title: In vitro exposure of Leydig cells to an environmentally relevant mixture of organochlorines represses early steps of steroidogenesis.
abstract: Leydig cell steroidogenesis is mainly regulated by LH via increased cAMP production leading to STAR protein activation. STAR is essential for cholesterol shuttling inside mitochondria where steroidogenesis is initiated. Accumulating evidence suggest that persistent organochlorine compounds disrupt testicular function, but the mechanism of action remains poorly characterized. Here we report that in vitro exposure of MA-10 and MLTC-1 Leydig cells to an environmentally relevant mixture of 15 organochlorines impairs steroidogenesis. While having no effect on cell viability and basal steroid production, the organochlorine mixture caused a 50% decrease in cAMP-induced progesterone production. The mixture also reduced cAMP-induced 30 kDa STAR protein by 50% while having no effect on basal STAR protein. Basal or cAMP-induced Star mRNA levels and promoter activity were unaffected by the mixture, indicating that the organochlorine mixture acted at the translational/posttranslational level. Further supporting this is the fact that in COS-7 cells overexpressing STAR, the organochlorine mixture caused a decrease in the 30 kDa form of STAR and an accumulation of the 37 kDa forms. In addition to STAR, we found that the organochlorine mixture also decreases the levels of CYP11A1 and ADXR, two proteins essential for the conversion of cholesterol into pregnenolone. In conclusion, our data show that organochlorine exposure disrupts Leydig cell function by targeting different components of the steroidogenic pathway.
authors.affiliation: Reproduction, Mother and Child Health, Centre de recherche du CHU de Québec, Québec, Canada.
authors.forename: Annick N
authors.initials: AN
authors.lastname: Enangue Njembele
authors.affiliation: Centre for Research in Biology of Reproduction, Department of Animal Sciences, Faculté des sciences de l'agriculture et de l'alimentation, Université Laval, Québec, Canada.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Bailey
authors.affiliation: Reproduction, Mother and Child Health, Centre de recherche du CHU de Québec, Québec, Canada Centre for Research in Biology of Reproduction, Department of Obstetrics, Gynecology, and Reproduction, Faculté de Médecine, Université Laval, Québec, Canada Jacques-J.Tremblay@crchul.ulaval.ca.
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Tremblay
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000494:pharmacology; D052244:Endocrine Disruptors / Q000633:toxicity; D004785:Environmental Pollutants / Q000633:toxicity*; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D006888:Hydroxycholesterols / Q000494:pharmacology; D007984:Leydig Cell Tumor; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*; D013736:Testicular Neoplasms; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D006843:Hydrocarbons, Chlorinated; D006888:Hydroxycholesterols; D010750:Phosphoproteins; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D011284:Pregnenolone; D000242:Cyclic AMP
keywords: Leydig cells; endocrine disrupter; environmental toxicology; organochlorines; steroidogenesis; testis