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Fish, first jawed vertebrate group appearing in evolution, have immune system similar to those of mammals. These early animals' innate and adaptive immune systems are completely developed, having head kidney and thymus as primary, spleen and mucosa associated lymphoid tissue as secondary immune organs. The adaptive immunity performs key role in defence against recurring infections and elimination of fish pathogens with the help of its memory cells, T‐cell‐receptors and immunoglobulins. Epidermal secretions including antibacterial peptides, lysozymes, lectins, complement and C‐reactive proteins which function in disruption of antigens, phagocytosis, inflammatory response and mending of tissue injury play a significant role as elements of fish immune system. Fish, however, have greater innate immunity than humans do. Estrogens play crucial role in immunomodulation through nuclear oestrogen receptors, which are found in majority of immune cells and lymphoid organs in fish. There is mounting proof that xenoestrogens, that can attach as agonists to oestrogen receptors, pose significant ecotoxicological risk by disrupting the defence mechanism in fish. Though less potent than natural oestrogen, they can bioaccumulate to finally reach a substantial dose. This review's objective is to give an overview of the fish defence system, its estrogenic regulation and estrogenic‐endocrine disruption. [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. [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]

The mammary gland is responsive to endogenous hormones and environmental chemicals that are estrogen receptor (ER) agonists. The mouse mammary gland offers the opportunity to dissect the most sensitive windows of exposure. 17α-ethinyl estradiol (EE2) is a pharmaceutical ER agonist that often serves as a positive control for estrogen-active chemicals. Here, adult female mice were exposed to EE2 starting either at pregnancy day 7, or on lactational day 1, and exposures continued until the litters were weaned. The pups were therefore exposed during gestation + the juvenile period, or during the juvenile period alone. The morphology of the mammary gland was evaluated in both male and female offspring at two life stages: weaning (postnatal day [PND]21) and at puberty (PND32). Other hormone-sensitive outcomes evaluated included body weight, anogenital index, frequency of open vagina, and weight of the uterus. We found age- and sex-dependent effects of EE2 on these estrogen-responsive endpoints including the morphology of the mammary gland. Importantly, EE2 altered mammary gland morphology even when exposures were limited to the juvenile period. However, the number of endpoints that were affected in animals from the EE2-Juvenile-Only period were fewer, and typically of a lower magnitude, compared to those observed in the EE2-Gest-Juvenile group. Understanding the effects of environmental estrogen exposures during the juvenile period is critical because humans are exposed to estrogenic pollutants throughout life, including in early childhood., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laura N. Vandenberg reports financial support was provided by SUDOC, LLC. Joshua P. Mogus reports financial support was provided by UMass Amherst School of Public Health & Health Sciences. Additional support was provided by the National Institutes of Health. Laura N. Vandenberg reports a relationship with Sudoc LLC that includes: consulting or advisory. LNV serves on the editorial board of Reproductive Toxicology. The other authors do not have conflicts to disclose., (Copyright © 2024. Published by Elsevier Inc.)

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.

Bisphenol A (BPA) is the main ingredient of plastic materials that are the most used in the world and can cause environmental problems as a result of anthropogenic effects. It is adversely effect on organisms, especially in the degradation of the endocrine system. This study focused on short-term exposure of different BPA concentrations on two fish species (Onchorhynchus mykiss and Vimba vimba). The study configuration was prepared as a 96-h exposure design in BPA aquariums according to concentrations of 500, 1000, and 1500 μg/L. The results showed that turbidity, one of the water quality parameters, was significantly higher in BPA groups than in the control group (p<0.05). In addition, while turbidity showed an increasing trend with increasing time in the BPA group, it did not show any change for the control group. Deteriorations in fish behaviors observed such as loss of balance and high mucus secretion in BPA groups. Hematological results showed that WBC, RBC, HGB, and HCT values in O. mykiss were significantly higher in 1000 and 1500 μg/L BPA groups compared to the control (p<0.01). On the contrary, hematological parameters in V. vimba BPA groups showed similar or lower values compared to control. The current study revealed that fish in the culture environment may be adversely affected physiologically and behaviorally by BPA exposure. [ABSTRACT FROM AUTHOR]

Due to the prevalence of hypertension (one of the major risk factors of CVD) in the population, it is necessary to explore the adverse effects of daily tolerable and "safe" dose of bisphenol A (BPA) under hypertensive conditions. The current study exposed the Nω-nitro-l-arginine methyl ester (L-NAME, 40 mg/kg b.w/day) induced hypertensive Wistar rats to BPA (50 μg/kg b.w/day) by oral administration along with appropriate controls for 30 days period. The results illustrate that a 'safe' dose of BPA does not influence the systolic blood pressure (SBP) and levels of circulatory biomarkers of tissue damage. On the other hand, BPA exposure significantly (p < 0.05) elevates the thiobarbituric acid reactive substances (TBARS) content in plasma and tissues (heart, aorta, liver and kidney) in hypertensive rats when compared with respective control (BPA alone exposed) rats. Similarly, a significant modulation of ROS generation in RBC, plasma nitric oxide (NO) level and angiotensin-converting enzyme (ACE) activity was observed only under hypertensive milieu. In conclusion, the observed adverse effects during 'safe' dose of BPA exposure are specific to the hypertensive condition. Therefore, a precise investigation to explore the effects of BPA exposure in vulnerable hypertensive populations is highly suggested. [ABSTRACT FROM AUTHOR]

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.

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In the last decades, oestrogenic compounds have often been reported in environmentally relevant concentrations in aquatic environments around the world. Most laboratory studies of oestrogens try to understand the effects of a single contaminant, but in natural environments, the effects may be quite different due to interactions with other compounds. The present study aimed to compare the action of oestrone (E1) and bisphenol-A (BPA), acting singularly and in combination, on the spermatogenesis of Astyanax bimaculatus. After exposure to 100 ng/L of E1, BPA and a mixture of the two for 15 days, our results showed that E1 and the E1 + BPA mixture significantly altered the number of spermatogenic cells. BPA presented high cytotoxicity when compared to other treatments. Analysis of the two oestrogenic compounds suggests that the E1 + BPA mixture has no additive or synergistic effects. Together, the results of the present study indicate that endocrine-disrupting chemicals (EDCs) analysed alone may behave differently than when administered with other substances. [ABSTRACT FROM AUTHOR]

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.

Many chemicals released into the environment are believed to disrupt normal endocrine functions in humans and animals. A major group of endocrine disrupting chemicals (EDCs) that could be responsible for reproductive defects are those that mimic natural oestrogens, known as xenoestrogens. A number of in vivo and in vitro screening strategies are being developed to identify and classify xenoestrogens, in order to determine whether they pose a health risk to humans and animals. Oestrogens and androgens mediate their activity via intracellular receptors, directly in muscular tissue, as well as indirectly via stimulation of growth hormones from the pituitary glands and other growth factors from liver plus several other organs. Mancozeb is a metal ethylenebisdithiocarbamate (EBDC) fungicide used to protect many fruits and vegetables and field crops against pathogenic fungal. The T47D-KBluc, GH3.TRE-Luc and MDA-kb2 reporter gene assays were used to determine the possible endocrine disrupting activity/potential of mancozeb. No activity was detected in any of the assays and no mancozeb was detected in any of the dams either. Oestrogenic activity was detected in Albasini Dam, Nandoni Dam and Xikundu weir, but all values were below 0.7 ng l−1 trigger value for oestrogenic activity in drinking water. [ABSTRACT FROM AUTHOR]

Endogenous oestrogens regulate essential functions to include menstrual cycles, energy balance, adipose tissue distribution, pancreatic β -cell function, insulin sensitivity and lipid homeostasis. Oestrogens are a family of hormones which include oestradiol (E2), oestrone (E1) and oestriol (E3). Oestrogens function by binding and activating oestrogen receptors (ERs). Phytoestrogens are plant-derived compounds which exhibit oestrogenic-like activity and can bind to ERs. Phytoestrogens exert potential oestrogenic-like benefits; however, their effects are context-dependent and require cautious consideration regarding generalised health benefits. Xenoestrogens are synthetic compounds which have been determined to disrupt endocrine function through binding to ERs. Xenoestrogens enter the body through various routes and given their chemical structure they can accumulate, posing long-term health risks. Xenoestrogens interfere with endogenous oestrogens and their functions contributing to conditions like cancer, infertility, and metabolic disorders. Understanding the interplay between endogenous and exogenous oestrogens is critical in order to determine their potential health consequences and requires further investigation. This manuscript provides a summary of the role endogenous oestrogens have in regulating metabolic functions. Additionally, we discuss the impact phytoestrogens and synthetic xenoestrogens have on biological systems across various life stages. We highlight their mechanisms of action, potential benefits, risks and discuss the need for further research to bridge gaps in understanding and mitigate exposure-related health risks.

Organohalogenated compounds contaminations in feed ingredients and feeds pose threats to the safety of food animals, and public health. Pigs are exposed through ingestions of feed contaminated with organohalogenated compounds. Microbes - organohalogens interactions in the gut cause changes in mean species diversities of bacteria, and induce gut dysbiosis. Along with metabolites from first-pass metabolisms, they affect proteins and molecular pathways that regulate ROS sensing, and induce oxidative stress. They also bind to estrogen receptors and mimic estrogen activities to impair reproductive endocrine functions. Nutritional interventions such as feed and feed ingredients substitutions, and harnessing non-conventional feed resources (NCFR) can offer sustainable alleviations. This will mitigate the risk of exposure to organohalogens whilst providing the needed nutrients to meet the animals' nutritional requirements. In addition, it will enhance the biological defense mechanisms in pigs. Phytonutrition can enhance biodegradation, and detoxification of recalcitrant organohalogenated xenobiotics. This provides a low cost, "green" strategy to alleviate adverse effects of organohalogenated xenobiotics in pigs. The low costs associated with makes this a viable remedy, especially for low income countries. [ABSTRACT FROM AUTHOR]

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]

• Perinatal oxybenzone exposure alters anogenital index in a dose specific manner. • Oxybenzone reduces the size and complexity of the male mammary gland before puberty. • Oxybenzone induces modest changes in female mammary gland morphology at puberty. • Perinatal oxybenzone exposure induces alveolar bud development in adult females. • Oxybenzone alters hormone receptor expression and proliferation in the mammary gland. Oxybenzone (benzophenone-3) is an ultraviolet radiation filter commonly used in personal care products including sunscreens, textiles and inks, and food and beverage containers, among others. Due to its widespread use, human exposures to oxybenzone are widespread. Oxybenzone is considered an endocrine disrupting chemical due to its antiestrogenic and antiandrogenic properties. We evaluated the effects of oral exposures to oxybenzone on the growth and morphology of the mammary gland, body weight and anogenital distance in BALB/c mice exposed to 30, 212 or 3000 μg/kg/day in utero and during lactation. Developmental exposures to oxybenzone reduced the size and growth of mammary gland in males prior to and during puberty. In exposed females, oxybenzone reduced mammary cell proliferation, decreased the number of cells expressing estrogen receptor α, and altered mammary gland morphology in adulthood. These results suggest that even low doses of oxybenzone can disrupt hormone sensitive organs during critical windows of development. [ABSTRACT FROM AUTHOR]

This study was conducted to verify a hypothesis that immune cells are a target for the action of endocrine disrupting chemicals (EDCs) by investigating whether methylparaben (MeP) modulates human neutrophil functions. Neutrophils isolated from 15 donor samples were studied. Cells were incubated in the presence of increasing MeP concentrations (0.06, 0.8, 10, and 20 μM). The cytotoxic effect of MeP on neutrophils was evaluated by the MTT test. The ability of the neutrophils for chemotaxis, phagocytosis, NADPH oxidase activity, and superoxide anion generation was assessed in Boyden's chamber, Park's method with latex, the NBT test, and the cytochrome C reduction test, respectively. The total nitric oxide (NO) concentration was measured by the Griess reaction. There was no observable cytotoxic effect of MeP on human neutrophils. MeP (10 and 20 μM) exposure decreased neutrophilic ability for the tested functions, except for NO production. In neutrophils incubated with MeP (0.8 μM as well as 0.06 and 0.8 μM, respectively), we observed a decreased activity of NADPH oxidase as well as decreased generation of superoxide anion. Our results suggest a suppressive effect of MeP on the tested functions of human neutrophils, which confirms that immune cells are vulnerable to EDC action. Therefore, the disturbance of neutrophils' oxygen-dependent phagocytic function as a result of exposure to environmental doses of MeP action could lead to impairment of innate immune responses in humans exposed to xenoestrogens. [ABSTRACT FROM AUTHOR]

Human activity has increased concentrations of endocrine-disrupting contaminants (EDCs) in many ecological systems. Many EDCs are xenoestrogens, which imitate naturally derived estrogen like estradiol 17-β (E2). These pollutants can critically affect a broad range of biological functions, particularly in organisms inhabiting aquatic environments. E2 and associated receptors are involved in regulating innate immune responses, where documentation of exogenous E2 on immune parameters is important for understanding health consequences. In this study, we explore the impact of environmentally relevant concentrations of E2 on circulating glucocorticoid levels and several innate immune parameters in hatchling American alligators (Alligator mississippiensis). Twenty-three hatchling alligators were randomly placed in one of three groups that differed in dietary E2 concentration: control (no E2 exposure), low E2 (0.5 μg/kg E2), or high E2 (1 μg/kg E2) for 10 weeks. Following this period, several biomarkers were quantified to monitor the impact of E2: growth, change in body condition, white blood cell (WBC) counts, glucocorticoid levels, and general antibody response. Blood E2 concentrations were greater in individuals exposed to E2, but plasma corticosterone levels were reduced among the experimental groups. Morphology, growth, and immune parameters of E2 exposed animals did not differ from controls. These results suggest that acute exposure to increased environmental estrogen concentrations may alter plasma hormone concentrations but have little to no impact on immediate morphology or immune responses. Future studies may expand on this by monitoring biomarkers in wild populations across time, which will provide insight into how different ontogenetic stages are impacted by environmental contaminants. [Display omitted] • Estradiol exposed animals and control group did not differ in morphology, growth, and immune parameters. • Sex did not influence final body mass, head length, total length, neck girth, or tail girth. • Environmental estrogens may impact hormone concentrations. [ABSTRACT FROM AUTHOR]

Zearalenone (ZEN) is a mycoestrogen produced by Fusarium fungi contaminating cereals and in grain-based products threatening human and animal health due to its endocrine disrupting effects. Germane to the mechanisms of action, ZEN may activate the estrogen receptors and inhibit the estrogens-producing enzyme aromatase (CYP19A1). Both show single nucleotide variants (SNVs) among humans associated with a diverse susceptibility of being activated or inhibited. These variations might modify the endocrine disrupting action of ZEN, requiring dedicated studies to improve its toxicological understanding. This work focused on human aromatase investigating via 3D molecular modelling whether some of the SNVs reported so far (n = 434) may affect the inhibitory potential of ZEN. It has been also calculated the inhibition capability of α-zearalenol, the most prominent and estrogenically potent phase I metabolite of ZEN, toward those aromatase variants with an expected diverse sensitivity of being inhibited by ZEN. The study: i) described SNVs likely associated with a different susceptibility to ZEN and α-zearalenol inhibition - like T310S that is likely more susceptible to inhibition, or D309G and S478F that are possibly inactive variants; ii) proofed the possible existence of inter-individual susceptibility to ZEN; iii) prioritized aromatase variants for future investigations toward a better comprehension of ZEN xenoestrogenicity at an individual level. [Display omitted] • Aromatase is known to show single nucleotide variants (SNVs) among human population. • The mycotoxin ZEN inhibits aromatase, but there is no data for its metabolite αZEL. • A set of SNVs have been investigated through a molecular modelling approach. • T310S was predicted to have an enhanced susceptibility to ZEN and αZEL inhibition. • D309G and S478F have been described as potentially inactive aromatase variants. [ABSTRACT FROM AUTHOR]

The mammary gland undergoes comprehensive reorganization during pregnancy, lactation, and subsequent involution. Following involution, the mammary gland has structural and functional differences compared to the gland of a nulliparous female. These parity-associated changes are regulated by hormones and may be vulnerable to endocrine-disrupting chemicals (EDCs). In this study, we evaluated the long-term effects of butyl benzyl phthalate (BBP), an estrogenic plasticizer, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 3, 500, or 18000 µg/kg/day BBP throughout both pregnancy and the lactational period. The litters born to these females were evaluated for litter size and growth. The parous females were then kept for five weeks following weaning of the pups, during which period there was no exposure to BBP. After five weeks of post-weaning, mammary glands were collected and assessed for changes in histomorphology, steroid receptor expression, innate immune cell number, and gene expression. An unexposed age-matched nulliparous control was also evaluated as a comparator group. BBP increased male and female pup weight at puberty and female offspring in adulthood. BBP also altered innate immune cells in the post-involution mammary gland, reducing the effect of parity on macrophages. Lastly, BBP modestly increased mammary gland ductal complexity and periductal structure, but had no effect on expression of estrogen receptor, progesterone receptor, or a marker of proliferation. These results suggest that BBP may interfere with some effects of parity on the mouse mammary gland and induce weight gain in exposed offspring. • BBP exposures during pregnancy and lactation induce effects after exposures cease. • BBP alters litter size in perinatally exposed mouse litters. • BBP exposure induces modest changes to mammary gland morphology in exposed mothers. • BBP exposure diminishes macrophage populations in the post-involution mammary gland. [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]