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.
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.
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuandong Road, University Town, Guangzhou 510006, China.
Li-Chen
LC
Ge
Department of Pharmacy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Zhuo-Jia
ZJ
Chen
Center for Reproductive Medicine, Third Affiliated Hospital of Guangzhou Medical University, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou 510150, China.
Han-Yan
HY
Liu
Department of Pharmacy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China.
Kun-Shui
KS
Zhang
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuandong Road, University Town, Guangzhou 510006, China.
Hao
H
Liu
Department of Pharmacy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Hong-Bin
HB
Huang
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuandong Road, University Town, Guangzhou 510006, China.
Ge
G
Zhang
Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong SAR, Kowloon Tong China.
Chris K C
CK
Wong
Department of Veterinary Biomedical Sciences & Toxicological Center, University of Saskatchewan, Saskatoon, SK, Canada.
John P
JP
Giesy
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuandong Road, University Town, Guangzhou 510006, China. Electronic address: dujun@mail.sysu.edu.cn.
Jun
J
Du
Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuandong Road, University Town, Guangzhou 510006, China. Electronic address: whongsh@sysu.edu.cn.
Hong-Sheng
HS
Wang
D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010636:Phenols / Q000633:toxicity*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D012708:Sertoli Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D066246:ErbB Receptors; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010636:Phenols; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C532507:GPER1 protein, mouse; C541485:EGFR protein, mouse; C535148:Mapk1 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds
Estrogen receptor α/β (ERα/β); GPR30; Male; Reproduction; Sertoli cell; TM4