The Cannabinoid Receptor CB1 Stabilizes Sperm Chromatin Condensation Status During Epididymal Transit by Promoting Disulphide Bond Formation

• Main Authors: Teresa Chioccarelli, Francesco Manfrevola, Veronica Porreca, Silvia Fasano, Lucia Altucci, Riccardo Pierantoni, Gilda Cobellis
• Format: Article
• Language: English
• Published: MDPI AG 2020-04-01
• Series: International Journal of Molecular Sciences
• Subjects: estrogens and endocannabinoids; caput and <i>cauda</i> epididymis; type-1 cannabinoid receptor (CB1); sperm chromatin condensation and maturation; protamine thiol oxidation; chromatin remodeling and histone displacement
• Online Access: https://www.mdpi.com/1422-0067/21/9/3117
• ISSN: 1661-6596; 1422-0067

The cannabinoid receptor CB1 regulates differentiation of spermatids. We recently characterized spermatozoa from <i>caput</i> epididymis of <i>CB1</i>-knock-out mice and identified a considerable number of sperm cells with chromatin abnormality such as elevated histone content and poorly condensed chromatin. In this paper, we extended our findings and studied the role of CB1 in the epididymal phase of chromatin condensation of spermatozoa by analysis of spermatozoa from <i>caput</i> and <i>cauda</i> epididymis of wild-type and <i>CB1</i>-knock-out mouse in both a homozygous or heterozygous condition. Furthermore, we studied the impact of <i>CB1</i>-gene deletion on histone displacement mechanism by taking into account the hyperacetylation of histone H4 and players of displacement such as Chromodomain Y Like protein (CDYL) and Bromodomain testis-specific protein (BRDT). Our results show that CB1, via local and/or endocrine cell-to-cell signaling, modulates chromatin remodeling mechanisms that orchestrate a nuclear condensation extent of mature spermatozoa. We show that <i>CB1</i>-gene deletion affects the epididymal phase of chromatin condensation by interfering with inter-/intra-protamine disulphide bridges formation, and deranges the efficiency of histone removal by reducing the hyper-acetylation of histone H4. This effect is independent by gene expression of <i>Cdyl</i> and <i>Brdt</i> mRNA. Our results reveal a novel and important role for CB1 in sperm chromatin condensation mechanisms.