Project Details
Projekt
The roles of glucocorticoids in peritubular cells of the testis
Subject Area
Reproductive Medicine, Urology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 427588170
The importance of glucocorticoids (GC) in the regulation of human testicular functions is not well known. In the adult male gonad, testicular peritubular cells are a dominant site of expression of the glucocorticoid receptor (GR; NR3C1) and the results of our previous project # 427588170 provide evidence for roles of GC in the regulation of the peritubular compartment and its cellular components in the human/nonhuman primate testis. These testicular peritubular cells, have long been neglected but are by now being recognized to have a number of important roles in the testis. In humans, they can be isolated (HTPCs) and examined in vitro, and were recently shown to be a highly relevant and unique cellular model for this human testicular compartment. Cellular studies revealed that the synthetic GC Dexamethasone (Dex), at a therapeutic concentration, has massive consequences for peritubular cell functions, including testicular immunological roles, cell contractility and a fostering role in testicular fibrosis, which is a hallmark of male infertility due to impaired spermatogenesis. The changes not only became more pronounced with increasing exposure time (i.e. more alterations of the proteome with time) but, in part, also change qualitatively, as evidenced, for example, by the increased production of ECM proteins after 7 days. We also found that Dex rapidly affects clock gene expression of HTPCs and thus may off-set the endogenous circadian rhythm. Furthermore, Dex can promote cellular senescence. The last point, as well as consequences of long-term exposure to Dex, are however, not yet well examined. Importantly, whether Dex-induced changes are reversible, completely or only partially, upon cessation of the Dex stimulus is also not known. In man, idiopathic infertility with impaired spermatogenesis is often associated with inflammation and phenotypic alterations of peritubular cells, including loss of contractility and enhanced ECM formation, changes which can also be found in the testes of elderly men. These alterations mimic the changes induced by Dex in HTPCs. Given the wide-spread, short term or chronic use of Dex and other synthetic GC-drugs in medicine, and given that GC levels are elevated in stress and disease, it may be possible that (chronically) elevated GC levels, may contribute to male sub-/infertility by targeting peritubular cells. Therefore, we plan a focused, short-term (18 month) follow-up study. We want to pinpoint further Dex-induced changes and aim to answer the question, whether Dex effects are reversible. An array of cellular and molecular techniques is at our hands, which will together with established cooperation partners allow us to examine these important points.
DFG Programme
Research Grants
