Peroxisome proliferator-activated receptor-gamma 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.


OBJECTIVE
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 (PPARgamma)], as well as 17beta-estradiol (E2) secretion. KGN cells were transfected with a PPARgamma-containing vector, followed by assessment of aromatase and IGF-I expression.


RESULTS
BPA reduced FSH-induced IGF-1 and aromatase expression and E2 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 PPARgamma, an inhibitor of aromatase, was significantly up-regulated by BPA in a dose-dependent manner, with simultaneous decrease of aromatase. Overexpression of PPARgamma in KGN cells reduced FSH-stimulated aromatase and IGF-1 mRNAs, with increasing concentrations of the transfected 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 PPARgamma, which mediates down-regulation of FSH-stimulated IGF-1, SF-1, GATA4, aromatase, and E2 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.
Kwintkiewicz
Jakub
J
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, USA.
Nishi
Yoshihiro
Y
Yanase
Toshihiko
T
Giudice
Linda C
LC
D001141:Aromatase / Q000378:metabolism*; D001559:Benzhydryl Compounds; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity; D004781:Environmental Exposure / Q000009:adverse effects; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006107:Granulosa Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D010636:Phenols / Q000633:toxicity*; D013997:Time Factors; D000098826:Bisphenol A Compounds
D001141:Aromatase; D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D007334:Insulin-Like Growth Factor I; D047495:PPAR gamma; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds