ROLE OF THE ENDOCANNABINOID SYSTEM IN SPERMATOGENESIS: SYSTEMS BIOLOGY APPROACH

The spermatogenesis is a complex process that requires the differentiation of male gametes within the male genital tract. It involves a series of cellular events including mitosis, meiosis, cell migration, apoptosis, and differentiation of diploid germ cells (spermatogonia) to form haploid germ cells (spermatozoa). Recently, the endocannabinoid system (ECS) has been proposed to be involved in this process. It is composed by endogenous bioactive lipids, the N-arachidonoyl ethanolammine (AEA, anandamide) and the 2 arachidonoyl glycerol (2-AG), that recognize intracellular and extracellular receptors and by the enzymes responsible for their synthesis, degradation and transport (1). An innovative, computational modeling- based, approach was adopted to investigate the role of the ECS in control of spermatogenesis. In particular, we realized a network (the endocannabinoid system in spermatogenesis, ECSS) in which the nodes represented the molecules of ECS involved in spermatogenesis and the links were the interaction among them (2). The information on ECS molecules involved in spermatogenesis, from peer-reviewed papers from PubMed, published in last 10 years, were used to realize a database (Microsoft Office Excel 2003). The data were used to build the ECSS network and the statistical analysis of main topological parameters was carried out (Cytoscape 3.0.1 software) (3, 4). In particular the node degree (the number of links per node) distribution, the clustering coefficient (the presence of nodes clusters), the network diameter (the longest shortest path among all pairs of nodes), the mean number of neighbors (the mean number of connections per node), and the characteristic path length (the expected distance between two connected nodes) were assessed. It was found that ECSS network follows a scale free topology, characterized by a low clustering and easy navigability. In addition, the most connected ECS molecules (the hubs) are: AEA (25 links) CB1 and CB2 receptors (19 and 17 links), FAAH (11 links), NO (8 links). Thus, showing that AEA and the molecules directly involved in its signaling (its hydrolyzing enzyme, the FAAH, its receptors CB1 and CB2, and the related second messengers cAMP, Ca2+ and NO) play the key role in controlling spermatogenesis. From these data it is possible to infer some relevant information, not otherwise obtainable, and to achieve an important goal, the understanding of the role of ECS in spermatogenesis, potentially opening new prospective in drug discovery, diagnosis and clinical application. The ECS appears to be a new potential target for improving reproductive health in humans.