Interaction of Methoxychlor and Related Compounds with Estrogen Receptor α and β, and Androgen Receptor: Structure-Activity Studies

We previously demonstrated differential interactions of the methoxychlor metabolite 2,2-bis( p -hydroxyphenyl)-1,1,1-trichloroethane (HPTE) with estrogen receptor α (ERα), ERβ, and the androgen receptor (AR). In this study, we characterize the ERα, ERβ, and AR activity of structurally related methoxychlor metabolites. Human hepatoma cells (HepG2) were transiently transfected with human ERα, ERβ, and AR plus an appropriate steroid-responsive luciferase reporter vector. After transfection, cells were treated with various concentrations of HPTE or structurally related compounds in the presence (for detecting antagonism) and absence (for detecting agonism) of 17β-estradiol and dihydrotestosterone. The monohydroxy analog of methoxychlor, as well as monohydroxy and dihydroxy analogs of 2,2-bis( p -hydroxyphenyl)-1,1-dichloroethylene, had ERα agonist activity and ERβ and AR antagonist activity similar to HPTE. The trihydroxy metabolite of methoxychlor displayed only weak ERα agonist activity and did not alter ERβ or AR activities. Replacement of the trichloroethane or dichloroethylene group with a methyl group resulted in a compound with ERα and ERβ agonist activity that retained antiandrogenic activities. This study identifies some of the structural requirements for ERα and ERβ activity and demonstrates the complexity involved in determining the mechanism of action of endocrine-active chemicals that simultaneously act as agonists or antagonists through one or more hormone receptors.