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

Abstract

BackgroundBisphenol 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.ObjectivesWe investigated whether BPA affects human ovarian granulosa cell function.MethodsWe 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.ResultsBPA 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.ConclusionsOverall, 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.

Scientific Opinion on Bisphenol A: evaluation of a study investigating its neurodevelopmental toxicity, review of recent scientific literature on its toxicity and advice on the Danish risk assessment of Bisphenol A

“…Micromolar BPA concentrations inhibited purified and microsomal aromatase activities (Benachour et al, 2007) and potentially reduced oestrogen synthesis by reducing aromatase activity in placental cells (Huang and Leung, 2009) or aromatase expression in granulosa cells (Kwintkiewicz et al, 2010). This is in line with other recent studies (Zhou et al, 2008;Huang and Leung, 2009).…”

Bisphenol A modulates the metabolic regulator oestrogen-related receptor-α in T-cells

“…ERRa is present in a wide variety of cell types and is highly expressed in cells with elevated metabolic demand such as heart, skeletal muscle and brown adipose tissue (Eichner & Giguère 2011). It is suggestive to note that BPA has shown affinity for the metabolic regulator PPARg in a previous study (Kwintkiewicz et al 2010) and in addition there is evidence of agonist interaction between PPARg and ERRa (Willy et al 2004) and PPARg and ERb (Foryst-Ludwig et al 2008). More recently, Marmugi et al (2012) have used a transcriptomic approach to show that exposure of male CD1 mice to low doses of BPA was able to influence de novo fatty acid synthesis through alterations in lipogenic genes.…”

“…Many of the physiological effects of BPA have been studied in relation to its widely reported activity as an oestrogen agonist (Lee et al 2003, Chapin et al 2008. A number of additional receptor-mediated effects have been reported including anti-androgen activity (Bonefeld-Jørgensen et al 2007), thyroid hormone disruption (Moriyama et al 2002), altered pancreatic b-cell function (Ropero et al 2008, Soriano et al 2012 and obesity-promoting effects (Newbold et al 2008, Marmugi et al 2012, binding to oestrogen-related receptor gamma (ERRg; Takayanagi et al 2006, Okada et al 2008) and activation of peroxisome proliferatoractivated receptor-g (PPARg)-mediated pathways (Kwintkiewicz et al 2010). A confirmation of BPA interaction with a large number of different pathways was obtained from computational analysis of the extensive in vitro tests carried out within the ToxCast program (Reif et al 2010).…”

Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling

“…Furthermore, BPA (100 mM) decreased progesterone production, decreased expansion of cumulus cells and inhibited oocyte maturation in porcine oocyte-cumulus complexes (Mlynarcíková et al 2009). BPA treatment (40-100 mM) decreased aromatase mRNA and protein, and reduced E 2 production by primary human granulosa cells and a human ovarian granulosa-like tumor cell line (Kwintkiewicz et al 2010). Neonatal female caiman exposed in ovum to BPA at 1.4 and 140 ppm had increased E 2 serum levels, while 1.4 ppm BPA resulted in decreased testosterone levels compared with vehicle-treated controls (Stoker et al 2008).…”