title: Inhibition of testicular steroidogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats: evidence that the key lesion occurs prior to or during pregnenolone formation.
abstract: The mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment decreases testosterone (T) secretion without significantly altering plasma luteinizing hormone (LH) concentrations was investigated. Testes from sexually mature Sprague-Dawley rats dosed 7 days earlier with 100 micrograms TCDD/kg secreted 30-75% less T than did testes from control rats when perfused in vitro with the LH analog human chorionic gonadotropin (hCG). This decrease confirms that testicular responsiveness to LH, the hormone which regulates T secretion in vivo, is impaired by TCDD treatment. Because TCDD also reduced intratesticular T content, the decrease in T secretion is due to an inhibition of T synthesis rather than to a failure of the secretion process. These effects of TCDD are not secondary to undernutrition, because perfused testes from feed-restricted control rats were fully hCG responsive. TCDD treatment neither increased the hCG-stimulated secretion of any T precursor nor significantly decreased the efficiency with which testes converted the pregnenolone (PREG) they synthesized into T (PREG is the initial steroidogenic intermediate). In addition, TCDD did not inhibit T secretion when steroidogenesis was supported by exogenous PREG at approximately the in vivo rate. We conclude that TCDD does not inhibit the conversion of PREG to T. The inhibition of T biosynthesis must instead result from an inhibition of PREG formation. The finding that TCDD treatment substantially decreased the rate at which hCG-perfused testes secreted PREG and its metabolites (a decrease seen across all hCG concentrations) confirms this conclusion. This inhibition of LH/hCG-stimulated PREG formation by TCDD must be due to a reduction in the activity of the enzyme which converts cholesterol to PREG (cytochrome P450scc), and/or an impairment in the multistep process responsible for mobilizing cholesterol to this enzyme.
authors: Environmental Toxicology Center, University of Wisconsin, Madison 53706.
authors: J M
authors: JM
authors: Kleeman
authors: R W
authors: RW
authors: Moore
authors: R E
authors: RE
authors: Peterson
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007986:Luteinizing Hormone / Q000494:pharmacology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011284:Pregnenolone / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis*
chemical_list: D006063:Chorionic Gonadotropin; D000072317:Polychlorinated Dibenzodioxins; D013739:Testosterone; D011284:Pregnenolone; D007986:Luteinizing Hormone