BPA activates EGFR and ERK1 /2 through PPARγ to increase expression of steroidogenic acute regulatory protein in human cumulus granulosa cells

Bisphenol A (SPA) negatively affects steroid production in human luteinized granulosa cells (GC). This study was designed to address two important questions: (1) whether BPA exerts the same disruptive effect in human cumulus granulosa cells (hCGC) and (2) to reveal the molecular mechanism underlying the BPA's action on steroidogenesis. We used cultured hCGC since these cells exert the properties of CC from early antral follicles. Results showed that BPA at 100 mu M decreased estradiol level and CYPI9AI mRNA, but increased progesterone production, steroidogenic acute regulatory protein (STAR) and peroxisome proliferator-activated receptor gamma (PPAR gamma) mRNA expression after 48 h. Shorter (6 h) exposure to BPA elevated PPAR gamma mRNA level in hCGC. Addition of ERK1/2 (U0126), EGFR (AG1478) and PPAR gamma (GW9662) inhibitors prevented the BPA-induced STAR and PPAR gamma mRNA expression. Western blot analysis showed that BPA induced a rapid EGFR and ERK1/2 activation. The BPA-induced EGFR phosphorylation was prevented by addition of the PPAR gamma inhibitor, whereas the BPA-induced ERK1 /2 activation was prevented by addition of the EGFR or PPAR gamma inhibitor. These data show that BPA increases the progesterone and decreases the estradiol biosynthetic pathway in hCGC. Augmentation of the progesterone biosynthetic pathway is mediated through the PPAR gamma-dependent activation of EGFR and ERK1/2, leading to increased expression of STAR mRNA. (C) 2019 Elsevier Ltd. All rights reserved.