Cannabinoid Receptor 1 Influences Chromatin Remodeling in Mouse Spermatids by Affecting Content of Transition Protein 2 mRNA and Histone Displacement
Cannabinoid Receptor 1 Influences Chromatin Remodeling in Mouse Spermatids by Affecting Content of Transition Protein 2 mRNA and Histone Displacement
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DOI：
10.1210/en.2010-0133
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发表时间：
2010-10-01
期刊：
影响因子：
4.8
通讯作者：
Cobellis, Gilda
中科院分区：
文献类型：
--
作者：
Chioccarelli, Teresa;Cacciola, Giovanna;Cobellis, Gilda
吸食大麻的人和接受大麻主要成分 Delta(9)-四氢大麻酚治疗的动物表现出精子形态的改变，表明大麻素在精子分化和/或成熟中发挥作用。由于大麻素受体 1 (CNR1) 激活似乎在精子发生（DNA 重塑的发育阶段）中发挥着关键作用，因此我们假设 CNR1 受体也可能影响精子中的染色质质量。我们使用 Cnr1 无效突变 (Cnr1(-/-)) 小鼠来研究精子发生过程中内源性大麻素对精子染色质的可能作用。我们证明 CNR1 激活通过增加 Tnp2 水平或增强组蛋白置换来调节精子细胞的染色质重塑。对野生型、Cnr1(+/-) 和 Cnr1(-/-) 动物的比较分析表明，CNR1 控制 Tnp2 转换可能出现单倍体不足，而组蛋白置换受到较小程度的破坏。此外，流式细胞术分析表明，Cnr1 的遗传缺失会降低精子染色质质量，并与精子 DNA 碎片相关。这种损伤在附睾从头到尾的运输过程中增加。总的来说，我们的结果表明，CNR1 的表达/活性控制着精子发生和附睾转运过程中 DNA 包装的生理变化。鉴于精子 DNA 损伤对男性生育能力的有害影响，我们认为大麻使用者的生殖功能也可能因内源性内源性大麻素系统的失调而受到损害。 （内分泌学151：5017-5029，2010）
Marijuana smokers and animals treated with Delta(9)-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. (Endocrinology 151: 5017-5029, 2010)