Bisphenol A and Related Alkylphenols Exert Nongenomic Estrogenic Actions Through a G Protein-Coupled Estrogen Receptor 1 (Gper)/Epidermal Growth Factor Receptor (Egfr) Pathway to Inhibit Meiotic Maturation of Zebrafish Oocytes.
Xenobiotic estrogens, such as bisphenol A (BPA), disrupt a wide variety of genomic estrogen actions, but their nongenomic estrogen actions remain poorly understood. We investigated nongenomic estrogenic effects of low concentrations of BPA and three related alkylphenols on the inhibition of zebrafish oocye maturation (OM) mediated through a G protein-coupled estrogen receptor 1 (Gper)-dependent epidermal growth factor receptor (Egfr) pathway. BPA (10-100 nM) treatment for 3 h mimicked the effects of estradiol-17beta (E2) and EGF, decreasing spontaneous maturation of defolliculated zebrafish oocytes, an effect not blocked by coincubation with actinomycin D, but blocked by coincubation with a Gper antibody. BPA displayed relatively high binding affinity (15.8% that of E2) for recombinant zebrafish Gper. The inhibitory effects of BPA were attenuated by inhibition of upstream regulators of Egfr, intracellular tyrosine kinase (Src) with PP2, and matrix metalloproteinase with ilomastat. Treatment with an inhibitor of Egfr transactivation, AG1478, and an inhibitor of the mitogen-activated protein kinase (MAPK) 3/1 pathway, U0126, increased spontaneous OM and blocked the inhibitory effects of BPA, E2, and the selective GPER agonist, G-1. Western blot analysis showed that BPA (10-200 nM) mimicked the stimulatory effects of E2 and EGF on Mapk3/1 phosphorylation. Tetrabromobisphenol A, 4-nonylphenol, and tetrachlorobisphenol A (5-100 nM) also inhibited OM, an effect blocked by cotreatment with AG1478, as well as with the GPER antagonist, G-15, and displayed similar binding affinities as BPA to zebrafish Gper. The results suggest that BPA and related alkylphenols disrupt zebrafish OM by a novel nongenomic estrogenic mechanism involving activation of the Gper/Egfr/Mapk3/1 pathway.
University of Texas at Austin Marine Science Institute, Port Aransas, Texas.
Amanda C
AC
Fitzgerald
University of Texas at Austin Marine Science Institute, Port Aransas, Texas.
Candace
C
Peyton
University of Texas at Austin Marine Science Institute, Port Aransas, Texas.
Jing
J
Dong
University of Texas at Austin Marine Science Institute, Port Aransas, Texas peter.thomas@utexas.edu.
Peter
P
Thomas
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002733:Chlorophenols / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D008540:Meiosis / Q000187:drug effects* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011075:Polybrominated Biphenyls / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D002733:Chlorophenols; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases; D010636:Phenols; D011075:Polybrominated Biphenyls; D043562:Receptors, G-Protein-Coupled; D029961:Zebrafish Proteins; C549840:gper1 protein, zebrafish; C041181:tetrachlorodian; C020806:tetrabromobisphenol A; C041594:4-nonylphenol; C006780:bisphenol A; D000098826:Bisphenol A Compounds
EGFR; GPER; GPR30; MAPkinase; bisphenol A; endocrine disruptors; meiotic arrest; nonylphenol; oocyte maturation; tetrabromobisphenol A; tetrachorobisphenol A; zebrafish