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Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation.

ABSTRACT: BACKGROUND:Endocrine-disrupting chemicals (EDCs) are environmental chemicals/toxicants that humans are exposed to, interfering with the action of multiple hormones. Bisphenol A (BPA) is classified as an EDC with xenoestrogenic activity with potentially adverse effects in reproduction. Currently, a significant knowledge gap remains regarding the complete spectrum of BPA-induced effects on the human placenta. As such, the present study examined the effects of physiologically relevant doses of BPA in vitro. METHODS:qRT-PCR, Western blotting, immunofluorescence, ELISA, microarray analyses, and bioinformatics have been employed to study the effects of BPA using nonsyncytialised (non-ST) and syncytialised (ST) BeWo cells. RESULTS:Treatment with 3 nM BPA led to an increase in cell number and altered the phosphorylation status of p38, an effect mediated primarily via the membrane-bound estrogen receptor (GPR30). Nonbiased microarray analysis identified 1195 and 477 genes that were differentially regulated in non-ST BeWo cells, whereas in ST BeWo cells, 309 and 158 genes had altered expression when treated with 3 and 10 nM, respectively. Enriched pathway analyses in non-ST BeWo identified a leptin and insulin overlap (3 nM), methylation pathways (10 nM), and differentiation of white and brown adipocytes (common). In the ST model, most significantly enriched were the nuclear factor erythroid 2-related factor 2 (NRF2) pathway (3 nM) and mir-124 predicted interactions with cell cycle and differentiation (10 nM). CONCLUSION:Collectively, our data offer a new insight regarding BPA effects at the placental level, and provide a potential link with metabolic changes that can have an impact on the developing fetus.

SUBMITTER: de Aguiar Greca SC

PROVIDER: S-EPMC7074564 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation.

de Aguiar Greca Sophie-Christine SC Kyrou Ioannis I Pink Ryan R Randeva Harpal H Grammatopoulos Dimitris D Silva Elisabete E Karteris Emmanouil E

Journal of clinical medicine 20200203 2

<h4>Background</h4>Endocrine-disrupting chemicals (EDCs) are environmental chemicals/toxicants that humans are exposed to, interfering with the action of multiple hormones. Bisphenol A (BPA) is classified as an EDC with xenoestrogenic activity with potentially adverse effects in reproduction. Currently, a significant knowledge gap remains regarding the complete spectrum of BPA-induced effects on the human placenta. As such, the present study examined the effects of physiologically relevant doses ...[more]

PMID: 32028606

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Project description:Aim: Evidence suggests that bisphenol A diglycidyl ether (BADGE), bisphenol A (BPA), and BPA analogs can interfere with human male fertility. However, the effect directly on human sperm function is not known. The CatSper Ca2+ channel in human sperm controls important sperm functions and is necessary for normal male fertility. Environmental chemicals have been shown to activate CatSper and thereby affect Ca2+ signaling in human sperm. BPA has previously been investigated for effects on Ca2+ signaling human sperm, whereas the effects of other BPA analogs are currently unknown. The aim of this study is thus to characterize the effect of BADGE, BPA, and the eight analogs BPG, BPAF, BPC, BPB, BPBP, BPE, BPF, BPS on Ca2+ signaling, and CatSper in human sperm. Methods: Direct effects of the bisphenols on Ca2+ signaling in human sperm cells were evaluated using a Ca2+ fluorimetric assay measuring changes in intracellular Ca2+. Effects via CatSper were assessed using the specific CatSper inhibitor RU1968. Effects on human sperm function was assessed using an image cytometry-based acrosome reaction assay and the modified Kremer's sperm-mucus penetration assay. Results: At 10 ?M the bisphenols BPG, BPAF, BPC, BADGE, BPB, and BPBP induced Ca2+ signals in human sperm cells, whereas BPE, BPF, BPS, and BPA had no effect. The efficacy of the chemicals at 10 ?M is BPG > BPAF > BPC > BADGE > BPB > BPBP. Dose-response relations of BPG, BPAF, BPC, BADGE, BPB, and BPBP yielded EC50-values in the nM-?M range. The induced Ca2+ signals were almost completely abolished using the CatSper inhibitor RU1968, indicating an effect of the bisphenols on CatSper. All bisphenols, except BPBP, were found to dose-dependently inhibit progesterone-induced Ca2+ signals, with BPG and BPAF displaying inhibition even in low ?M doses. BPG and BPAF were shown to affect human sperm function in a progesterone-like manner. Conclusion: Our results show that the bisphenols BPG, BPAF, BPC, BADGE, BPB, and BPBP can affect Ca2+ signaling in human sperm cells through activation of CatSper. This could potentially disrupt human sperm function by interfering with normal CatSper-signaling and thus be a contributing factor in human infertility, either alone or in mixtures with other chemicals.

Project description:Glucocorticoid signaling plays a critical role in regulating energy metabolism. Emerging data implicate environmental endocrine-disrupting chemicals as contributors to the obesity and diabetes epidemics. Previous studies have shown that the phenylsulfamide fungicide tolylfluanid (TF) augments glucocorticoid receptor (GR)-dependent luciferase expression in 3T3-L1 preadipocytes while modulating insulin action in primary murine and human adipocytes. Studies were performed to interrogate glucocorticoid signaling in primary adipocytes exposed to TF. TF mimicked the gene transcription profile of the murine glucocorticoid corticosterone (Cort). Cellular fractionation assays demonstrated that TF treatment promoted the activating serine phosphorylation of GR, augmenting its cytoplasmic-to-nuclear translocation as well as its enrichment at glucocorticoid response elements on the glucocorticoid-induced leucine zipper gene promoter. After acute treatment, Cort or TF promoted insulin receptor substrate-1 (IRS-1) gene and protein expression. Either treatment also enriched GR binding at an identified glucocorticoid response element in the IRS-1 gene. TF or Cort each increased insulin-stimulated lipogenesis, an effect resulting from increased lipogenic gene expression and enhanced insulin-stimulated dephosphorylation of acetyl-coenzyme A carboxylase. The augmentation of insulin-stimulated lipogenesis was mediated through a specific enhancement of Akt phosphorylation at T308. These findings support modulation of IRS-1 levels as a mechanism for glucocorticoid-mediated changes in insulin action in primary adipocytes. Albeit with less affinity than Cort, in silico analysis suggests that TF can interact with the ligand binding pocket of GR. Collectively, these studies identify TF as a structurally unique environmental glucocorticoid. Glucocorticoid signaling may thus represent a novel pathway by which environmental toxicants promote the development of metabolic diseases.

Dataset Information

Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation.

Publications

Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation.

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