Effects of methoxychlor (M) or its active metabolite, 2,2-BIS(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), on testosterone (T) formation by cultured neonatal (fetal) leydig cells (LC).
Toxicologist 2003 Mar; 72(S-1):273
M is a pesticide developed as a replacement for dichlorodiphenyltrichloroethane (DDT). Its active metabolite is thought to be HPTE. Both M and HPTE have been reported to exhibit weak estrogenic or antiandrogenic activities, their proposed mechanism(s) of action. In the present studies, we examined the effects of M or HPTE on T biosynthesis by cultured LC from neonatal rats, which represent fetal LC. Increasing concentrations of M or HPTE (100-1000 nM) caused a progressive decline in both basal and 10 mIU/ml human chorionic gonadotropin (hCG)- or 1 mM 8 Br-cAMP-stimulated T following exposure for 4 or 24 h, although the declines with HPTE were greater. To localize the site(s) of action of HPTE, LC were exposed to HPTE (100-1000 nM) for 24 h (both alone or with hCG), then fresh media containing steroid precursors of T were added to assess their conversion to T over 4 h. The conversion of 0.01 mM pregenolone, progesterone or adnrostenedione to T was unaffected by prior exposure to HPTE; however, the conversion of 22(R) hydroxycholesterol to T progressively decreased, suggesting that among the enzymes involved in converting cholesterol to T, P450 cholesterol side-chain cleavage activity is inhibited by HPTE. The concomitant inclusion of the "pure" estrogen antagonist, ICI 182, 780, did not alter the inhibitive effects of HPTE, suggesting that the effects of HPTE are not mediated through the estrogen receptor (ER) pathway. Furthermore, the antiandrogen through the androgen receptor (AR). These results suggest that the two prevailing proposed modes of action of MC/HPTE in altering male reproductive function (weakly estrogenic through the ER or antiandrogenic through the AR) do not apply with respect to their inhibitive effect of T formation by fetal LC.
Metabolites; Pesticides; Estrogenic-hormones; Exposure-levels; Laboratory-animals; Animal-studies; Animals; Reproductive-system
Disease and Injury: Fertility and Pregnancy Abnormalities
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah