title: Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis.
abstract: Type 2 cannabinoid receptor (CB2) has been proposed to play a pivotal role in meiotic entry of male germ cells, 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(-6)M) mimics epigenetic events induced by RA (IC5010(-7)M) in spermatogonia. Both JWH133 and RA treatments stimulate the expression of the meiotic genes c-KitandStra8, by up-regulating H3K4me3 and down-regulating H3K9me2 levels in genomic regions flanking the transcription start site. Moreover, both agents increase the expression ofPrdm9, 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.-Di Giacomo, D., De Domenico, E., Sette, C., Geremia, R., Grimaldi, P. Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis.
authors.affiliation: *Department of Biomedicine and Prevention, Section of Anatomy, University of Rome "Tor Vergata," Rome, Italy; and Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Di Giacomo
authors.affiliation: *Department of Biomedicine and Prevention, Section of Anatomy, University of Rome "Tor Vergata," Rome, Italy; and Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: De Domenico
authors.affiliation: *Department of Biomedicine and Prevention, Section of Anatomy, University of Rome "Tor Vergata," Rome, Italy; and Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
authors.affiliation: *Department of Biomedicine and Prevention, Section of Anatomy, University of Rome "Tor Vergata," Rome, Italy; and Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Geremia
authors.affiliation: *Department of Biomedicine and Prevention, Section of Anatomy, University of Rome "Tor Vergata," Rome, Italy; and Laboratory of Neuroembryology, Fondazione Santa Lucia, Rome, Italy p.grimaldi@med.uniroma2.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Grimaldi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002186:Cannabinoids / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D008297:Male; D008540:Meiosis / Q000187:drug effects / Q000235:genetics; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013091:Spermatogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013093:Spermatogonia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D002186:Cannabinoids; D006657:Histones; D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; D014212:Tretinoin; D011495:Histone-Lysine N-Methyltransferase; C534829:prdm9 protein, mouse; D008239:Lysine; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C094023:iodopravadoline
keywords: endocannabinoid system; histone methylation; meiosis; retinoic acid