In vivo inhibition of steroidogenic acute regulatory protein expression by dexamethasone parallels induction of the negative transcription factor DAX-1.

In this study, we investigated the effect of dexamethasone on the synthesis of steroidogenic acute regulatory protein (StAR) and the expression of DAX-1 (dosage sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1) and SF-1 (steroidogenic factor-1) in vivo. Male rats were treated with dexamethasone (0.4 and 4 mg/kg body wt per day) by intraperitoneal injections using phosphate-buffered saline as the vehicle for 7 d. At the end of 7 d, serum testosterone levels were decreased. Response to luteinizing hormone (LH) and 8-bromo-cyclic-AMP (8-Br-cAMP) in vitro was reduced in testicular cells isolated from dexamethasone-treated rat testes. Dexamethasone decreased LH-stimulated cAMP production. The conversion of 22(R)-hydroxycholesterol, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, and androstenedione to testosterone was not affected by dexamethasone. Dexamethasone increased DAX-1 expression and concordantly decreased StAR protein and mRNA in testicular cells. The increase in DAX-1 protein corresponded to a 57% reduction in StAR mRNA levels concomitant with a 79% reduction in serum testosterone levels. Dexamethasone had no effect on the level of SF-1, but increased the amount of complexed DAX-1-SF-1. Dexamethasone in vitro suppressed StAR promoter activity when an increasing amount of DAX-1 cDNA was transfected. These results demonstrate that dexamethasone increases expression of DAX-1, which results in increased amounts of complexed DAX-1-SF-1, in the absence of any change in the expression of SF-1. These observations strongly support the concept that dexamethasone suppresses rat testicular testosterone production, at least in part, by increasing the amount of complexed DAX-1-SF-1 in these cells, which leads directly to decreased availability of free SF-1 and, therefore, decreased activation of transcription of the rat StAR gene.