Abstract
Dehydroepiandrosterone sulfate (DHEAS) is a circulating sulfated steroid considered to be a pro-androgen in mammalian physiology. Here we show that at a physiological concentration (1 μM), DHEAS induces the phosphorylation of the kinase Erk1/2 and of the transcription factors CREB and ATF-1 in the murine Sertoli cell line TM4. This signaling cascade stimulates the expression of the tight junction (TJ) proteins claudin-3 and claudin-5. As a consequence of the increased expression, tight junction connections between neighboring Sertoli cells are augmented, as demonstrated by measurements of transepithelial resistance. Phosphorylation of Erk1/2, CREB, or ATF-1 is not affected by the presence of the steroid sulfatase inhibitor STX64. Erk1/2 phosphorylation was not observed when dehydroepiandrosterone (DHEA) was used instead of DHEAS. Abrogation of androgen receptor (AR) expression by siRNA did not affect DHEAS-stimulated Erk1/2 phosphorylation, nor did it change DHEAS-induced stimulation of claudin-3 and claudin-5 expression. All of the above indicate that desulfation and conversion of DHEAS into a different steroid hormone is not required to trigger the DHEAS-induced signaling cascade. All activating effects of DHEAS, however, are abolished when the expression of the G-protein Gnα11 is suppressed by siRNA, including claudin-3 and -5 expression and TJ formation between neighboring Sertoli cells as indicated by reduced transepithelial resistance. Taken together, these results are consistent with the effects of DHEAS being mediated through a membrane-bound G-protein-coupled receptor interacting with Gnα11 in a signaling pathway that resembles the non-classical signaling pathways of steroid hormones. Considering the fact that DHEAS is produced in reproductive organs, these findings also suggest that DHEAS, by acting as an autonomous steroid hormone and influencing the formation and dynamics of the TJ at the blood-testis barrier, might play a crucial role for the regulation and maintenance of male fertility.
Highlights
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant circulating steroid in humans
In the spermatogenic cell line GC-2 interaction of DHEAS with a membrane-bound receptor activates the Src/Ras/Raf/Erk1/2 signaling cascade and stimulates the transcription factors CREB and ATF-1 [25]. Both CREB and ATF-1 are members of the bZIP superfamily of transcription factors and stimulate transcription when activated by phosphorylation at either Ser63 (ATF-1) or Ser133 (CREB)
Our first aim in the current investigation was to examine whether DHEAS might induce Erk1/2, CREB, and ATF-1 activation in the Sertoli cell line TM4
Summary
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant circulating steroid in humans. Its concentration in plasma is between 1.3 and 6.8 μM, which is about 200-fold higher than the plasma concentrations of dehydroepiandrosterone (DHEA) (7–31 nM) [1]. DHEAS is produced mainly in the adrenal zona reticularis. It is derived from DHEA, which is almost entirely converted to DHEAS by a sulfotransferase. The sulfated steroid is secreted into the serum [2]. Sulfated steroids like DHEAS have long been considered to be physiologically inactive waste products of steroid hormone metabolism. DHEAS has been considered to be a pro-androgen that has to be converted into testosterone or other steroid hormones in order to exert its biological activity [3]
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