Target For Endocrine Disruption Research Articles

Thyroid Function: A Target for Endocrine Disruptors, Air Pollution and Radiofrequencies.

Thyroid diseases, including congenital hypothyroidism, thyroiditis, and childhood thyrotoxicosis, are progressively increasing. The incidence of thyroid cancer in children and adolescents has also increased in recent decades, mirroring the trends observed in adults. These epidemiologic trends develop in parallel with the rising costs associated with diagnosis and treatment of thyroid diseases. Both genetic and environmental factors are involved in these diseases, and a number of widely diffused toxic chemicals of anthropogenic origin can impair thyroid function and make thyroid cancer worse. Synthetic substances persistently contaminate environmental matrices (i.e., air, soil, water) and the food chain and bio-accumulate in humans, starting from in utero life. Environmental toxins such as air pollutants, endocrine disruptors, and high-frequency electromagnetic fields can act on common targets through common pathways, combined mechanisms, and with trans-generational effects, all of which contribute to thyroid damage. Both experimental and epidemiologic observations show that mechanisms of damage include: modulation of synthesis; transportation and metabolism of thyroid hormones; direct interference with hormone receptors: modulation of gene expression; and autoimmunity. We should not underestimate the available evidence linking environmental pollutants with thyroid disease, cancer included, since toxic substances increasingly diffuse and thyroid hormones play a key role in maintaining systemic metabolic homeostasis during body development. Thus, primary prevention measures are urgently needed in particular to protect children, the most exposed and vulnerable subjects.

Membrane Hormone Receptors and Their Signaling Pathways as Targets for Endocrine Disruptors.

The endocrine disruptors are mostly small organic molecules developed for numerous and very diverse industrial applications. They essentially act through nuclear receptors with small and hydrophobic endogenous ligands. Nevertheless, potential adverse effects through membrane hormone receptors cannot be ruled out, and have indeed been observed. The present paper reviews how orthosteric and allosteric binding sites of the different families of membrane receptors can be targets for man-made hydrophobic molecules (components of plastics, paints, flame retardants, herbicides, pesticides, etc.). We also review potential target proteins for such small hydrophobic molecules downstream of membrane receptors at the level of their intracellular signaling pathways. From the currently available information, although endocrine disruptors primarily affect nuclear receptors’ signaling, membrane receptors for hormones, cytokines, neuro-mediators, and growth factors can be affected as well and deserve attention.

Prenatal phthalate exposure in relation to placental corticotropin releasing hormone (pCRH) in the CANDLE cohort.

Phthalates may disrupt maternal-fetal-placental endocrine pathways, affecting pregnancy outcomes and child development. Placental corticotropin releasing hormone (pCRH) is critical for healthy pregnancy and child development, but understudied as a target of endocrine disruption. To examine phthalate metabolite concentrations (as mixtures and individually) in relation to pCRH. Secondary data analysis from a prospective cohort study. Prenatal clinics in Tennessee, USA. 1018 pregnant women (61.4% non-Hispanic Black, 32% non-Hispanic White, 6.6% other) participated in the CANDLE study and provided data. Inclusion criteria included: low-medical-risk singleton pregnancy, age 16-40, and gestational weeks 16-29. None. Plasma pCRH at two visits (mean gestational ages 23.0 and 31.8weeks) and change in pCRH between visits (ΔpCRH). In weighted quantile sums (WQS) regression models, phthalate mixtures were associated with higher pCRH at Visit 1 (β=0.07, 95%CI: 0.02, 0.11) but lower pCRH at Visit 2 (β=-0.08, 95%CI: -0.14, -0.02). In stratified analyses, among women with gestational diabetes (n=59), phthalate mixtures were associated with lower pCRH at Visit 1 (β=-0.17, 95%CI: -0.35, 0.0006) and Visit 2 (β=-0.35, 95%CI: -0.50, -0.19), as well as greater ΔpCRH (β=0.16, 95%CI: 0.07, 0.25). Among women with gestational hypertension (n=102), phthalate mixtures were associated with higher pCRH at Visit 1 (β=0.20, 95%CI: 0.03, 0.36) and Visit 2 (β=0.42; 95%CI: 0.19, 0.64) and lower ΔpCRH (β=-0.17, 95%CI: -0.29, -0.06). Significant interactions between individual phthalate metabolites and pregnancy complications were observed. Phthalates may impact placental CRH secretion, with differing effects across pregnancy. Differences in results between women with and without gestational diabetes and gestational hypertension suggest a need for further research examining whether women with pregnancy complications may be more vulnerable to endocrine-disrupting effects of phthalates.

Antipredator phenotype in crucian carp altered by a psychoactive drug.

Predator‐inducible defenses constitute a widespread form of adaptive phenotypic plasticity, and such defenses have recently been suggested linked with the neuroendocrine system. The neuroendocrine system is a target of endocrine disruptors, such as psychoactive pharmaceuticals, which are common aquatic contaminants. We hypothesized that exposure to an antidepressant pollutant, fluoxetine, influences the physiological stress response in our model species, crucian carp, affecting its behavioral and morphological responses to predation threat. We examined short‐ and long‐term effects of fluoxetine and predator exposure on behavior and morphology in crucian carp. Seventeen days of exposure to a high dose of fluoxetine (100 µg/L) resulted in a shyer phenotype, regardless of the presence/absence of a pike predator, but this effect disappeared after long‐term exposure. Fluoxetine effects on morphological plasticity were context‐dependent as a low dose (1 µg/L) only influenced crucian carp body shape in pike presence. A high dose of fluoxetine strongly influenced body shape regardless of predator treatment. Our results highlight that environmental pollution by pharmaceuticals could disrupt physiological regulation of ecologically important inducible defenses.

Comparison of Machine Learning Models for the Androgen Receptor.

The androgen receptor (AR) is a target of interest for endocrine disruption research, as altered signaling can affect normal reproductive and neurological development for generations. In an effort to prioritize compounds with alternative methodologies, the U.S. Environmental Protection Agency (EPA) used in vitro data from 11 assays to construct models of AR agonist and antagonist signaling pathways. While these EPA ToxCast AR models require in vitro data to assign a bioactivity score, Bayesian machine learning methods can be used for prospective prediction from molecule structure alone. This approach was applied to multiple types of data corresponding to the EPA's AR signaling pathway with proprietary software, Assay Central. The training performance of all machine learning models, including six other algorithms, was evaluated by internal 5-fold cross-validation statistics. Bayesian machine learning models were also evaluated with external predictions of reference chemicals to compare prediction accuracies to published results from the EPA. The machine learning model group selected for further studies of endocrine disruption consisted of continuous AC50 data from the February 2019 release of ToxCast/Tox21. These efforts demonstrate how machine learning can be used to predict AR-mediated bioactivity and can also be applied to other targets of endocrine disruption.

Human Reproduction: Target of Endocrine Disruptors

György Csaba* Author Affiliations Department of Genetics, Cell and Immunobiology, Budapest, Hungary Received: June 24, 2019 | Published: July 03, 2019 Corresponding author: György Csaba, Department of Genetics, Cell and Immunobiology, Budapest, Hungary DOI: 10.26717/BJSTR.2019.19.003288 Also View In:

The parental brain and behavior: A target for endocrine disruption.

During pregnancy, the sequential release of progesterone, 17β-estradiol, prolactin, oxytocin and placental lactogens reorganize the female brain. Brain structures such as the medial preoptic area, the bed nucleus of the stria terminalis and the motivation network including the ventral tegmental area and the nucleus accumbens are reorganized by this specific hormonal schedule such that the future mother will be ready to provide appropriate care for her offspring right at parturition. Any disruption to this hormone pattern, notably by exposures to endocrine disrupting chemicals (EDC), is therefore likely to affect the maternal brain and result in maladaptive maternal behavior. Development effects of EDCs have been the focus of intense study, but relatively little is known about how the maternal brain and behavior are affected by EDCs. We encourage further research to better understand how the physiological hormone sequence prepares the mother's brain and how EDC exposure could disturb this reorganization.

Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis

Retinoids are essential for reproduction. Most research has focused on the role of retinoic acid signaling in the regulation of meiosis during early fetal germ cell development. However, less attention has been paid to the possible effects of retinoic acid signaling in adult female gonads. Retinoic acid, its receptors, and the key enzymes required for retinoic acid synthesis are expressed in the ovaries and they are involved in the regulation of folliculogenesis and steroidogenesis. Exposure to compounds that can interfere with normal retinoic acid signaling is associated with adverse ovarian outcomes, including altered steroidogenesis and reduction in indicators of ovarian reserve in women and laboratory animal models. These observations call for more attention to retinoids as regulators of adult ovarian physiology and as possible targets of endocrine disruption by environmental chemicals. In this review, we summarize the current knowledge of retinoids in folliculogenesis and steroidogenesis in post-pubertal mammalian ovaries.

The Protein Arginine Methyltransferase 5‐mediated Symmetric Dimethylation of Histone H4R3 as a Target of Endocrine Disruptors and its Molecular Consequences

Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT that catalyzes the symmetric dimethylation of arginine residues of many histone and non‐histone proteins. The resultant symmetrically dimethylated arginine on histone H4 (H4R3me2s) is a critical histone mark found to be associated with repressed genes. Endocrine disruptors (EDs) are chemicals whose environmental and occupational exposure significantly affects the endocrine homeostasis and have been associated with health hazards. However, the underlying mechanisms including epigenetic alterations are not well understood. In the present study, we show that PRMT5/H4R3me2s is a target of four common environmental EDs (bisphenol A, 4‐nonylphenol, di‐2‐ethylhexyl phthalate, and cadmium) resulting in cellular proliferation in vitro. Exposure of these four EDs to the MCF‐7 or HEK293 cells exhibited a significant increase of both PRMT5 expression and global level of H4R3me2s. The western blotting and chromatin immunoprecipitation analysis suggest these chemicals coincidently increased the level of specificity protein 1 (SP1) and nuclear factor Y alpha (NFYA) and their enrichment in the PRMT5 proximal promoter. Interestingly, all the EDs exerted dose‐dependent inhibitory action on p21CDKN1A expression while cyclin D1 expression was increased. Finally, we demonstrated an enhanced selective enrichment of H4R3me2s at the proximal promoter of p21 but not cyclin D1. We propose this significant alteration in the p21 promoter might have contributed in increased recruitment of DNMT3A and HDAC1 and subsequent hypermethylation of p21 promoter CpG island and deacetylation of the promoter histones. As PRMT5 is an oncogene often overexpressed in many cancers, elevation of its activity and function by these exogenous EDs could potentially initiate cancer through epigenetic mechanisms as observed in this study.Support or Funding InformationThe authors are thankful to SERB, Central University of Kerala, and KSCSTE for financial support for the experiments.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Disruption of oocyte maturation by selected environmental chemicals in zebrafish

Oocyte maturation can be a target of endocrine disruption by environmental chemicals capable of acting as hormone mimics, receptor blockers, and/or enzyme inhibitors. Six environmental chemicals (genistein, endosulfan, malathion, iprodione, carbaryl, and glyphosate) were selected to determine their ability to interfere with oocyte maturation in zebrafish. The translucent oocytes undergoing germinal vesicle (nucleus) breakdown (GVBD) were counted and expressed as a ratio of oocytes undergoing GVBD and total oocytes exposed. The GVBD increased significantly in oocytes exposed to 10 IU/ml to 100 IU/ml human chorionic gonadotropin (hCG). The lowest effective concentration of genistein that inhibited hCG-induced GVBD was 30 μM, while endosulfan inhibited it at 0.03 μM concentration. In addition, malathion inhibited hCG-induced GVBD at the lowest concentration of 60 μM. These inhibitory effects were likely due to the chemicals acting as estrogen mimics, induction of estrogen receptors, or increase in aromatase activity resulting in enhanced estrogen action. Fungicide iprodione, possibly acting as a progestin mimic, promoted hCG-induced GVBD at the lowest concentration of 20 μM, while the weed killer glyphosate inhibited hCG-induced GVBD starting at the 50 μM concentration. These results demonstrate the feasibility of using fully grown zebrafish oocytes arrested at the prophase I stage in an in vitro incubation system to evaluate the effects of a variety of environmental chemicals on oocyte maturation.

Wastewater treatment plant effluent alters pituitary gland gonadotropin mRNA levels in juvenile coho salmon (Oncorhynchus kisutch)

It is well known that endocrine disrupting compounds (EDCs) present in wastewater treatment plant (WWTP) effluents interfere with reproduction in fish, including altered gonad development and induction of vitellogenin (Vtg), a female-specific egg yolk protein precursor produced in the liver. As a result, studies have focused on the effects of EDC exposure on the gonad and liver. However, impacts of environmental EDC exposure at higher levels of the hypothalamic-pituitary-gonad axis are less well understood. The pituitary gonadotropins, follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh) are involved in all aspects of gonad development and are subject to feedback from gonadal steroids making them a likely target of endocrine disruption. In this study, the effects of WWTP effluent exposure on pituitary gonadotropin mRNA expression were investigated to assess the utility of Lh beta-subunit (lhb) as a biomarker of estrogen exposure in juvenile coho salmon (Oncorhynchus kisutch). First, a controlled 72-h exposure to 17α-ethynylestradiol (EE2) and 17β-trenbolone (TREN) was performed to evaluate the response of juvenile coho salmon to EDC exposure. Second, juvenile coho salmon were exposed to 0, 20 or 100% effluent from eight WWTPs from the Puget Sound, WA region for 72h. Juvenile coho salmon exposed to 2 and 10ng EE2L⿿1 had 17-fold and 215-fold higher lhb mRNA levels relative to control fish. Hepatic vtg mRNA levels were dramatically increased 6670-fold, but only in response to 10ng EE2L⿿1 and Fsh beta-subunit (fshb) mRNA levels were not altered by any of the treatments. In the WWTP effluent exposures, lhb mRNA levels were significantly elevated in fish exposed to five of the WWTP effluents. In contrast, transcript levels of vtg were not affected by any of the WWTP effluent exposures. Mean levels of natural and synthetic estrogens in fish bile were consistent with pituitary lhb expression, suggesting that the observed lhb induction may be due to estrogenic activity of the WWTP effluents. These results suggest that lhb gene expression may be a sensitive index of acute exposure to estrogenic chemicals in juvenile coho salmon. Further work is needed to determine the kinetics and specificity of lhb induction to evaluate its utility as a potential indicator of estrogen exposure in immature fish.

Androgens modulate gene expression and specific DNA methylation pattern of steroid 5α-reductases in the frog Silurana tropicalis

In vertebrates, androgens are essential in many biological functions, including reproduction, immune system, metabolism, cardiovascular function, and the central nervous system. The most potent androgen 5α-dihydrotestosterone (5α-DHT), which is actively involved in sexual differentiation and development, is converted from testosterone (T) by the steroid 5α-reductases type 1, 2, and 3 (Srd5α1, Srd5α2, and Srd5α3). Alternatively, steroid 5β-reductase (Srd5β) converts T to 5β-dihydrotestosterone (5β-DHT), a metabolite believed to be involved in steroid clearance. Recent studies suggested that Srd5 isoforms are targets for endocrine disruption. Thus, understanding the regulation of Srd5 is important to expand our knowledge on how exogenous compounds can interfere with these enzymes. In this study, we exposed frog brain, liver, and gonads ex vivo to T, 5α-DHT, and 5β-DHT in order to investigate the regulation of srd5 in response to androgens as a simulation of endocrine disrupting chemicals with androgenic properties. Androgens did not modulate srd5α2, suggesting that this isoform is not regulated by T and 5α-DHT in frogs. However, the DNA methylation of srd5α2 increased following 5α-DHT treatment suggesting that androgens can modulate epigenetic mechanisms in amphibians. In contrast, the DNA methylation of srd5α1 and srd5α3 remained stable after androgen exposure, but the mRNA levels of srd5α1 and srd5α3 were modulated by T, 5α-DHT, and 5β-DHT in a sex- and tissue-specific manner. While T positively regulates srd5α1 and srd5α3 in testes, T negatively regulates srd5α3 in ovaries. Moreover, exposure to T also increased the mRNA level of srd5β in the male brain suggesting a mechanism to protect the brain from androgen action by elimination of T into 5β-DHT. Thus, exogenous compounds with androgenic properties potentially interact with srd5 transcription and DNA methylation pattern, which could adversely affect biological functions of vertebrates during development and reproduction.

Environmental endocrine disruptors and kisspeptin system

Environmental endocrine disruptors have garnered considerable attention in recent years be-cause of their endocrine disruption on sex development disorders. Kisspeptin system might be a novel target for endocrine disruption at the hypothalamic-pituitary-gonad axis. Environmental endocrine disruptors′estrogenic properties make them capable of interacting with the kisspeptin system,and then confer lifelong consequences in-cluding altered pubertal timing, infertility, and metabolic disorders. To date, three compounds have been well studied for their capacity to interfere with kisspeptin signaling pathways：BPA,PCB mixtures,and the phytoestro-gen GEN. Key words: Environmental endocrine disruptors; Kisspeptin system

Reprint of “Current perspectives on the androgen 5 alpha-dihydrotestosterone (DHT) and 5 alpha-reductases in teleost fishes and amphibians”

The androgen 5 alpha-dihydrotestosterone (DHT) is a steroidogenic metabolite that has received little attention in non-mammalian species. DHT is produced by the reduction of the double-bond of testosterone by a group of enzymes called 5 alpha-reductases of which there can be multiple isoforms (i.e., srd5a1, srd5a2, and srd5a3). Data from amphibians suggest that the expression of the srd5a genes occurs in early development, and continues until adulthood; however insufficient data exist in fish species, where DHT is thought to be relatively biologically inactive. Here, we demonstrate that fathead minnow (FHM; Pimephales promelas) developing embryos and adults express srd5a enzyme isoforms. During FHM embryogenesis, both srd5a1 and srd5a3 mRNA levels were significantly correlated in expression levels while srd5a2 showed a more unique pattern of expression. In adult FHMs, males had significantly higher levels of srd5a2 in the liver and gonad compared to females. In the male and female liver, transcript levels for srd5a2 were more abundant compared to srd5a1 and srd5a3, suggesting a prominent role for srd5a2 in this tissue. Interestingly, the ovary expressed higher mRNA levels of srd5a3 than the testis. Thus, data suggest that srd5a isoforms can show sexually dimorphic expression patterns in fish. We also conducted a literature review of the biological effects observed in embryonic and adult fish and amphibians after treatments with DHT and DHT-related compounds. Treatments with DHT in teleost fishes and amphibians have resulted in unexpected biological responses that are characteristic of both androgens and anti-androgens. For example, in fish DHT can induce vitellogenin in vitro from male and female hepatocytes and can increase 17β-estradiol production from the teleost ovary. We propose, that to generate further understanding of the roles of DHT in non-mammals, studies are needed that (1) address how DHT is synthesized within tissues of fish and amphibians; (2) examine the full range of biological responses to endogenous DHT, and its interactions with other signaling pathways; and (3) investigate how DHT production varies with reproductive stage. Lastly, we suggest that the Srd5a enzymes can be targets of endocrine disruptors in fish and frogs, which may result in disruptions in the estrogen:androgen balance in aquatic organisms.

Regulation of vitellogenin genes in insects

AbstractVitellogenins (Vg) genes code for the major egg yolk protein precursor in insects and many other oviparous species. In insects, the Vg gene is expressed extra‐ovarially in the fat body in sex‐, tissue‐ and stage‐specific manners. During the reproductive phase, the Vg mRNA is expressed in large quantities, which is then translated, secreted into hemolymph and ultimately taken up by the developing oocytes through receptor‐mediated endocytosis. Once sequestered, the Vgs are stored as vitellin (Vn), the main nutritional reserve for the developing embryo. The regulation of Vg genes is directly under the control of hormones at the transcriptional level. Hormones involved in Vg gene transcription are juvenile hormone (JH), ecdysteroids and some neuropeptides. The overall understanding that has emerged is that the insects can be classified, based on the system of hormonal regulation of Vg gene transcription, into three groups: (i) insects (like most of hemipterans) that use only JH for Vg gene transcription; (ii) insects (like dipterans) that need both JH and ecdysteroids for Vg regulation; and (iii) insects like lepidopterans that require JH, ecdysteroids and additional hormones to regulate their reproductive biology. However, why insect species diverge in using different hormones to govern their reproductive physiology remains unclear. The present contribution focuses on the current status of knowledge regarding the regulation of Vg genes in insects. Besides a brief information on biochemical and molecular features, the role of Vg genes as a target of endocrine disruptors will be addressed. Also, the molecular mechanism of Vg gene regulation will be discussed.

The microbiome as a target for endocrine disruptors: Novel chemicals may disrupt androgen and microbiome-mediated autoimmunity

In non-obese diabetic (NOD) mice, there is a sex-biased increase in female incidence of type 1 diabetes. Recently, the microbiome was found to protect male mice from type 1 diabetes. Transfer of microbiota from adult NOD male mice to pre-pubertal female mice protects against later incidence of sex-biased type 1 diabetes. This protection involves, in part, microbiome-mediated increased testosterone synthesis, which up-regulates the interleukin and interferon pathways. The microbiome-derived signals that mediate this response are unknown, although due to the diversity of chemicals synthesized in the microbiome some are likely to have structures unlike androgens. This suggests that novel synthetic and/or plant-derived chemicals may affect sex-biased autoimmune diseases through disruption of protective signaling networks between the microbiome and its host.

Current perspectives on the androgen 5 alpha-dihydrotestosterone (DHT) and 5 alpha-reductases in teleost fishes and amphibians

The androgen 5 alpha-dihydrotestosterone (DHT) is a steroidogenic metabolite that has received little attention in non-mammalian species. DHT is produced by the reduction of the double-bond of testosterone by a group of enzymes called 5 alpha-reductases of which there can be multiple isoforms (i.e., srd5a1, srd5a2, and srd5a3). Data from amphibians suggest that the expression of the srd5a genes occurs in early development, and continues until adulthood; however insufficient data exist in fish species, where DHT is thought to be relatively biologically inactive. Here, we demonstrate that fathead minnow (FHM; Pimephales promelas) developing embryos and adults express srd5a enzyme isoforms. During FHM embryogenesis, both srd5a1 and srd5a3 mRNA levels were significantly correlated in expression levels while srd5a2 showed a more unique pattern of expression. In adult FHMs, males had significantly higher levels of srd5a2 in the liver and gonad compared to females. In the male and female liver, transcript levels for srd5a2 were more abundant compared to srd5a1 and srd5a3, suggesting a prominent role for srd5a2 in this tissue. Interestingly, the ovary expressed higher mRNA levels of srd5a3 than the testis. Thus, data suggest that srd5a isoforms can show sexually dimorphic expression patterns in fish. We also conducted a literature review of the biological effects observed in embryonic and adult fish and amphibians after treatments with DHT and DHT-related compounds. Treatments with DHT in teleost fishes and amphibians have resulted in unexpected biological responses that are characteristic of both androgens and anti-androgens. For example, in fish DHT can induce vitellogenin in vitro from male and female hepatocytes and can increase 17β-estradiol production from the teleost ovary. We propose, that to generate further understanding of the roles of DHT in non-mammals, studies are needed that (1) address how DHT is synthesized within tissues of fish and amphibians; (2) examine the full range of biological responses to endogenous DHT, and its interactions with other signaling pathways; and (3) investigate how DHT production varies with reproductive stage. Lastly, we suggest that the Srd5a enzymes can be targets of endocrine disruptors in fish and frogs, which may result in disruptions in the estrogen:androgen balance in aquatic organisms.

No substantial changes in estrogen receptor and estrogen-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals

Estrogen receptor orthologues in molluscs may be targets for endocrine disruptors, although mechanistic evidence is lacking. Molluscs are reported to be highly susceptible to effects caused by very low concentrations of environmental estrogens which, if substantiated, would have a major impact on the risk assessment of many chemicals. The present paper describes the most thorough evaluation to-date of the susceptibility of Marisa cornuarietis ER and ERR gene transcription to modulation by vertebrate estrogens in vivo and in vitro. We investigated the effects of estradiol-17β and 4-tert-Octylphenol exposure on in vivo estrogen receptor (ER) and estrogen-related receptor (ERR) gene transcription in the reproductive and neural tissues of the gastropod snail M. cornuarietis over a 12-week period. There was no significant effect (p>0.05) of treatment on gene transcription levels between exposed and non-exposed snails. Absence of a direct interaction of estradiol-17β and 4-tert-Octylphenol with mollusc ER and ERR protein was also supported by in vitro studies in transfected HEK-293 cells. Additional in vitro studies with a selection of other potential ligands (including methyl-testosterone, 17α-ethinylestradiol, 4-hydroxytamoxifen, diethylstilbestrol, cyproterone acetate and ICI182780) showed no interaction when tested using this assay. In repeated in vitro tests, however, genistein (with mcER-like) and bisphenol-A (with mcERR) increased reporter gene expression at high concentrations only (>10−6M for Gen and >10−5M for BPA, respectively). Like vertebrate estrogen receptors, the mollusc ER protein bound to the consensus vertebrate estrogen-response element (ERE). Together, these data provide no substantial evidence that mcER-like and mcERR activation and transcript levels in tissues are modulated by the vertebrate estrogen estradiol-17β or 4-tert-Octylphenol in vivo, or that other ligands of vertebrate ERs and ERRs (with the possible exception of genistein and bisphenol A, respectively) would do otherwise.

Stem Cell-Derived in Vitro Models for Investigating the Effects of Endocrine Disruptors on Developing Neurons and Neuroendocrine Cells

Neuroendocrine cells are a set of specialized hormone-releasing neurons that control most vital functions in humans and wildlife, such as growth, reproduction, metabolism, and stress responses. Increasing evidence points to neuroendocrine cells as the primary neuronal target of endocrine disruptors. Endocrine disruption appears to be most significant during prenatal and early postnatal development. However, limitations with traditional cell culture models of neuronal development led to a lack of understanding regarding the mechanisms by which endocrine disruptors affect neurodevelopment. In recent years, Stem Cell-derived neuronal models have become available and may offer distinct advantages over other in vitro model systems for investigating the effects of endocrine disruptors on the developing brain. Further, recently new models of Stem Cell-derived neuroendocrine cells that may provide more effective ways for studying the effects of endocrine disruptors directly on developing neuroendocrine cells in vitro were developed. This constitutes a review of currently available cell models of developing neurons that have been used to investigate in vitro effects of endocrine disruptors on developing brain. The review also presents recently developed models of Stem Cell-derived neuroendocrine cells that might be used to investigate in vitro effects of endocrine disruptors and their mechanisms of action directly on the developing neuroendocrine cells.

Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

BackgroundProstaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics.Objectives and MethodsUsing cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption.ResultsWe found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator–activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes.ConclusionOur findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades.