title: The reported active metabolite of methoxychlor, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane, inhibits testosterone formation by cultured Leydig cells from neonatal rats.
abstract: Methoxychlor (MC) is an insecticide that is presently used on agricultural crops, especially after the ban on the use of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) in the United States. Following administration in vivo, MC is converted to 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which is thought to be the active agent. However, both MC and HPTE have been reported to have weak estrogenic and antiandrogenic activities, and they are thought to exert their potential adverse (endocrine disruptive) effects through the estrogen and androgen receptors, respectively. In a recent study, HPTE was shown to inhibit both basal and hCG-stimulated testosterone production by cultured Leydig cells from immature and adult rats, and these effects were reported to be mediated through the estrogen receptor. Because fetal Leydig cells represent a separate population from adult Leydig cells and many of the reported adverse actions of endocrine disruptors are thought to have their effects during gestational exposure, the present studies examined the effects of HPTE on testosterone formation by cultured fetal Leydig cells from neonatal rats to determine whether these cells are sensitive to HPTE. Our studies demonstrated that HPTE inhibited both basal and hCG-stimulated testosterone formation in a dose-dependent manner. Significant declines in testosterone were observed at about 100nM HPTE, and this effect was detected as early as 1h after exposure. The main effects of HPTE appeared to be localized to the cholesterol side-chain cleavage step which converts cholesterol to pregnenolone. In addition, this effect did not appear to be mediated through the estrogen receptor as a weak estrogen or the androgen receptor as an antiandrogen, which are the currently proposed 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 26505-2888, 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; D000831:Animals, Newborn; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D007306:Insecticides / Q000378:metabolism*; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008731:Methoxychlor / Q000378:metabolism*; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism*; D013997:Time Factors
chemical_list: D006063:Chorionic Gonadotropin; D052244:Endocrine Disruptors; D007306:Insecticides; D010636:Phenols; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013739:Testosterone; D002786:Cholesterol Side-Chain Cleavage Enzyme; C404910:2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane; D008731:Methoxychlor