Abstract
Heavy use of cannabis (marijuana) has been associated with decreased semen quality, which may reflect disruption of the endocannabinoid system (ECS) in the male reproductive tract by exogenous cannabinoids. Components of ECS have been previously described in human spermatozoa and in the rodent testis but there is little information on the ECS expression within the human testis. In this study we characterised the main components of the ECS by immunohistochemistry (IHC) on archived testis tissue samples from 15 patients, and by in silico analysis of existing transcriptome datasets from testicular cell populations. The presence of 2-arachidonoylglycerol (2-AG) in the human testis was confirmed by matrix-assisted laser desorption ionization imaging analysis. Endocannabinoid-synthesising enzymes; diacylglycerol lipase (DAGL) and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), were detected in germ cells and somatic cells, respectively. The cannabinoid receptors, CNR1 and CNR2 were detected at a low level in post-meiotic germ cells and Leydig- and peritubular cells. Different transcripts encoding distinct receptor isoforms (CB1, CB1A, CB1B and CB2A) were also differentially distributed, mainly in germ cells. The cannabinoid-metabolising enzymes were abundantly present; the α/β-hydrolase domain-containing protein 2 (ABHD2) in all germ cell types, except early spermatocytes, the monoacylglycerol lipase (MGLL) in Sertoli cells, and the fatty acid amide hydrolase (FAAH) in late spermatocytes and post-meiotic germ cells. Our findings are consistent with a direct involvement of the ECS in regulation of human testicular physiology, including spermatogenesis and Leydig cell function. The study provides new evidence supporting observations that recreational cannabis can have possible deleterious effects on human testicular function.
Highlights
Heavy use of cannabis has been associated with decreased semen quality, which may reflect disruption of the endocannabinoid system (ECS) in the male reproductive tract by exogenous cannabinoids
Several of the ECS components have been detected previously in human ejaculated spermatozoa[2,3,17,18,19,20,21,22], our study is the first to demonstrate the presence of a specific pattern of this signalling pathway in various human testicular cell types, including germ cells at different stages of spermatogenesis, and in the somatic cells
We clearly demonstrated that the human testis has a machinery to synthesise and metabolise endocannabinoids, which are recognised by different testicular cell types within the seminiferous epithelium and the interstitial tissue
Summary
Heavy use of cannabis (marijuana) has been associated with decreased semen quality, which may reflect disruption of the endocannabinoid system (ECS) in the male reproductive tract by exogenous cannabinoids. The ECS signalling is further regulated by a complex system of degrading enzymes; AEA is metabolised by the fatty acid amide hydrolase (FAAH) and 2-AG predominantly by the monoacylglycerol lipase (MGLL, known as MAGL), but alternative metabolising pathways e.g. by oxidation have been described[7,8]. Other ECS components were identified in rodent testes mainly at the transcriptional level, including CNR2 and FAAH in Sertoli cells, and FAAH, NAPE-PLD, MGLL and DAGL in germ cells (reviewed in 11). The ECS receptors were found in human spermatozoa, with some discrepancies; while most studies demonstrated the presence of CNR1 alone[17,18], some studies detected in sperm the other canonical receptor, CNR2, albeit at a much lower expression level[18,19]. It was experimentally demonstrated that excess of 2-AG impaired function of human spermatozoa in vitro, causing premature acrosome reaction and loss of sperm motility[22]
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