The roles of glucocorticoids and catecholamines for the testis and peritubular cells

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Human testicular peritubular cells (HTPCs) express the receptors for glucocorticoids (GR; NR3C1) and the receptors for catecholamines (including alpha 1; ADRA1). This implies actions of these hormones, which are however to this day not well defined. This topic has gained interest, because it is becoming clear that elevated levels of glucocorticoids (GC) and catecholamines during different forms of stress in man are being associated with impaired testicular functions and fertility. Based on our previous and our preliminary data, we postulate that this is mediated, in part, by direct actions of GCs and catecholamines at the level of the testis and specifically at the level of the peritubular cell. Peritubular cells can be isolated from the human, nonhuman primate and mouse testis and together with organotypic cultures they serve as experimental windows into the testis. It has become clear from the previous study using human TPCs that they are important for many aspects of testicular functions, as they transport sperm, contribute to the spermatogonial stem cell niche and secrete factors, which are involved in the control of blood vessels. In addition, our recent data in human TPCs show that catecholamines, via activation of the alpha 1 receptors, stimulate the secretion of pro-inflammatory factors. Our preliminary data also show that activation of GR in human TPCs entails changes in their smooth muscle phenotype, extracellular matrix proteins production and influences cytokine production. Hence we hypothesize that GC and catecholamines have a crucial influence on the functions of peritubular cells, and thereby they may affect testicular homeostasis and consequently fertility and infertility. We propose to examine the testicular roles of GR/alpha 1 receptor-related signaling in a human-focused study by combining the expertise of three laboratories. We will gain knowledge about GR/ alpha 1 receptors in the testis, by studying different states of development, age and infertility. Since a predominant expression of both receptors is seen in peritubular cells, we will elucidate their functional roles in isolated TPCs from three species and in immortalized nonhuman primate TCPs from Callithrix jacchus, which represents a translational model. Ex vivo studies in nonhuman primate testes and mouse fragments will complement the experiments. In addition, we plan to employ relevant knockout mouse models. We expect that the results of the detailed functional studies, transcriptomic and proteomic analyses will enable us to decipher the testicular roles of GCs and catecholamines.