Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichlor with estrogen receptors alpha and beta

Concern that some chemicals in our environment may affect human health by d isrupting normal endocrine function has prompted research on interactions o f environmental contaminants with steroid hormone receptors. We compared th e activity of 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), an es trogenic metabolite of the organochlorine pesticide methoxychlor, at estrog en receptor alpha (ER alpha) and estrogen receptor beta (ER beta). Human he patoma cells (CHepG2) were transiently transfected with either human or rat ER alpha or ER beta plus an estrogen-responsive, complement 3-luciferase c onstruct containing a complement 3 gene promoter sequence Linked to a lucif erase reporter gene. After transfection, cells were treated with various co ncentrations of HPTE in the presence (for detecting antagonism) or absence (for detecting agonism) of 17 beta-estradiol. HPTE was a potent ER alpha ag onist 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 minima l agonist activity with either human or rat ERP and almost completely aboli shed 17 beta-estradiol-induced ERP-mediated activity. Moreover, HPTE behave d as an ER alpha agonist and an ER beta antagonist with other estrogen-resp onsive promoters (ERE-MMTV and vtERE) in HepG2 and HeLa cells. This study d emonstrates the complexity involved in determining the mechanism of action of endocrine-active chemicals that may act as agonists or antagonists throu gh one or more hormone receptors.