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

• Published in: Environmental health perspectives Vol. 118; no. 3; pp. 400 - 406
• Main Authors: Kwintkiewicz, Jakub, Nishi, Yoshihiro, Yanase, Toshihiko, Giudice, Linda C.
• Format: Journal Article
• Language: English
• Published: Research Triangle Park, NC National Institute of Environmental Health Sciences 01.03.2010; US Department of Health and Human Services
• Subjects: Aromatase - metabolism; Benzhydryl Compounds; Biological and medical sciences; Bisphenols; Business publications audits; Cell Line, Tumor; Cell lines; Cell Proliferation - drug effects; Chemical and industrial products toxicology. Toxic occupational diseases; DNA; Dose-Response Relationship, Drug; Down regulation; Endocrine disruptors; Endocrine Disruptors - toxicity; Environmental Exposure - adverse effects; Estradiol - metabolism; Female; Follicle Stimulating Hormone - pharmacology; Granulosa cells; Granulosa Cells - drug effects; Granulosa Cells - enzymology; Granulosa Cells - metabolism; Humans; Insulin-Like Growth Factor I - metabolism; Medical sciences; Messenger RNA; Phenols - toxicity; PPAR gamma - agonists; PPAR gamma - metabolism; Receptors; Steroidogenesis; Time Factors; Toxicology; Various organic compounds; Human; aromatase; Enzyme; Toxicity; Estrogen; Endocrine disruptor; IGF-1; Estrogen synthase; Insulin like growth factor 1; Estradiol; In vitro; PPARγ; Bisphenol A; Ovary; FSH; Granulosa; Inhibition; Peroxisome proliferator activated receptor; Public health; Follicle stimulating hormone
• ISSN: 0091-6765; 1552-9924; 1552-9924
• DOI: 10.1289/ehp.0901161

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-γ (PPARγ)], as well as 17β-estradiol (E₂) secretion. KGN cells were transfected with a PPARγ-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 PPARγ, an inhibitor of aromatase, was significantly up-regulated by BPA in a dose-dependent manner, with simultaneous decrease of aromatase. Overexpression of PPARγ 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 PPARγ, 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.