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

PROTEIN metabolism; ANIMAL experimentation; BIOPHYSICS; CELL physiology; DOSE-effect relationship in pharmacology; EPIDERMAL growth factor; RESEARCH methodology; MICE; PHENOLS; POLYMERASE chain reaction; RESEARCH funding; SPERMATOZOA; T-test (Statistics); THIAZOLES; WESTERN immunoblotting; DATA analysis software; DESCRIPTIVE statistics

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-α, which in turn stimulates GC-1 cell proliferation. The present study provides a novel insight regarding the potential role of GPR30 and ER-α in mediating the proliferative effects of BPA in male germ cells. [ABSTRACT FROM AUTHOR]

Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)