Peroxisome Proliferator-Activated Receptor-γ Mediates Bisphenol A Inhibition of FSH-Stimulated IGF-1, Aromatase, and Estradiol in Human Granulosa Cells

BACKGROUND: Bisphenol A (BPA), a chemical used as a plasticizer, is a potent endocrine disruptor that, even in low concentrations, disturbs normal development and functions of reproductive organs in different species. OBJECTIVES: We investigated whether BPA affects human ovarian granulosa cell function. METHODS: We treated KGN granulosa cells and granulosa cells from subjects undergoing in vitro fertilization (IVF) with follicle-stimulating hormone (FSH), BPA, or BPA plus FSH in a dose- and time-dependent manner. We then evaluated expression of insulin-like growth factor 1 (IGF-1), aromatase, and transcription factors known to mediate aromatase induction by FSH [including steroidogenic factor-1 (SF-1), GATA4, cAMP response element binding protein-1 (CREB-1), and peroxisome proliferator-activated receptor-gamma (PPAR gamma)], as well as 17 beta-estradiot (E-2) secretion. KGN cells were transfected with a PPAR gamma-containing vector, followed by assessment of aromatase and IGF-1 expression. RESULTS: BPA reduced FSH-induced IGF-1 and aromatase expression and E-2 secretion in a dose-dependent fashion. Similar effects on aromatase were observed in IVF granulosa cells. SF-1 and GATA4, but not CREB-1, were reduced after BPA treatment, although PPAR gamma, an inhibitor of aromatase, was significantly up-regulated by BPA in a dose-dependent manner, with simultaneous decrease of aromatase. Overexpression of PPAR gamma in KGN cells reduced FSH-stimulated aromatase and IGF-1 mRNAs, with increasing concentrations of the transfiected expression vector, mimicking BPA action. Also, BPA reduced granulosa cell DNA synthesis without changing DNA fragmentation, suggesting that BPA does not induce apoptosis. CONCLUSIONS: Overall, the data demonstrate that BPA induces PPAR gamma, which mediates down-regulation of FSH-stimulated IGF-1, SF-1, GATA4, aromatase, and E-2 in human granulosa cells. These observations support a potential role of altered steroidogenesis and proliferation within the ovarian follicular compartment due to this endocrine disruptor.