Low Concentrations of Bisphenol A Induce Mouse Spermatogonial Cell Proliferation by G Protein–Coupled Receptor 30 and Estrogen Receptor-α

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  • BACKGROUND: Bisphenol A (BPA) is one of the most prevalent chemicals in daily-use materials; therefore, human exposure to BPA is ubiquitous. The estrogenicity of BPA is generally mediated by nuclear estrogen receptors (ERs). However, low concentrations of BPA stimulate seminoma cell proliferation by an uncertain mechanism that does not involve activation of ERs. OBJECTIVE: We investigated the possible promoting effects of low-concentration BPA and the possible mechanism(s) using the murine ER-β negative spermatogonial GC-1 cell line. METHODS AND RESULTS: Using the specific signaling inhibitor, BPA at test concentrations ranging from 10⁻¹⁰ to 10⁻⁸ M markedly induced proliferation of GC-1 cells by activating both cGMP-dependent protein kinase (PKG) and epidermal growth factor receptor (EGFR) extracellular regulated kinase (ERK) pathways. BPA stimulated a rapid (15-min) phosphorylation of the transcription factor cAMP response element binding protein (CREB) and the cell cycle regulator retinoblastoma protein (Rb). Interestingly, ER-α phosphorylation is involved in the proliferation, whereas BPA does not directly transactivate ER-α in gene reporter assays. Using specific agonists and gene silencing, we further observed that BPA mediates the proliferation and fos gene expression of GC-1 cells by G protein-coupled receptor 30 (GPR30) and ER-α. CONCLUSIONS: Our data suggest that low concentrations of BPA activate the PKG and EGFR/ERK/c-fos pathways through a cross-talk between GPR30 and ER-alpha, which in turn stimulates GC-1 cell proliferation. The present study provides a novel insight regarding the potential role of GPR30 and ER-alpha in mediating the proliferative effects of BPA in male germ cells.
  • Keywords: GPR30, Beta, Activation, Breast cancer, mouse spermatogonial GC-1 cells, G protein-coupled receptor 30, Growth factor receptor, Phosphorylation, Pathway, Ovarian cancer cells, Bisphenol A, Expression, 17 [beta]-estradiol, Estrogen receptor-[alpha]
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  • Sheng, Z., & Zhu, B. (2011). Low concentrations of bisphenol A induce mouse spermatogonial cell proliferation by G protein-coupled receptor 30 and estrogen receptor-α. Environmental Health Perspectives, 119(12), 1775-1780. doi: 10.1289/ehp.1103781
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  • 119
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  • 12
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  • This work was supported by grant 8CB418106 from the Major State Basic Research Development Program of China and grant 20907070 from the National Natural Science Foundation of China (NSFC) to Z.‑G.S., and by grants 20925724, 20877081, 20890112, and 20921063 from the NSFC and and grants ES11497, RR01008, and ES00210 from the U.S. National Institutes of Health to B.‑Z.Z.
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