DHEAS-Specific Signalling in Cells of the Reproductive System

二氢表雄酮(DHEA)和二氢表雄酮硫酸盐(DHEAS)由肾上腺皮质、大脑和性腺产生。Dheas是最丰富的循环雄激素。它的生理意义和脱氢表雄酮的意义还没有被充分了解。DHEA和DHEAS在脑内的主要生物学作用被认为是神经保护作用。然而，最近的研究表明，DHEAS产生的特定效应与DHEA诱导的不同。令人惊讶的是，人们对DHEAS对生殖系统细胞的生理影响知之甚少。在第一次尝试解决DHEAS对生殖系统细胞可能的生物学意义的某些方面，我们在这里提供了关于它对生精细胞系GC-2的影响的数据。因此，我们发现，纳米分子浓度的DHEAS触发了胞浆信号级联反应的诱导，导致ERK1/2以及核转录因子CREB和ATF-1的激活。由于到目前为止还没有发现与DHEA或DHEAS高亲和力结合的细胞质受体，我们不得不假设在GC-2细胞中看到的DHEAS效应是通过膜结合受体介导的，在其他系统中已知这种受体激活了这种信号通路。在我们的建议框架内，我们计划：1)揭示DHEAS在生精细胞系GC-2中诱导的整个胞浆信号级联反应，并确定DHEAS的膜受体；2)研究DHEAS诱导转录因子CREB和ATF-1激活的生理学意义；以及3)研究DHEAS在其他类型的性腺细胞(支持细胞、颗粒细胞)中的可能作用。到目前为止，所获得的结果首次证明了DHEAS对生精细胞系的非基因组效应。拟议的继续调查应为与生育和生殖有关的生理机制提供新的见解。

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.