title: Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption.
abstract: A wide variety of environmental contaminants have been shown to exert estrogenic actions in wildlife and laboratory animals through binding to nuclear estrogen receptors (ERs) and subsequent transcription of estrogen responsive genes. We show here that several of these environmental estrogens also bind to the novel seven-transmembrane estrogen receptor, GPR30, to activate alternative estrogen signaling pathways in an ER-negative cell line (HEK293) stably transfected with the receptor. Genestein was the most effective competitor for the receptor (IC(50) 133 nM), with a relative binding affinity (RBA) 13% that of estradiol-17beta (E2). Bisphenol A, zearalonone, and nonylphenol also had relatively high binding affinities for GPR30 with RBAs of 2-3%. Kepone, p,p'-DDT, 2,2',5',-PCB-4-OH and o,p'-DDE had lower affinities with RBAs of 0.25-1.3%, whereas o,p'-DDT, p,p'-DDE, methoxychlor and atrazine caused less than 50% displacement of [(3)H]-E2 at concentrations up to 10 microM. Overall, the binding affinities of these compounds for GPR30 are broadly similar to their affinities to the ERs. Environmental estrogens with relatively high binding affinities for GPR30 (genestein, bisphenol A, nonylphenol and Kepone) also displayed estrogen agonist activities in an in vitro assay of membrane-bound adenylyl cyclase activity, a GPR30-dependent signaling pathway activated by estrogens. The results indicate that nontraditional estrogen actions mediated through GPR30 are potentially susceptible to disruption by a variety of environmental estrogens.
authors.affiliation: Marine Science Institute, University of Texas at Austin, 750 Channel View Drive, Port Aransas, TX 78373, USA. thomas@utmsi.utexas.edu
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001559:Benzhydryl Compounds; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D007631:Chlordecone / Q000494:pharmacology; D003164:Competitive Bidding; D004967:Estrogens / Q000494:pharmacology*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007306:Insecticides / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D000098826:Bisphenol A Compounds
chemical_list: D000262:Adenylyl Cyclases; D000970:Antineoplastic Agents; D001559:Benzhydryl Compounds; D007631:Chlordecone; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D019833:Genistein; D007306:Insecticides; D010636:Phenols; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C109584:GPER1 protein, human; C025256:nonylphenol; C006780:bisphenol A; D000098826:Bisphenol A Compounds