[Toxicity of bisphenol S on human normal ovarian epithelial cells mediated by ERβ-MAPK signaling pathway]

To investigate the effects of long-term(7 days and 14 days) bisphenol S(BPS) exposure on the ERβ-MAPK signaling pathway, hormone secretion phenotype and cell cycle in human normal ovarian epithelial cells IOSE 80 at actual human exposure level.

Physiologically based pharmacokinetic model combined with BPS levels in the serum of women along the Yangtze River in China was used to determine the dosing concentrations of BPS, and vehicle control and 17 β-estradiol(E_2) control were used. Complete medium with corresponding concentrations(0, 6.79×10~(-6), 6.79×10~(-4), 6.79×10~(-2), 6.79 μmol/L BPS and 10 nmol/L E_2) was replaced every 2 days. mRNA expressions of estrogen receptor(ERβ and GPR30), key genes in MAPK signaling pathway(P38/JNK/ERK signaling pathway) and gonadotropin-releasing hormone-related genes(GnRH-I, GnRH-II and GnRH-R) were measured by qPCR. The ERβ-MAPK signaling pathway inhibitors were employed to detect the effect of long-term exposure to BPS on the cell cycle by flow cytometry. Dose-response relationship analysis was performed to calculate the benchmark does lower confidence limits.

Compared to the vehicle control, after 7 days exposure to BPS, the ratio of G_2/M phase was significantly increased(P<0.05), and the mRNA expressions of GnRH-I, GnRH-II and GnRH-R were significantly decreased(P<0.05); after 14 days exposure to BPS, the mRNA expressions of ESR2, MAPK3, and MAPK9 were significantly increased(P<0.05), and the mRNA expressions of GnRH-II and GnRH-R were significantly decreased(P<0.05). The GnRH-II mRNA expression level of BPS treatment for 7 days; the G_0/G_1 phase ratio, MAPK3 and MAPK8 mRNA expression level of BPS exposure for 14 days; and the GnRH-I mRNA expression level after BPS treatment for 7 days and 14 days showed a good dose-response relationship but with poor fit.

Long-term low-dose exposure to BPS may cause cell cycle arrest by activating the ERβ-MAPK signaling pathway, and may lead to changes in the hormone secretion of IOSE 80 cells.