Involvement of activating ERK1/2 through G protein coupled receptor 30 and estrogen receptor α/β in low doses of bisphenol A promoting growth of Sertoli TM4 cells

Toxicol Lett. 2014 Apr 7;226(1):81-9. doi: 10.1016/j.toxlet.2014.01.035. Epub 2014 Feb 2.


Sertoli cells play a pivotal role in supporting proliferation of germ cells and differentiation during spermatogenesis in mammals. Nanomolar concentrations of Bisphenol A (BPA) can significantly stimulate the proliferation of mouse immature Sertoli (TM4) cells. However, mechanisms by which BPA caused these effects were still unclear. In the present study, an inverse U-shaped curve was observed when treating TM4 cells with increasing doses of BPA: 1 to 10nM BPA significantly stimulated the proliferation of TM4 cells and increased the proportion of cells in S phase; >1 μM BPA caused lesser proliferation of cells. Exposure of TM4 cells to G15 or ICI 182,780, which are specific antagonists of GPR30 and estrogen receptor α/β (ERα/β), respectively, abolished BPA-induced proliferation of cells, which suggests that both GPR30 and ERα/β were involved in the observed effects of BPA. Furthermore, exposure to BPA caused rapid (5 min) activation of ERK1/2 via both GPR30 and ERα/β. Blocking the GPR30/EGFR signal transduction pathway by antagonists suppressed both phosphorylation of ERK and BPA-induced cell proliferation. BPA up-regulated mRNA and protein expression of GPR30 in a concentration-dependent manner. In summary, the results reported here indicated that activating ERK1/2 through GPR30 and ERα/β is involved in low doses of BPA that promoted growth of Sertoli TM4 cells. The GPR30/EGFR/ERK signal is the downstream transduction pathway in BPA-induced proliferation of TM4 Sertoli cells.

Keywords: Estrogen receptor α/β (ERα/β); GPR30; Male; Reproduction; Sertoli cell; TM4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / toxicity*
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Endocrine Disruptors / toxicity*
  • Enzyme Activation
  • ErbB Receptors / drug effects
  • ErbB Receptors / metabolism
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / drug effects*
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / drug effects*
  • Estrogen Receptor beta / metabolism
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phenols / toxicity*
  • Phosphorylation
  • RNA, Messenger / metabolism
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled / drug effects*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • S Phase / drug effects
  • Sertoli Cells / drug effects*
  • Sertoli Cells / enzymology
  • Sertoli Cells / pathology
  • Signal Transduction / drug effects
  • Time Factors
  • Up-Regulation


  • Benzhydryl Compounds
  • Endocrine Disruptors
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • GPER1 protein, mouse
  • Phenols
  • RNA, Messenger
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • EGFR protein, mouse
  • ErbB Receptors
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • bisphenol A