title: The effects of the reported active metabolite of methoxychlor, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane, on testosterone formation by cultured Leydig cells from young adult rats.
abstract: Methoxychlor (MC) is an insecticide that is currently used on a variety of agricultural crops, especially following the ban of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) use in the United States. Following in vivo administration, MC is converted to 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which is proposed to be the active agent. Both MC and HPTE have been demonstrated to exhibit weak estrogenic and antiandrogenic activities, and they are thought to exert their effects through estrogen or androgen receptors, respectively. A recent study reported that HPTE inhibited both basal and hCG-stimulated testosterone formation by immature and adult cultured rat Leydig cells and that this effect was mediated through the estrogen receptor. In the current studies, we examined the effects of HPTE on basal and hCG-stimulated testosterone formation by cultured Leydig cells from young adult rats. In addition, we evaluated whether the effects of HPTE on rat Leydig cell testosterone biosynthesis were mediated through the estrogen receptor as an estrogen agonist or the androgen receptor as an antiandrogen. The current studies demonstrated that HPTE inhibited both basal and hCG-stimulated testosterone formation in a dose-dependent manner with significant declines in testosterone being observed at approximately 100 nM. The effects of HPTE were localized to the cholesterol side-chain cleavage step; however, these effects were not mediated through the classic estrogen receptor or by its acting as an antiandrogen, the currently recognized modes of action of MC and HPTE.
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Pathology and Physiology Research Branch, M/S L-2015, 1095 Willowdale Road, Morgantown, WV 26505, USA. eem8@cdc.gov
authors.forename: Eisuke P
authors.initials: EP
authors.lastname: Murono
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Derk
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004965:Estrogen Antagonists / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D007306:Insecticides / Q000378:metabolism*; D007985:Leydig Cells / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008731:Methoxychlor / Q000031:analogs & derivatives / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism*
chemical_list: D006063:Chorionic Gonadotropin; D004338:Drug Combinations; D004965:Estrogen Antagonists; D007306:Insecticides; D010080:Oxazoles; D010636:Phenols; D015124:8-Bromo Cyclic Adenosine Monophosphate; C014290:hydroxyflutamide; D013739:Testosterone; D005485:Flutamide; D002786:Cholesterol Side-Chain Cleavage Enzyme; C404910:2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane; C025643:vinclozolin; D008731:Methoxychlor