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Increasing contamination of the environment by toxic compounds such as endocrine disrupting chemicals (EDCs) is one of the major causes of reproductive defects in both sexes. Estrogen/androgen pathways are of utmost importance in gonadal development, determination of secondary sex characteristics and gametogenesis. Most of the EDCs mediate their action through respective receptors and/or downstream signaling. The purpose of this review is to highlight the mechanism by which EDCs can trigger antagonistic or agonistic response, acting through estrogen/androgen receptors causing reproductive defects that lead to infertility. In vitro, in vivo and in silico studies focusing on the impact of EDCs on estrogen/androgen pathways and related proteins published in the last decade were considered for the review. PUBMED and PUBCHEM were used for literature search. EDCs can bind to estrogen receptors (ERα and ERβ) and androgen receptors or activate alternative receptors such as G protein-coupled receptors (GPCR), GPR30, estrogen-related receptor (ERRγ) to activate estrogen signaling via downstream kinases. Bisphenol A, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethylene, polychlorinated biphenyls and phthalates are major toxicants that interfere with the normal estrogen/androgen pathways leading to infertility in both sexes through many ways, including DNA damage in spermatozoids, altered methylation pattern, histone modifications and miRNA expression.

Many pesticides can antagonize the androgen receptor (AR) or inhibit androgen synthesis but their potential to cause reproductive toxicity related to disruption of androgen action during fetal life is difficult to predict. Currently no approaches for using data to anticipate such effects exist. Prioritization schemes that limit unnecessary testing are urgently needed. The aim was to develop a quantitative to extrapolation (QIVIVE) approach for predicting anti-androgenicity arising from gestational exposures and manifesting as a shortened anogenital distance (AGD) in male rats. We built a physiologically based pharmacokinetic (PBK) model to simulate concentrations of chemicals in the fetus resulting from maternal dosing. The predicted fetal levels were compared with analytically determined concentrations, and these were judged against active concentrations for AR antagonism and androgen synthesis suppression. We first evaluated our model by using and anti-androgenic data for procymidone, vinclozolin, and linuron. Our PBK model described the measured fetal concentrations of parent compounds and metabolites quite accurately (within a factor of five). We applied the model to nine current-use pesticides, all with evidence for anti-androgenicity but missing data. Seven pesticides (fludioxonil, cyprodinil, dimethomorph, imazalil, quinoxyfen, fenhexamid, -phenylphenol) were predicted to produce a shortened AGD in male pups, whereas two ( , pyrimethanil) were anticipated to be inactive. We tested these expectations for fludioxonil, cyprodinil, and dimethomorph and observed shortened AGD in male pups after gestational exposure. The measured fetal concentrations agreed well with PBK-modeled predictions. Our QIVIVE model newly identified fludioxonil, cyprodinil, and dimethomorph as anti-androgens. With the examples investigated, our approach shows great promise for predicting anti-androgenicity (i.e., AGD shortening) for chemicals with activity and for minimizing unnecessary testing. https://doi.org/10.1289/EHP6774.

Experimental reproductive and developmental toxicity studies with polychlorinated biphenyls (PCBs) are reviewed in brief to determine their relevance for current environmental exposure of humans during the prenatal and postnatal developmental periods. Additional material is published in electronic form only, which contains graphic overviews on individual PCBs and various mixtures that are linked with the relevant citations. In this comprehensive article we focus on interactions of PCBs with biological substrates that could mediate adverse effects observed in experimental animals and in children, and the shortcomings of many of the animal studies available. A main point of criticism involves the relative lack of animal data on several of those persistent congeners, either as individual compounds or as environmentally relevant mixtures, which are currently used as a measure of human exposure. Experimental studies in animals are frequently conducted with commercial PCB mixtures, a test design that does not reflect the exposure situation in humans. Important improvements of animal experiments could be achieved by more complete reporting of litter data (pre- and post-natal losses, toxic signs in the dam and the offspring, birth weights and postnatal growth data), the inclusion of endpoints that have been found previously to be affected by PCBs, and measurements of internal exposure data.

Both supraphysiological and subphysiological testosterone levels are associated with increased cardiovascular risk. Testosterone consumption at supraphysiological doses has been linked to increased blood pressure, left ventricular hypertrophy, vascular dysfunction, and increased levels of inflammatory markers. Activation of the NLRP3 inflammasome contributes to the production of proinflammatory cytokines, leading to cardiovascular dysfunction. We hypothesized that supraphysiological levels of testosterone, via generation of mitochondrial reactive oxygen species (mROS), activates the NLRP3 inflammasome and promotes vascular dysfunction. Male, 12 week-old C57Bl/6J (WT) and NLRP3 knockout (NLRP3 ) mice were used. Mice were treated with testosterone propionate [TP (10 mg/kg) ] or vehicle for 30 days. In addition, vessels were incubated with testosterone [Testo (10 M, 2 h) ]. Testosterone levels, blood pressure, vascular function (thoracic aortic rings), pro-caspase-1/caspase-1 and interleukin-1β (IL-1β) expression, and generation of reactive oxygen species were determined. Testosterone increased contractile responses and reduced endothelium-dependent vasodilation, both and . These effects were not observed in arteries from NLRP3 mice. Aortas of TP-treated WT mice ( ), as well as aortas from WT mice incubated with testo ( ), exhibited increased mROS levels and increased caspase-1 and IL-1β expression. These effects were not observed in arteries from NLRP3 mice. Flutamide [Flu, 10 M, androgen receptor (AR) antagonist], carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 10 M, mitochondrial uncoupler) and MCC950 (MCC950, 10 M, a NLRP3 receptor inhibitor) prevented testosterone-induced mROS generation. Supraphysiological levels of testosterone induce vascular dysfunction via mROS generation and NLRP3 inflammasome activation. These events may contribute to increased cardiovascular risk.

Zearalenone (ZEN) and deoxynivalenol (DON) and their derivatives are well-known mycotoxins, which can occur not only in crops but also in water bodies, including drinking water sources. In vitro bioassays can be used to detect biological effects of hazardous compounds in water. To this, when studying biological effects and toxicity in vitro , metabolism is important to consider. In this study, ZEN, α-zearalenol (α-ZEL), DON, 3-acetyl DON, and 15-acetyl DON were evaluated in vitro for hormone receptor–mediated effects (estrogen receptor [ER] and androgen receptor [AR]) and genotoxicity (micronucleus assay) in the presence of an exogenous metabolic activation system (MAS). The ER bioassay proved to be a highly sensitive method to detect low concentrations of the ZEN compounds (EC 10 values of 31.4 pM for ZEN, 3.59 pM for α-ZEL) in aqueous solutions. In the presence of the MAS, reduced estrogenic effects were observed for both ZEN compounds (EC 10 values of 6.47 × 10 3  pM for ZEN, 1.55 × 10 2  pM for α-ZEL). Of the DON compounds, only 3-acetyl DON was estrogenic (EC 10 of 0.31 µM), and the effect was removed in the presence of the MAS. Anti-androgenic effects of the ZEN compounds and androgenic effects of the DON compounds were detected in the micromolar range. No induction of genotoxicity was detected for ZEN or DON in the presence of the MAS. Our study highlighted that inclusion of exogenous MAS is a useful tool to detect biological effects of metabolites in in vitro bioassays.

During the last decade, a number of studies have shown that, in addition to their classically described reproductive function, estrogens and androgens also regulate the immune system in teleosts. Today, several molecules are known to interfere with the sex-steroid signaling. These chemicals are often referred to as endocrine disrupting contaminants (EDCs). We review the growing evidence that these compounds interfere with the fish immune system. These studies encompass a broad range of approaches from field studies to those at the molecular level. This integrative overview improves our understanding of the various endocrine-disrupting processes triggered by these chemicals. Furthermore, the research also explains why fish that have been exposed to EDCs are more sensitive to pathogens during gametogenesis. In this review, we first discuss the primary actions of sex-steroid-like endocrine disruptors in fish and the specificity of the fish immune system in comparison to mammals. Then, we review the known interactions between the immune system and EDCs and interpret the primary effects of sex steroids (estrogens and androgens) and their related endocrine disruptors on immune modulation. The recent literature suggests that immune parameters may be used as biomarkers of contamination by EDCs. However, caution should be used in the assessment of such immunotoxicity. In particular, more attention should be paid to the specificity of these biomarkers, the external/internal factors influencing the response, and the transduction pathways induced by these molecules in fish. The use of the well-known mammalian models provides a useful guide for future research in fish.

Chemical contamination of wastewater is a problem of great environmental concern, as it poses a hazard to both the ecosystem and to human health. In this study, we have performed a bioanalytical evaluation of the presence and removal efficiency for bioactive chemicals in wastewater treatment plants (WWTPs), using in vitro assays for toxicity endpoints of high relevance for human health. Water samples were collected at the inlet and outlet of five Swedish WWTPs, all adopting a treatment technology including pretreatment, primary treatment (sedimenation), seconday treatment (biological processes), post-sedimentation, and sludge handling. The water samples were analyzed for cytotoxicity, estrogenicity, androgenicity, aryl hydrocarbon receptor (AhR) activity, oxidative stress response (Nrf2) and the ability to activate NFĸB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling. We observed clear androgenic and estrogenic activities in all inlet samples. Androgenic and estrogenic activities were also observed in all outlet samples, but the activities were lower than the respective inlet sample. AhR activity was observed in all samples, with higher activities in the inlet samples compared to the outlet samples. The removal efficiency was found to be high for androgenic (>99% for two plants and 50–60% for two plants) and estrogenic (>90% for most plants) compounds, while the removal efficiency for AhR-inducing compounds was 50–60% for most plants and 16% for one plant.

Abstract Although the misuse of androgenic-anabolic steroids is increasing, not much research has been done to determine how it affects renal function. Our research sought to ascertain how Nandrolone decanoate (ND) treatment affected kidney function and histological changes in adult male albino rats. Additionally, we sought to evaluate the impact of combining ND therapy with anaerobic exercise. A total of 39 male rats were divided into three groups (n = 13 each): control, ND treated (15mg/kg/day for 8 weeks; SC), and trained-ND treated (8-12 ladder climbs, three times per week for eight weeks). Blood and kidney samples were taken after eight weeks of anaerobic exercise and therapy. The study assessed organ weight, serum urea, and creatinine levels, inflammation (TNF-α, IL-6), oxidative stress markers (MDA, SOD, TAC), kidney histology, and collagen content. Caspase3 and BAX immunohistochemistry were performed, whereas Sirt1, Beclin-1, and microtubule-associated protein light chain 3 (LC3) mRNA were analyzed using RT-PCR. The current study illustrated that exercise significantly improved kidney function, histological results, and damage score while reducing collagen deposition, inflammation, and oxidative stress. Apoptosis proteins (CASPASE3 and BAX) were dramatically reduced, whereas Sirt1 and autophagy proteins (Beclin-1 and LC3) mRNA levels were increased. In our conclusion, because of its anti-inflammatory, antioxidative, and antiapoptotic properties as well as its modification of autophagy protein mRNA, anaerobic exercise in conjunction with ND administration in rats led to a reduction in renal damage and kidney fibrosis. Resumo Embora o uso indevido de esteroides anabolizantes androgênicos esteja aumentando, poucas pesquisas foram realizadas para determinar como ele afeta a função renal. Nossa pesquisa buscou verificar como o tratamento com decanoato de nandrolona (ND) afetou a função renal e as alterações histológicas em ratos albinos machos adultos. Além disso, buscamos avaliar o impacto da combinação da terapia de ND com exercício anaeróbico. Um total de 39 ratos machos foram divididos em três grupos (n = 13 cada): controle, tratado com ND (15 mg/kg/dia por 8 semanas; SC) e tratado com ND treinado (8 a 12 subidas em escada, três vezes por semana, durante oito semanas). Amostras de sangue e rim foram coletadas após oito semanas de exercício anaeróbico e terapia. O estudo avaliou o peso dos órgãos, os níveis séricos de ureia e creatinina, a inflamação (TNF-α, IL-6), os marcadores de estresse oxidativo (MDA, SOD, TAC), a histologia renal e o conteúdo de colágeno. Foram realizadas imuno-histoquímicas para caspase-3 e BAX, enquanto o mRNA de Sirt1, Beclin-1 e da cadeia leve 3 da proteína associada a microtúbulos (LC3) foi analisado por RT-PCR. O presente estudo demonstrou que o exercício físico melhorou significativamente a função renal, os resultados histológicos e o escore de dano, reduzindo a deposição de colágeno, a inflamação e o estresse oxidativo. As proteínas de apoptose (Caspase-3 e BAX) foram drasticamente reduzidas, enquanto os níveis de mRNA de Sirt1 e das proteínas de autofagia (Beclin-1 e LC3) aumentaram. Em nossa conclusão, devido às suas propriedades anti-inflamatórias, antioxidantes e antiapoptóticas, bem como à sua modificação do mRNA da proteína de autofagia, o exercício anaeróbico, em conjunto com a administração de ND em ratos, levou à redução do dano renal e da fibrose renal.

The Organisation for Economic Co-operation and Development (OECD) has completed phase 2 of an international program to validate the rodent Hershberger bioassay. The Hershberger bioassay is designed to identify suspected androgens and antiandrogens based on changes in the weights of five androgen-responsive tissues (ventral prostate, paired seminal vesicles and coagulating glands, the levator ani and bulbocavernosus muscles, the glans penis, and paired Cowper's or bulbourethral glands). Protocol sensitivity and reproducibility were tested using two androgen agonists (17alpha-methyl testosterone and 17beta-trenbolone), four antagonists [procymi-done, vinclozolin, linuron, and 1,1-dichoro-2,2-bis-(p-chlorophenyl)ethylene (p,p'-DDE)], and a 5alpha-reductase inhibitor (finasteride). Sixteen laboratories from seven countries participated in phase 2. In 40 of 41 studies, the laboratories successfully detected substance-related weight changes in one or more tissues. The one exception was with the weakest antiandrogen, linuron, in a laboratory with reduced sensitivity because of high coefficients of variation in all tissue weights. The protocols performed well under different experimental conditions (e.g., strain, diet, housing protocol, bedding, vehicle). There was good agreement and reproducibility among laboratories with regard to the lowest dose inducing significant effects on tissue weights. The results show that the OECD Hershberger bioassay protocol is reproducible and transferable across laboratories with androgen agonists, weak androgen antagonists, and a 5alpha-reductase inhibitor. The next validation phase will employ coded test substances, including positive substances and negative substances having no androgenic or antiandrogenic activity.

Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the “expected NOEL” was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose–response curve or effects at low levels.