ERα/E2 signaling suppresses the expression of steroidogenic enzyme genes via cross-talk with orphan nuclear receptor Nur77 in the testes

Estrogen receptor alpha (ER alpha) has been reported to affect steroidogenesis in testicular Leydig cells, but its molecular mechanism remains unclear. Here, we investigate the effect of estrogen and ER alpha on Nur77, a major transcription factor that regulates the expression of steroidogenic enzyme genes. In MA-10 Leydig cells, estradiol (E2) treatment, and interestingly ER alpha overexpression, suppressed the cAMP-induced and Nur77-activated promoter activity of steroidogenic enzyme genes via the suppression of Nur77 transactivation. ER alpha physically interacted with Nur77 and inhibited its DNA binding activity. In addition, ER alpha/E2 signaling decreased Nur77 protein levels. Consistent with the above results, the testicular testosterone level was higher in Leydig cell-specific ER alpha knock-out mice (ER alpha(flox/flox)Cyp17iCre) than in wild-type mice (ER alpha(flox/flox)). Taken together, these results suggest that ER alpha/E2 signaling controls the Nur77-mediated expression of steroidogenic enzyme genes in Leydig cells. These findings may provide a mechanistic explanation for the local regulation of testicular steroidogenesis by estrogenic compounds and ER alpha. (C) 2012 Elsevier Ireland Ltd. All rights reserved.