Physiological implications of DHEAS-induced non-classical steroid hormone signaling

In the spermatogenic cell line GC-2, dehydroepiandrosterone sulfate (DHEAS), activates the Src/Ras/c-Raf/Erk1/2/CREB(ATF-1) signaling cascade. Since DHEAS is present in the gonads, and since spermatogenesis and maturation of spermatogonia to haploid spermatozoa requires activation of Erk1/2, the triggering of these signaling events by DHEAS might have physiological relevance. In the Sertoli cell line TM4, DHEAS-induces activation of Erk1/2, CREB, and ATF-1, stimulates expression of claudin-3 and claudin-5 and augments transepithelial resistance, indicating the formation of tight junctions between adjacent Sertoli cells. Thus, by influencing the formation and dynamics of tight junctions at the blood-testis barrier, which protects germ cells from cells of the immune system, DHEAS might play a crucial role in the regulation and maintenance of male fertility. In bEnd.3 brain-derived endothelial cells, DHEAS stimulates the expression of zonula occludens-1 and claudin-3 and promotes tight junction formation between neighboring cells, which at the blood-brain barrier protects the brain from harmful factors and cells. If DHEAS supports the integrity of the blood-brain barrier also in vivo, the current findings might lead to new strategies for the prevention or treatment of neurological disorders associated with barrier defects.