence to EDC was low reaching a maximum of 11% for heavy metals with endocrine-disrupting properties. Although working in some industries was associated with increased melanoma risk [such as dry cleaning: odds ratio (OR) 6.15, 95% confidence interval (95% CI) 2.0–18.96 and working in the glass manufacturing industry: OR 3.49, 95% CI 1.10–11.10], agent-specific risks were not elevated. The strongest possible risk increase was observed for organic solvents with endocrine-disrupting properties (OR 1.31, 95% CI 0.78–2.21). Calculation of exposure scores did not indicate consistently elevated results with higher score values. Sensitivity analyses did not alter these results. CONCLUSION: Occupational exposure to EDC was not associated with an increased risk for uveal melanoma.