Differential effect of bisphenols (BPA, BPF and BPS) in regulating gene expression and receptivity in endometrial epithelial Ishikawa cells

Abstract

Bisphenol A (BPA) is commonly found in epoxy resins used in the manufacture of plastic coatings in food packaging and beverage cans. There is growing concern about BPA as a weak estrogenic compound that can affect human endocrine function. Chemicals structurally similar to BPA including BPF and BPS have been developed as substitutes in the manufacturing industry. Whether these bisphenol substitutes have adverse effects on human endocrine systems and reproductive health remains largely unknown. This study aimed to investigate if BPA, BPF, and BPS affect endometrial stromal cell proliferation, receptor expression, gene transactivation and spheroid attachment in vitro. All three bisphenols inhibited Ishikawa cell proliferation at 100 μM with potency BPA>BPF>BPS. Bisphenol from 1-100μM could suppressed the expression of estrogen receptors (ERα and ERβ) and membrane receptor GPR30. BPA and BPF have stronger transactivation activities than BPS on ERE-Luciferase reporter assay in the transfected Ishikawa cells. Addition of ICI 182,780 (ERs antagonist) or MPP (ERα-specific antagonist), but not G15 (GPR30 antagonist) could nullify the transactivation activity of the reporter construct. Furthermore, microarray analysis of BPA, BPS and BPF treated Ishikawa cells induced similar transcriptomic changes, although the expression of several nuclear receptors and focal adhesion molecules were found to be differentially regulated. Importantly, the expression of progesterone receptor was up-regulated by bisphenols at micromolar concentrations. Taken together, BPA, BPS and BPF share similar structural and biological properties. Changes in steroid receptor expressions modulate various down-stream signaling pathway resulting in changes in receptivity of the endometrial epithelial cells in vitro. [This project is supported in part by grants from CRCG/HKU and GRF/RGC 17120415 to KFL]