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L Martin, Ontogeny-Reproduction, Rm. T1-49, CHUL Research Centre, Quebec City, Quebec, Canada
J Tremblay, Ontogeny-Reproduction, Rm. T1-49, CHUL Research Centre - Laval University, Quebec City, Quebec, G1V 4G2, Canada

Correspondence: Jacques J Tremblay, Email: Jacques-J.Tremblay{at}crchul.ulaval.ca

Abstract

It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor. So far, various mechanisms have been proposed to explain the mechanism of action of glucocorticoids on Leydig cell steroidogenesis including repression of genes involved in testosterone biosynthesis. Several steroidogenic genes, including steroidogenic acute regulatory protein (StAR), have been shown to be repressed by glucocorticoids in a glucocorticoid receptor-dependent manner but the underlying mechanisms remain to be fully elucidated. Here we found that dexamethasone, a potent synthetic glucocorticoid, partly antagonizes the cAMP-dependent stimulation of the mouse StAR promoter in MA-10 Leydig cells as revealed by transient transfection assays. This repression requires an element located at -95 bp previously implicated in the activation of the StAR promoter by the nuclear receptors NUR77 and SF-1. Dexamethasone was found to inhibit NUR77-dependent transactivation of the StAR promoter in Leydig cells by decreasing NUR77, but not SF-1, recruitment to the proximal StAR promoter as determined by chromatin immunoprecipitation assay. Western blots revealed that dexamethasone did not affect NUR77 or SF-1 expression in response to cAMP. These data suggests that NUR77 would be associated with the glucocorticoid receptor in a transcriptionally inactive complex as previously demonstrated in pituitary corticotrope cells. Thus, our data provide new molecular insights into the stress-mediated suppression of testosterone production in testicular Leydig cells.

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