Paternal activation of CB(2) cannabinoid receptor impairs placental and embryonic growth via an epigenetic mechanism

The cannabinoid receptor type 2 (CB(2)) 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(2), 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(2) 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(2) 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(2) 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(2) alters the sperm epigenome and compromises offspring growth. This study demonstrates, for the first time, a new role of CB(2) 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.