Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane with estrogen receptors α and β

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

Research output: Contribution to journalArticlepeer-review

167 Scopus citations

Abstract

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 α (ERα) and estrogen receptor β (ERβ). Human hepatoma cells (HepG2) were transiently transfected with either human or rat ERα or ERβ 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 17β-estradiol. HPTE was a potent ERα agonist in HepG2 cells, with EC50 values of approximately 5 x 10-8 and 10-8 M for human and rat ERα, respectively. In contrast, HPTE had minimal agonist activity with either human or rat ERβ and almost completely abolished 17β-estradiol-induced ERβ-mediated activity. Moreover, HPTE behaved as an ERa agonist and an ERβ 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.

Original languageEnglish (US)
Pages (from-to)5746-5753
Number of pages8
JournalEndocrinology
Volume140
Issue number12
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Endocrinology

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