Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: A potential novel mechanism of endocrine disruption

Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental... 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-17β (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 μM. 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Steroid Biochemistry and Molecular Biology Elsevier

Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: A potential novel mechanism of endocrine disruption

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Publisher
Elsevier
Copyright
Copyright © 2006 Elsevier Ltd
ISSN
0960-0760
eISSN
1879-1220
D.O.I.
10.1016/j.jsbmb.2006.09.017
Publisher site
See Article on Publisher Site

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-17β (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 μM. 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.

Journal

The Journal of Steroid Biochemistry and Molecular BiologyElsevier

Published: Dec 1, 2006

References

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  • Discovery of three novel G-protein-coupled receptor genes
    O’Dowd, B.F.; Nguyen, T.; Marchese, A.; Cheng, R.; Lynch, K.R.; Heng, H.H.Q.; Kolakowski, L.F.; George, S.R.
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