A low dose of bisphenol A stimulates estradiol production by regulating β-catenin-FOXL2-CYP19A1 pathway in human ovarian granulosa cells

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical that interferes with normal steroid hormone production in various species. However, the underlying mechanism of the effect of BPA on steroid production in the human ovary is not well understood. In the present study, we found that BPA, at very low concentrations (10−11 to 10−8 M), significantly increased the expression of FOXL2, a transcriptional factor essential for proper ovarian development and function, in a human ovarian granulosa cell-derived cell line (KGN). Furthermore, BPA enhanced CYP19A1 (aromatase) expression levels and estradiol (E2) production, but these effects were not observed in FOXL2 knockout (KO) cells. In addition, we found that BPA upregulates β-catenin (CTNNB1) and stimulates nuclear translocation of CTNNB1, leading to transcriptional activation of FOXL2 mRNA. Furthermore, BPA failed to induce CYP19A1 and E2 production in CTNNB1-silenced KGN cells. Thus, we reveal a comprehensive molecular signaling cascade encompassing BPA-CTNNB1-FOXL2-CYP19A1-E2 that contributes to the endocrine-disrupting activities of BPA in human ovarian granulosa cells.