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Endocrinology Vol. 140, No. 12 5746-5753
Copyright © 1999 by The Endocrine Society

ARTICLES

Differential Interaction of the Methoxychlor Metabolite 2,2-Bis-(p-Hydroxyphenyl)-1,1,1-Trichloroethane with Estrogen Receptors {alpha} and ß1

Kevin W. Gaido, Linda S. Leonard, Susan C. Maness, Julie M. Hall, Donald P. McDonnell, Brad Saville and Stephen Safe

Chemical Industry Institute of Toxicology (K.W.G., L.S.L., S.C.M.), Research Triangle Park, North Carolina 27709; the Department of Pharmacology and Cancer Biology, Duke University Medical Center (J.M.H., D.P.M.), Durham, North Carolina 27710; and the Department of Veterinary Physiology and Pharmacology, Texas A&M University (B.S., S.S.), College Station, Texas 77843

Address all correspondence and requests for reprints to: Dr. Kevin W. Gaido, Chemical Industry Institute of Toxicology, P.O. Box 12137, Research Triangle Park, North Carolina 27709. E-mail: gaido{at}ciit.org

Concern that some chemicals in our environment may affect human health by disrupting normal endocrine function has prompted research on interactions of environmental contaminants with steroid hormone receptors. We compared the activity of 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), an estrogenic metabolite of the organochlorine pesticide methoxychlor, at estrogen receptor {alpha} (ER{alpha}) and estrogen receptor ß (ERß). Human hepatoma cells (HepG2) were transiently transfected with either human or rat ER{alpha} or ERß plus an estrogen-responsive, complement 3-luciferase construct containing a complement 3 gene promoter sequence linked to a luciferase reporter gene. After transfection, cells were treated with various concentrations of HPTE in the presence (for detecting antagonism) or absence (for detecting agonism) of 17ß-estradiol. HPTE was a potent ER{alpha} agonist in HepG2 cells, with EC50 values of approximately 5 x 10-8 and 10-8 M for human and rat ER{alpha}, respectively. In contrast, HPTE had minimal agonist activity with either human or rat ERß and almost completely abolished 17ß-estradiol-induced ERß-mediated activity. Moreover, HPTE behaved as an ER{alpha} agonist and an ERß antagonist with other estrogen-responsive promoters (ERE-MMTV and vtERE) in HepG2 and HeLa cells. This study demonstrates the complexity involved in determining the mechanism of action of endocrine-active chemicals that may act as agonists or antagonists through one or more hormone receptors.




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