Sperm DNA methylation altered by THC and nicotine: Vulnerability of neurodevelopmental genes with bivalent chromatin

Men consume the most nicotine and cannabis products but impacts on sperm epigenetics are poorly characterized. Evidence suggests that preconception exposure to these drugs alters offspring neurodevelopment. Epigenetics may in part facilitate heritability. We therefore compared effects of exposure to tetrahydrocannabinol (THC) and nicotine on DNA methylation in rat sperm at genes involved in neurodevelopment. Reduced representation bisulfite sequencing data from sperm of rats exposed to THC via oral gavage showed that seven neurodevelopmentally active genes were significantly differentially methylated versus controls. Pyrosequencing data revealed majority overlap in differential methylation in sperm from rats exposed to THC via injection as well as those exposed to nicotine. Neurodevelopmental genes including autism candidates are vulnerable to environmental exposures and common features may mediate this vulnerability. We discovered that autism candidate genes are significantly enriched for bivalent chromatin structure, suggesting this configuration may increase vulnerability of genes in sperm to disrupted methylation.

Sperm Epigenetics and Its Impact on Male Fertility, Pregnancy Loss, and Somatic Health of Future Offsprings

Sperm epigenetic programming is tailored to meet the need of this specialized cell, which include its interaction with the oocyte during fertilization and early embryo development. The unique nature of the sperm epigenome has resulted in multiple studies investigating how perturbations in epigenetics might impact male fertility and early embryo development. In addition, sperm epigenetics appear to be altered by specific environmental exposures, which could provide a link for investigating the role of these triggers in somatic health of off springs produced. This has the potential of explaining otherwise missing heritability factors seen with several diseases. While this field of investigation is new and with limited validation, it is intriguing and further studies are warranted.