Lead affects steroidogenesis in rat Leydig cells in vivo and in vitro.
Lead is known to impede the male reproductive function, however, the mechanisms through which the adverse effects are mediated are not clearly elucidated. In order to get insight into those mechanisms, we have examined the effects of lead on the biosynthesis of steroid hormones by Leydig cells in the rat. To determine whether lead has a direct action on Leydig cells, we have compared the concentrations of testosterone secreted by Leydig cells in ex vivo experiments after animals had been injected with high doses of lead and in vitro experiments with Leydig cells from normal rats maintained in culture in presence or absence of lead. In ex vivo experiments male Spargue-Dawley rats were injected i.p. with lead acetate (8 mg lead/kg/day, 5 days a week for 5 weeks) or with sodium acetate. Testosterone production by Leydig cells isolated and maintained in culture for 48 h was then assessed under basal conditions or after stimulation by human chorionic gonadotrophin (hCG). Both basal and hCG-stimulated testosterone production dropped by 59% and 37%, respectively, with Leydig cells from lead-exposed rats. For in vitro experiments, cultures of Leydig cells from control rats were exposed to various concentrations of lead acetate for different periods. Dose and time-dependent reductions of testosterone level were observed in the culture medium. The effective doses of hCG for maximal and half-maximal testosterone production did not change, indicating that the sensitivity of Leydig cells to hCG was not impaired by exposure to lead in vitro. Progesterone production was also decreased after this exposure. The negative effect of lead on testosterone and progesterone production was correlated with the lower expression of the enzymes cytochromes P450scc (CYP11A1) and P450c17 (CYP17) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) involved in steroid hormone biosynthesis, as shown by immunohistochemistry. Ultrastructural alterations of the smooth endoplasmic reticulum observed after lead administration might be correlated with the lower expression of the microsomal enzymes P450c17 and 3 beta-HSD. Our results indicate that lead can adversely affect the Leydig cell function by impairing directly steroidogenesis.
Commissariat à l'Energie Atomique (CEA), Département de Pathologie et Toxicologie Expérimentales, Fontenay-aux Roses, France.
A
A
Thoreux-Manlay
C
C
Le Goascogne
D
D
Segretain
B
B
Jégou
G
G
Pinon-Lataillade
D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000085:Acetates / Q000008:administration & dosage; D019342:Acetic Acid; D000446:Aldehyde-Lyases / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018871:Endoplasmic Reticulum, Smooth / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007854:Lead / Q000633:toxicity*; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011374:Progesterone / Q000096:biosynthesis; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis*
D000085:Acetates; D006063:Chorionic Gonadotropin; D009942:Organometallic Compounds; D007854:Lead; D013739:Testosterone; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D015096:3-Hydroxysteroid Dehydrogenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases; D019342:Acetic Acid; C008261:lead acetate