ER[alpha]/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/floxCyp17iCre) 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].