Paternal Transgenerational Epigenetic Legacy from Use of Cannabis

The movement to legalize marijuana is growing across the US, with a corresponding increase in both medical and recreational contexts. While the intoxication produced by cannabis has been well studied, the longer-term neurotoxicity in individuals who use cannabis is only now being uncovered. Of particular importance is the very real possibility that cannabis users put at risk not only themselves, but also future generations. The risk of epigenetic mediated neurotoxicity through paternal cannabis use is quite likely but NOT currently studied by NIH supported projects. This is supported by our preliminary data, which shows that exposure to THC in rats, and cannabis in humans, is associated with substantial changes in sperm DNA methylation. We hypothesize that preconceptions exposure to cannabis induces widespread changes in DNA methylation and histone modifications in sperm that are transmissible to offspring and that this exposure is associated with detectable behavioral differences in the offspring relative to controls, that such changes are detectable (heritable) across generations. Furthermore, we hypothesize that cannabis-associated epigenetic alterations are reversible. In this project we seek to extend our initial findings and test these hypotheses by determining 1) how use of cannabis influences reprogramming of epigenetic information in sperm across the entirety of the epigenome, 2) how exposure of fathers influences behavior of offspring, 3) the extent to which these alterations and behaviors are transmitted across generations, and 4) if changes in the epigenome from cannabis use are reversible. The project will have significant academic and public policy appeal, as well as community outreach to help convey high fidelity information to clinicians and the public about the findings from the research and its implications.