title: Low concentrations of bisphenol A induce mouse spermatogonial cell proliferation by G protein-coupled receptor 30 and estrogen receptor-α.
abstract: 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.
  
  
  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.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Sheng
authors.forename: Ben-Zhan
authors.initials: BZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D008156:Luciferases; D008297:Male; D051379:Mice; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D010636:Phenols / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013093:Spermatogonia / Q000166:cytology* / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D053148:Caspase 3; D017362:Cyclic AMP Response Element-Binding Protein; D017869:Cyclic GMP-Dependent Protein Kinases; D017931:DNA Primers; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D008156:Luciferases; D020319:Oligodeoxyribonucleotides, Antisense; D010636:Phenols; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D016160:Retinoblastoma Protein; D013778:Tetrazolium Salts; D013844:Thiazoles; C492004:Creb1 protein, mouse; C532507:GPER1 protein, mouse; C022616:thiazolyl blue; C006780:bisphenol A; D000098826:Bisphenol A Compounds