Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy.
Sci Rep. 2019 Nov 19;9(1):17034. doi: 10.1038/s41598-019-53579-3.
The cannabinoid receptor type 2 (CB) is the peripheral receptor for cannabinoids, involved in the homeostatic control of several physiological functions. Male mitotic germ cells express a high level of CB, whose activation promotes their differentiation in both in vitro and in vivo experiments, controlling the correct progression of spermatogenesis. However, it remains elusive if CB activation in spermatogonia could affect reproductive success in terms of fertility and healthy pregnancy outcomes. In this study, we explored the effects of male CB activation on sperm number and quality and its influence on next generation health. We show that exposure of male mice to JWH-133, a selective CB agonist, decreased sperm count, impaired placental development and reduced offspring growth. These defects were associated with altered DNA methylation/hydroxymethylation levels at imprinted genes in sperm and conserved in placenta. Our findings reveal that paternal selective activation of CB alters the sperm epigenome and compromises offspring growth. This study demonstrates, for the first time, a new role of CB signaling in male gametes in causing epigenetic alterations that can be transmitted to the next generation by sperm, highlighting potential risks induced by recreational cannabinoid exposure.
大麻素受体 2（CB）是大麻素的外周受体，参与多种生理功能的稳态控制。雄性有丝分裂生殖细胞表达高水平的 CB，其激活促进了体外和体内实验中生殖细胞的分化，控制了精子发生的正确进展。然而，CB 在精原细胞中的激活是否会影响生育能力和健康妊娠结局的生殖成功仍不清楚。在这项研究中，我们探讨了雄性 CB 激活对精子数量和质量的影响及其对下一代健康的影响。我们发现，暴露于选择性 CB 激动剂 JWH-133 的雄性小鼠精子数量减少，胎盘发育受损，后代生长受限。这些缺陷与精子中印记基因的 DNA 甲基化/羟甲基化水平改变有关，并在胎盘组织中得到了保守。我们的研究结果表明，选择性激活 CB 会改变精子的表观基因组，并损害后代的生长。这项研究首次证明了 CB 信号在雄性配子中的新作用，导致可通过精子传递给下一代的表观遗传改变，突出了娱乐性大麻素暴露所带来的潜在风险。
