Search

Non-persistent endocrine-disrupting chemicals (EDCs) are of significant concern due to their reproductive toxicity. Previous research reported a relationship between a single type of EDCs and endometriosis. Yet, evidence regarding mixed exposure of multiple categories of EDCs is scarce. Between 2014 and 2018, our hospital-based case-control study recruited 238 endometriosis cases diagnosed by laparoscopy and 296 normal controls in China. Seventeen non-persistent EDCs (phthalates and bisphenols) were measured in urine. The association of single EDC with endometriosis was estimated using logistic regression, while the association between EDC mixture and endometriosis was modeled by Bayesian kernel machine regression (BKMR), quantile-based g-computation (q-gcomp), and principal component analysis (PCA). Consistent results were observed in both single and mixture models where phthalates and bisphenols were associated with increased risk of endometriosis (mixture effect: adjusted odds ratio (aOR)=1.44, 1.22-1.70) and the major contributors were bisphenol A (BPA) and the metabolites of di(2-ethylhexyl) phthalate (DEHP). Interaction analysis showed that bisphenols exhibited significant synergistic interactions with phthalates. Our results suggest that non-persistent EDCs are associated with endometriosis but the underlying mechanisms remain to be elucidated. Our finding may have important public health implications in preventing endometriosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study reports the effects of bisphenol A (BPA) on the rotifer Brachionus plicatilis, focusing on growth performance, reproductive output, oxidative stress responses, and lipid metabolism genes. High BPA levels disrupted peak daily offspring production and led to oxidative stress and increased superoxide dismutase and catalase activity. The research identified distinctive monoacylglycerol O-acyltransferase (MGAT) and diacylglycerol O-acyltransferase (DGAT) genes in B. plicatilis, B. rotundiformis, and B. koreanus, enhancing understanding of lipid metabolism in these species. BPA exposure significantly altered MGAT and DGAT expression, and feeding status affected these regulatory patterns. When food was unavailable, BPA reduced DGAT2 and MGAT2a expression. However, under feeding conditions, DGAT2 and MGAT1 levels increased, indicating that nutritional status and BPA exposure interact to affect gene expression., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cumulative human exposure to the environmental toxin, bisphenol A (BPA), has raised important health concerns in recent decades. However, the direct genomic regulation of BPA in skeletal muscles and its clinical significance are poorly understood. Therefore, we conducted a genome-wide transcriptome analysis after daily oral administration of BPA at the lowest observed adverse-effect level (LOAEL, 50 mg/kg) in male mice for six weeks to explore the gene-expression regulations in skeletal muscle induced by BPA. The primary Gene Ontology terms linked to BPA-dependent, differentially expressed genes at LOAEL comprised adaptive-immune response, positive regulation of T cell activation, and immune system process. The gene-set enrichment analysis disclosed increased complement-associated genes [complement components 3 (C3) and 4B, complement factor D, complement receptor 2, and immunoglobulin lambda constant 2] in the group administered with BPA, with a false-discovery rate of <0.05. Subsequent validation analysis conducted in BPA-fed animal skeletal muscle tissue and in vitro experiments confirmed that BPA induced immune activation, as evidenced by increased levels of C3 and C4α proteins in mice, C2C12 myoblasts, and mouse skeletal muscle cells. In addition, BPA markedly upregulated the transcription of tumor necrosis factor-α (Tnfα) in C2C12 myoblasts and mouse skeletal muscle cells, which was substantially inhibited by 5z-7-oxozeanol and parthenolide, providing further evidence of BPA-induced inflammation in muscle cells. Our bioinformatics and subsequent animal and in vitro validations demonstrate that BPA can activate inflammation in skeletal muscle, which could be a risk factor underlying chronic muscle weakness and wastage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Recent studies have shown that prenatal BPA exposure altered the transcriptome profiles of autism-related genes in the offspring's hippocampus, disrupting hippocampal neuritogenesis and causing male-specific deficits in learning. However, the sex differences in the effects of prenatal BPA exposure on the developing prefrontal cortex, which is another brain region highly implicated in autism spectrum disorder (ASD), have not been investigated., Methods: We obtained transcriptome data from RNA sequencing analysis of the prefrontal cortex of male and female rat pups prenatally exposed to BPA or control and reanalyzed. BPA-responsive genes associated with cortical development and social behaviors were selected for confirmation by qRT-PCR analysis. Neuritogenesis of primary cells from the prefrontal cortex of pups prenatally exposed to BPA or control was examined. The social behaviors of the pups were assessed using the two-trial and three-chamber tests. The male-specific impact of the downregulation of a selected BPA-responsive gene (i.e., Sema5a) on cortical development in vivo was interrogated using siRNA-mediated knockdown by an in utero electroporation technique., Results: Genes disrupted by prenatal BPA exposure were associated with ASD and showed sex-specific dysregulation. Sema5a and Slc9a9, which were involved in neuritogenesis and social behaviors, were downregulated only in males, while Anxa2 and Junb, which were also linked to neuritogenesis and social behaviors, were suppressed only in females. Neuritogenesis was increased in males and showed a strong inverse correlation with Sema5a and Slc9a9 expression levels, whereas, in the females, neuritogenesis was decreased and correlated with Anxa2 and Junb levels. The siRNA-mediated knockdown of Sema5a in males also impaired cortical development in utero. Consistent with Anxa2 and Junb downregulations, deficits in social novelty were observed only in female offspring but not in males., Conclusion: This is the first study to show that prenatal BPA exposure dysregulated the expression of ASD-related genes and functions, including cortical neuritogenesis and development and social behaviors, in a sex-dependent manner. Our findings suggest that, besides the hippocampus, BPA could also exert its adverse effects through sex-specific molecular mechanisms in the offspring's prefrontal cortex, which in turn would lead to sex differences in ASD-related neuropathology and clinical manifestations, which deserves further investigation., (© 2024. The Author(s).)

Bisphenol A, endocrine-disrupting chemicals (EDCs) impacting disease development via epigenetic modifications, is crucial in transcriptional regulation. However, ecotoxicology's limited exploration of epigenetics prompted our study's objective: examining the extended exposure of riverine Bisphenol A (BPA), a potent EDC, on DNA methylation during female paradise threadfin (Polynemus paradiseus) reproductive maturation. Assessing BPA contamination in riverine water, we collected fish samples from two locations with distinct contamination levels. In the highly contaminated region (Hc), we observed elevated DNA methylation in aromatase (7.5-fold), 20β-HSD (3-fold), and FSHR (2-fold) genes. Hormone receptor investigation highlighted an escalating connection between transcriptional hyper-methylation and contamination levels. Additionally, our study revealed a positive correlation between oocyte growth and global DNA methylation, suggesting BPA's potential to modify DNA methylation in female paradise threadfins. This effect likely occurs through changes in hormone receptor expression, persisting throughout oocyte maturation. Notably, our research, the first of its kind in estuarine areas, confirmed BPA contamination in paradise threadfins, raising concerns about potential health risks for humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Diisobutyl phthalate (DiBP) is a commonly used plasticizer in manufacturing consumer and industrial products to improve flexibility and durability. Despite of the numerous studies, however, the direct mechanism underlying the male reproductive damage of DiBP is poorly understood. In this study, we investigated the male germ cell toxicity of DiBP using GC-1 spermatogonia (spg) cells. Our results indicated that DiBP exposure causes oxidative stress and apoptosis in GC-1 spg cells. In addition, DiBP-derived autophagy activation and down-regulation of phosphoinositide 3-kinase (PI3K)-AKT and extracellular signal-regulated kinase (ERK) pathways further inhibited GC-1 spg cell proliferation, indicating that DiBP can instigate male germ cell toxicity by targeting several pathways. Importantly, a combined treatment of parthenolide, N-acetylcysteine, and 3-methyladenine significantly reduced DiBP-induced male germ cell toxicity and restored proliferation. Taken together, the results of this study can provide valuable information to the existing literature by enhancing the understanding of single phthalate DiBP-derived male germ cell toxicity and the therapeutic interventions that can mitigate DiBP damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome-interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring's prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring's prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.

Bisphenol F (BPF) is widely used in the plastic manufacturing industry as a replacement for bisphenol A (BPA) because BPF and BPA have similar structures and comparable properties. However, BPF is ubiquitously present in the environment and has higher toxicity to humans. This study is the first to report BPF degradation using the white-rot fungus Phanerochaete sordida YK-624 under ligninolytic conditions (pH=4.5, 30 °C). P. sordida YK-624 almost completely degraded BPF within 4 days. Moreover, functional genes involved in BPF degradation were detected by RNA-Seq. Metabolic processes and peroxidases were enriched by GO analysis, and the metabolic pathway was enriched according to the KEGG pathway analysis. These results suggested that P. sordida YK-624 could secrete higher levels of ligninolytic enzymes lignin peroxidase (LiP) and manganese peroxidase (MnP) for BPF degradation. The results indicated that LiPs and MnPs are important for BPF degradation and cytochrome P450s play a small role. Furthermore, reliability of the RNA-Seq results was validated by qRT-PCR., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical (EDC), is increasingly hypothesized to be a factor contributing to changes in fetal growth velocity. BPA exposure may be environmental, occupational, and/or dietary, with canned foods and plastic bottles contributing significantly. Our systematic review aims to evaluate the current literature and to investigate the role of BPA in abnormal fetal growth patterns. A search was conducted in the PubMed and Cochrane databases. A total of 25 articles met the eligibility criteria and were included in this systematic review. Eleven of them failed to show a clear relationship between BPA and abnormal fetal growth. The majority of the remaining studies (9/14) found an inverse association of BPA with indicators of fetal growth, whereas three studies suggested increased fetal growth, and two studies produced contradictory findings. Of note, both of the studies that collected a sample (amniotic fluid) directly reflecting BPA concentration in the fetus during the first half of pregnancy revealed an inverse association with birth weight. In conclusion, there is mounting evidence that combined exposure to BPA from dietary and non-dietary sources during pregnancy may contribute to abnormal fetal growth; a tendency towards fetal growth restriction was shown, especially when exposure occurs during the first half.

Bisphenols are common chemicals found in plastics and epoxy resins. Over the past decades, many studies have shown that bisphenol A (BPA) is a potential endocrine-disrupting chemical that may cause multisystem toxicity. However, the relative safety of BPA analogues is a controversial subject. Herein, we conducted a review of the reproductive toxicity, neurotoxicity, immunotoxicity, metabolic toxicity and gut microbiome toxicity of the BPA analogues in various species, including Caenorhabditis elegans , zebrafish, turtles, sheep, rodents, and humans. In addition, the mechanisms of action were discussed with focus on bisphenol S and bisphenol F. It was found that these BPA analogues exert their toxic effects on different organs and systems through various mechanisms including epigenetic modifications and effects on cell signaling pathways, microbiome, and metabolome in different species. More research is needed to study the relative toxicity of the lesser-known BPA analogues compared to BPA, both systemically and organ specifically, and to better define the underlying mechanisms of action, in particular, the potentials of disrupting microbiome and metabolism.

Bisphenol A (BPA), an endocrine-disrupting chemical, is present in everyday-used consumables and common household products. Although the side effects of BPA have been sufficiently explored, little is known the effects of environmentally relevant low levels of BPA on chondrogenesis in skeletal development. Here we used a morphological approach to investigate whether exposure to BPA (0, 0.0038, 0.05, 0.1, 1.0 μM) could affect craniofacial cartilage development of zebrafish embryo. Furthermore, we sought to determine receptor-mediated BPA induced chondrogenesis toxicity by co-exposing developing embryos to BPA and various inhibitors. Low-dose BPA affected heart rate and induced body and head elongation of larvae. Quantitative morphometric and histopathological analysis revealed that BPA exposure changed the angle and length of craniofacial cartilage elements and disrupted chondrocytes. BPA induced pharyngeal cartilage defects via multiple cellular pathways, including estrogen receptor, androgen receptor, and estrogen-related receptors. Our findings demonstrate that BPA alters the normal development of cartilage and craniofacial structures in zebrafish embryos. Furthermore, in this study we find multiple cellular pathways mediating the effects of BPA-induced craniofacial chondrogenesis toxicity. Further experiments will allow for establishing a connection between BPA and increased risk of congenital malformation of the facial cranium in BPA-exposed populations., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Decidualization is a crucial precedent to embryo implantation, as its impairment is a major contributor to female infertility and pregnancy complications. Unraveling the molecular mechanisms involved in the impairment of decidualization has been a subject of interest in the field of reproductive medicine. Evidence from several experimental settings show that exposure to bisphenol A (BPA), an endocrine-disrupting chemical, affects the expression of several molecules that are involved in decidualization. Both low and high doses of BPA impair decidualization through the dysregulation of estrogen (ER) and progesterone (PR) receptors. Exposure to low doses of BPA leads to decreased levels and activities of several antioxidant enzymes, increased activity of endothelial nitric oxide synthase (eNOS), and increased production of nitric oxide (NO) via the upregulation of ER and PR. Consequently, oxidative stress is induced and decidualization becomes impaired. On the other hand, exposure to high doses of BPA downregulates ER and PR and impairs decidualization through two distinct pathways. One is through the upregulation of early growth response-1 (EGR1) via increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2; and the other is through a reduced serum glucocorticoid-induced kinase-1 (SGK1)-mediated downregulation of epithelial sodium channel-α and the induction of oxidative stress. Thus, regardless of the dose, BPA can impair decidualization to trigger infertility and pregnancy complications. This warrants the need to adopt lifestyles that will decrease the tendency of getting exposed to BPA., (© 2020 Wiley Periodicals LLC.)

Bisphenol A (BPA) is an endocrine-disrupting chemical widely used in the production of polycarbonate plastics and epoxy resins, which has been previously linked to diabetes among non-Hispanic populations. As part of a case control study for breast cancer, only controls with BPA information were included in this report. The final sample size comprises 70 self-reported diabetics and 334 non-diabetics. Urinary free bisphenol A (BPA-F) (μg/L) was determined by solid-phase extraction and HPLC/FLD analysis. Logistic regression models were used to evaluate the association between BPA-F and self-reported diabetes. After adjusting by age, urinary BPA-F (4.06-224.53 μg/g creatinine) was associated with diabetes exposure (OR = 1.85; 95% CI 1.04, 3.28) compared with women in the reference category (0.67-4.05 μg/g creatinine). BPA may be an environmental cofactor of diabetes. More studies are needed to confirm this result, especially in Hispanic populations.

Bisphenol A (BPA) is a high-production chemical used in a variety of applications worldwide. While BPA has been documented as an endocrine-disrupting chemical (EDC) having adverse health-related outcomes in multiple studies, risk assessment for BPA has lagged due to reliance on guideline toxicology studies over academic ones with end-points considered more sensitive and appropriate. To address current controversies on BPA safety, the United States National Institute of Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP) and the Food and Drug Administration (FDA) established the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) using the NCTR Sprague-Dawley rats. The goal of CLARITY-BPA is to perform a traditional regulatory toxicology study (Core study) in conjunction with multiple behavioural, molecular and cellular studies by academic laboratories focused on previously identified BPA-sensitive organ systems (Academic studies). Combined analysis of the data from both study types will be undertaken by the NTP with the aim of resolving uncertainties on BPA toxicity. To date, the Core study has been completed and a draft report released. Most of the academic studies have also been finalized and published in peer-reviewed journals. In light of this important milestone, the PPTOX-VI meeting held in the Faroe Islands, 27-30 May 2018 devoted a plenary session to CLARITY-BPA with presentations by multiple investigators with the purpose of highlighting key outcome. This MiniReview synthesizes the results of three academic studies presented at this plenary session, evaluates recently published findings by other CLARITY-BPA academic studies to provide an early combined overview of this emerging data and places this in the context of the Core study findings. This co-ordinated effort revealed a plethora of significant BPA effects across multiple organ systems and BPA doses with non-monotonic responses across the dose range utilized. Remarkably consistent across most studies, including the Core study, are low-dose effects (2.5, 25 and 250 μg BPA/kg body-weight). Collectively, the findings highlighted herein corroborate a significant body of evidence that documents adverse effects of BPA at doses relevant to human exposures and emphasizes the need for updated risk assessment analysis., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that is widely used in the manufacturing of plastics and inner linings of food cans. Previously, it was reported that BPA disturbed the sexual dimorphic nucleus of the hypothalamus and delaying the onset of puberty attributed to an estrogenic action. In addition, BPA during the perinatal period increased LH serum concentrations in male offspring of dams at doses below the reproductive NOAEL (No Observable Adverse Effect Level) based upon World Health Organization guidelines. Based upon these findings, the objective of this study was to (1) determine the effects of perinatal treatment with low doses of BPA on regulation of spermatogenesis in adult offspring and (2) elucidate molecular mechanisms involved in the pathogenesis of gonadal dysfunction. The expression of genes related to spermatogenesis was disrupted with adverse consequences on sperm production, reserves, and function. Both BPA treated groups exhibited reduction in sperm production and epithelial height of seminiferous tubules, accompanied by diminished integrity of the acrosome and plasma membrane, decreased mitochondrial activity and increased incidence of morphological abnormalities. The sperm transit time was also slower. However, only in the group receiving the higher BPA dose was transcript expression of genes affected (reduced Ar and increased Esr1). It is of interest that serum testosterone levels were elevated in the same group where Ar was decreased. Data suggest that exposure to low BPA doses during hypothalamic sexual differentiation period produces permanent deleterious effects on spermatogenesis in adulthood.

We investigated the effects of activated carbon, used as constructed wetlands (CWs) medium, on its ability to remove four emerging endocrine-disrupting chemicals (EDCs): bisphenol A (BPA), bisphenol F (BPF), bisphenol S (BPS) and 4-tert-butylphenol (4-tert-BP). Two types of CWs planted with common reed were constructed, one with pumice rock called normal CW and the other was amended with activated carbon (AC) called AC-CW. EDCs contaminated synthetic wastewater (5 mg/L of each) was treated by CWs for 8 weeks. AC-CW completely and sustainably removed all four EDCs (98-100%) starting immediately and continuing throughout the experiment. Removal performances of all EDCs by AC-CW were significantly higher than those by normal CW. After experiment, no BPA and BPF and very small amounts of BPS and 4-tert-BP were detected in AC. In AC-CW, final elimination step of EDCs might be biodegradation. In addition, bacterial populations on AC component of AC-CW were one-two orders higher than those on the pumice rock of normal CW. Therefore, in AC-CW, EDCs were initially adsorbed onto AC, where they could be effectively degraded by high bacterial population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Thousands of safety-related studies have been published on bisphenol A (BPA), an ubiquitous environmental pollutant with estrogenic activity and many other potential biological effects. In recent years, BPA exposure has been shown to cause anovulation and infertility through irreversible alteration of the hypothalamic-pituitary-gonadal axis in several organisms, including fish and mammals. Recently, the European Chemical Agency classified BPA as a "substance of very high concern" because of its endocrine-disrupting properties, which have serious effects on human health. Given the risk of exposure to BPA as a pollutant in the environment, food, and drinking water, the objective of our study was to assess the effects of this compound on the adeno-hypophysis by means of a histopathological and morphometric study of the gonadotroph cells. In addition, using quantitative real-time PCR (qRT-PCR) assays, we analyzed the changes in the expression of Cyp19b (an aromatase gene). Zebrafish were randomly distributed into five groups: a control group and 4 treated groups which were exposed to different BPA concentrations (1, 10, 100 and 1000 µg/L). The effects of the different doses on Cyp19b mRNA molecules followed a non-monotonic curve, with the 1 and 1000 µg/L doses causing dramatic decreases in the number of Cyp19b transcripts while the doses of 10 and 100 µg/L caused important increases. The consequences might be deregulation of gonadotropic hormones causing degeneration of gonadotropic cells, as observed in BPA treated animals. This is the first study in which the gonadotroph cells have been evaluated using histomorphological endpoints after BPA exposure in zebrafish., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Adverse outcome pathways (AOPs) are a novel concept that effectively considers the toxic modes of action and guides the ecological risk assessment of chemicals. To better use toxicity data including biochemical or molecular responses and mechanistic data, we further developed a species sensitivity-weighted distribution (SSWD) method for bisphenol A and 4-nonylphenol. Their aquatic predicted-no-effect concentrations (PNECs) were derived using the log-normal statistical extrapolation method. We calculated aquatic PNECs of bisphenol A and 4-nonylphenol with values of 4.01 and 0.721 µg/L, respectively. The ecological risk of each chemical in different aquatic environments near Tianjin, China, a coastal municipality along the Bohai Sea, was characterized by hazard quotient and probabilistic risk quotient assessment techniques. Hazard quotients of 7.02 and 5.99 at 2 municipal sewage sites using all of the endpoints were observed for 4-nonylphenol, which indicated high ecological risks posed by 4-nonylphenol to aquatic organisms, especially endocrine-disrupting effects. Moreover, a high ecological risk of 4-nonylphenol was indicated based on the probabilistic risk quotient method. The present results show that combining the SSWD method and the AOP concept could better protect aquatic organisms from adverse effects such as endocrine disruption and could decrease uncertainty in ecological risk assessment. Environ Toxicol Chem 2018;37:551-562. © 2017 SETAC., (© 2017 SETAC.)

Developmental exposure to bisphenol A (BPA) is associated with lung dysfunction and diseases. However, it is unknown if this association has a fetal origin. The present study addressed this important question by examining the effects of BPA on fetal lung development. BPA was administered to pregnant mice via diet from embryonic day (E) 7.5 to E18.5. Fetal lungs were analyzed at E18.5 for changes in structure and expression of key molecular markers of lung maturation. Our main findings were as follows: BPA severely retards fetal lung maturation, as evidenced by diminished alveolar airspace (15% of control) and thickened septa, hallmarks of lung immaturity; this immaturity is characterized by aberrant alveolar epithelial type I cell differentiation because expression of the type I cell marker, aquaporin 5, but not type II cell markers, is dramatically reduced (16% of control); and the effects of BPA are likely mediated through the glucocorticoid signaling pathway because the expression of epithelial sodium channel γ and glutathione peroxidase, 2 well-known glucocorticoid target genes, is down-regulated in BPA-exposed fetal lungs, and, importantly, maternal dexamethasone administration rescues the lung immaturity phenotype. Taken together, these findings demonstrate that BPA disrupts fetal lung maturation, thus suggesting a fetal origin for BPA-induced lung diseases., (© FASEB.)

Various assays with adult fish have been developed to identify potential endocrine-disrupting chemicals (EDCs) which may cause toxicity via alterations in the hypothalamic-pituitary-gonadal (HPG) axis. These assays can be sensitive and highly diagnostic for key mechanisms such as agonism of the estrogen and androgen receptors (ERs, ARs) and inhibition of steroid synthesis. However, most of the tests do not unambiguously identify AR antagonists. The purpose of this work was to explore the utility of a mixture test design with the fathead minnow (Pimephales promelas) for detecting different classes of EDCs including AR antagonists. Adults of both sexes were exposed via the water to EDCs with diverse mechanisms of action in the absence or presence of 17beta-trenbolone (TB), a potent AR agonist which masculinizes female fathead minnows. Similar to previous studies with the model AR antagonists flutamide and vinclozolin, exposure of females to the AR antagonist cyproterone acetate in the presence of TB decreased expression of an easily-observed masculinization response, nuptial tubercle formation. Mixture studies with TB and the model ER agonists, 17alpha-ethinylestradiol and bisphenol A, also showed inhibition of tubercle formation in the females, but unlike the AR antagonists, the estrogens markedly induced synthesis of vitellogenin (VTG: egg yolk protein), particularly in males. The ER agonists also offset TB-induced depressions in plasma VTG concentrations in female fish. Additional mixture experiments were conducted with TB and triclocarban, an anti-microbial reported to enhance AR-mediated responses, or ammonia, a "negative control" with no known direct effects on HPG function. Neither chemical affected VTG status in males or females in the absence or presence of TB; however, both slightly enhanced TB-induced tubercle formation in females. Based on studies described herein and elsewhere with the fathead minnow, a TB co-exposure assay appears to be an effective approach for clearly identifying AR antagonists as well as potential EDCs with other relevant mechanisms of action.

1 Agonistic neurosteroids, including pregnenolone, dehydroepiandrosterone and its sulfate (DHEAS), caused rapid degranulation in measurements of beta-hexosaminidase (beta-HEX) release from a mast cell line, RBL-2H3. This degranulation was blocked by BSA-conjugated progesterone (PROG-BSA) or 17beta-estradiol, both of which are antagonistic neurosteroids. 2 DHEAS-induced beta-HEX release was blocked by U-73122 or xestospongin C, but not by PTX or EGTA. DHEAS-induced beta-HEX release was also abolished by G(q/11)-AS, but not by G(q/11)-MS. Pharmacological analyses revealed that the neurosteroids stimulated a putative membrane receptor through activation of the novel G(q/11) and phospholipase C. 3 While representative endocrine-disrupting chemicals (EDCs) did not show any degranulation or nocifensive actions by themselves, they blocked the DHEAS-induced degranulation. 4 The binding of a PROG-BSA-fluorescein isothiocyanate conjugate (PROG-BSA-FITC) to cells was inhibited by neurosteroids and EDCs. 5 In the algogenic-induced biting and licking responses test, DHEAS caused agonistic nocifensive actions in a dose-dependent manner between 1 and 10 fmol (i.pl.). DHEAS-induced nocifensive actions were abolished by PROG-BSA or nonylphenol. 6 Taken together, these results suggest that a G(q/11)-coupled neurosteroid receptor may regulate the neuroimmunological activity related to sensory stimulation and that some EDCs have antagonistic actions for this receptor. [ABSTRACT FROM AUTHOR]