DHEAS-Specific Signalling in Cells of the Reproductive System

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Dihydroepiandrosterone (DHEA) and dihydroepiandrosterone sulfate (DHEAS) are produced by the adrenal cortex, the brain, and the gonads. DHEAS is the most abundant circulating androgen. Its physiological significance and that of DHEA are not yet sufficiently understood. The major biological action of DHEA and DHEAS in brain is considered to be neuroprotection. Recent investigations, however, indicate that DHEAS produces specific effects that are distinct from those induced by DHEA. Surprisingly little is known about the physiological effects of DHEAS on cells of the reproductive system. In a first attempt to address some aspects of a possible biological significance of DHEAS on cells of the reproductive system, we present here data concerning its effects on the spermatogenic cell line GC-2. Thus, we found that nanomolar concentrations of DHEAS trigger the induction of cytosolic signalling cascades that result in activation of Erk1/2 and of the nuclear transcription factors CREB and ATF-1. Since no cytosolic receptors have been thus far identified that bind either DHEA or DHEAS with high affinity, we have to assume that the DHEAS effects seen in the GC-2 cells are mediated through membrane-bound receptors, which are known in other systems to activate such signalling pathways. Within the framework of our proposal, we plan:1) to unveil the entire cytosolic signalling cascade induced by DHEAS in the spermatogenic cell line GC-2 and to identify the membrane receptor for DHEAS; 2) to investigate the physiological significance of the DHEAS-induced activation of the transcription factors CREB and ATF-1; and 3) to investigate possible effects of DHEAS in other cell types (Sertoli, granulosa) of the gonads.The results obtained thus far demonstrate for the first time non-genomic effects induced in a spermatogenic cell line by DHEAS. The proposed continuation of the investigation should provide new insights into physiological mechanisms associated with fertility and reproduction.