Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis

Type 2 cannabinoid receptor (CB2) has been proposed to play a pivotal role in meiotic entry of male germcells, similar to retinoic acid (RA). In this study, we showed that activation of CB2with the specific agonist JWH133 [3-(1′,1′-dimethylbutyl)-1-deoxy-8-THC] (IC5010-6M) mimics epigenetic events induced by RA (IC5010-7M) in spermatogonia. Both JWH133 and RA treatments stimulate the expression of the meiotic genes c-Kit and Stra8, by up-regulating H3K4me3 and down-regulating H3K9me2 levels in genomic regions flanking the transcription start site. Moreover, both agents increase the expression of Prdm9, the gene encoding a meiosis-specific histone, H3K4me3 methyltransferase, which marks hotspots of recombination in prophase I, thus resulting in a global increase in H3K4me3. Notably, prolonged administration of JWH133 to immature 7 dpp CD-1 mice induced an acceleration of the onset of spermatogenesis, whereas the specific CB2antagonist delayed germ cell differentiation. Thus, both hyper- and hypostimulation of CB2disrupted the temporal dynamics of the spermatogenic cycle. These findings highlight the importance of proper CB2signaling for the maintenance of a correct temporal progression of spermatogenesis and suggest a possible adverse effect of cannabis in deregulating this process.