title: Cannabinoid receptor 1 influences chromatin remodeling in mouse spermatids by affecting content of transition protein 2 mRNA and histone displacement.
abstract: Marijuana smokers and animals treated with Δ9-tetrahydrocannabinol, the principal component of marijuana, show alterations of sperm morphology suggesting a role for cannabinoids in sperm differentiation and/or maturation. Because the cannabinoid receptor 1 (CNR1) activation appears to play a pivotal role in spermiogenesis, the developmental stage where DNA is remodeled, we hypothesized that CNR1 receptors might also influence chromatin quality in sperm. We used Cnr1 null mutant (Cnr1-/-) mice to study the possible role of endocannabinoids on sperm chromatin during spermiogenesis. We demonstrated that CNR1 activation regulated chromatin remodeling of spermatids by either increasing Tnp2 levels or enhancing histone displacement. Comparative analysis of wild-type, Cnr1+/-, and Cnr1-/- animals suggested the possible occurrence of haploinsufficiency for Tnp2 turnover control by CNR1, whereas histone displacement was disrupted to a lesser extent. Furthermore, flow cytometry analysis demonstrated that the genetic loss of Cnr1 decreased sperm chromatin quality and was associated with sperm DNA fragmentation. This damage increased during epididymal transit, from caput to cauda. Collectively, our results show that the expression/activity of CNR1 controls the physiological alterations of DNA packaging during spermiogenesis and epididymal transit. Given the deleterious effects of sperm DNA damage on male fertility, we suggest that the reproductive function of marijuana users may also be impaired by deregulation of the endogenous endocannabinoid system.
authors.affiliation: Dipartimento di Medicina Sperimentale, Sez. Bottazzi, Seconda Università di Napoli, 80138 Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Chioccarelli
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cacciola
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Sheena E M
authors.initials: SE
authors.lastname: Lewis
authors.forename: Luke
authors.initials: L
authors.lastname: Simon
authors.forename: Giulia
authors.initials: G
authors.lastname: Ricci
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meccariello
authors.forename: Silvia
authors.initials: S
authors.lastname: Fasano
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pierantoni
authors.forename: Gilda
authors.initials: G
authors.lastname: Cobellis
mesh_terms: D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D042003:DNA Packaging / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011479:Protamines / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055101:Semen Analysis; D013087:Spermatids / Q000378:metabolism*; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C513176:Prm1 protein, mouse; D011479:Protamines; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; C489505:Tnp2 protein, mouse; C068621:protamine 2