Cannabinoid exposure and altered DNA methylation in rat and human sperm

Abstract

Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicleexposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline

“…For instance, adult‐onset prediabetic conditions (Wei et al., ), obesity (Fullston et al., ), and cocaine‐seeking motivation (Le et al., ) all modify the DNA methylome in sperm. One recent study reported similar changes in DNA methylation in sperm between tetrahydrocannabinol (THC)‐treated rats and cannabis‐smoking adults (Murphy et al., ). Other studies have reported effects of cocaine and stress on histone modifications in developing or mature sperm at specific gene loci that coincided with altered expression of the same gene in adult offspring brain, suggesting cross‐generational epigenetic memory (Dias and Ressler, ; Vassoler et al., ).…”

Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm

“…Using reduced representation bisulphite sequencing (RRBS) our group recently demonstrated that cannabis use in humans, and THC exposure in rats, is associated with decreased sperm concentrations and widespread changes in sperm DNA methylation [25]. Of the regions identified in humans, Discs-Large Associated Protein 2 (DLGAP2) exhibited significant hypomethylation in the sperm of cannabis-exposed men compared to controls (p < 0.05).…”

Multi-omics data analysis implicating epigenetic inheritance in evolution and disease

“…For disease significance, I first determined the overlap between genes showing differential methylation in sperm under various conditions and genes associated with certain diseases implicated earlier. The sperm samples included that of recreational users of cannabis 19 (Can), cigarette smokers 20 (Cig), enriched-risk cohort of fathers of autistic children 15 (Aut), men undergoing fertility treatment and showing association between differential sperm methylation and preconception urinary phthalate concentration 21 (Ph), exercise trained (ExT) and detrained (ExD) individuals 22 , men with experience of childhood abuse 23 (ChA), veterans with posttraumatic stress disorder 24 (PTSD), and obese men before (Ob) and after one week (Obw) or one year (Oby) of bariatric surgery 25 . The corresponding studies were identified through manual search for relevant literature.…”