Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation
Sophie-Christine de Aguiar Greca, Ioannis Kyrou, Ryan Pink, Harpal Randeva, Dimitris Grammatopoulos, Elisabete Silva, Emmanouíl Karteris
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.