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

Abstract

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.

Refraining from use diminishes cannabis-associated epigenetic changes in human sperm

“…Although the actual disease or function annotations were not identical, their comparable categorical associations support our prior findings showing an impact of male cannabis use on genes in sperm that are associated with early developmental processes. These findings are also concordant with our results using a rat model of paternal preconception exposure to THC and epidemiological studies associating perinatal cannabis exposure with adverse health outcomes in offspring [ 3 , 4 , 18 , 23 ]. Specifically, rat studies demonstrated DNA methylation and gene expression changes in nucleus accumbens tissues at genes implicated in neurodevelopment [ 2 , 24 ], while population-based studies have associated prenatal cannabis use with autism-like phenotypes, developmental delays, and cardiomyopathies [ 7 , 25 ].…”

“…Autism spectrum disorders (ASDs) have been put forth, with epidemiologic support, as the most common form of cannabis-associated teratology [ 26 ]. Our prior work identified associations between cannabis and THC exposure in humans and rats, respectively, and altered sperm methylation at genes implicated in ASD [ 2 , 18 ]. This is potentially relevant since a significant positive association between cannabis legalization and increased ASD incidence was reported [ 26 ].…”

“…pesticides and heavy metals) in the cannabis products. The majority of cannabis users also consume nicotine [ 30 , 31 ], and although nicotine users were excluded from our study, nicotine exposure also impacts methylation profiles in sperm [ 18 ]. Therefore, there is a need to examine epigenetic effects of paternal cannabis use in individuals who also use nicotine to generalize our findings to the broader population of cannabis users.…”

“…Our previous work identified hypomethylation in sperm of cannabis users relative to controls at autism candidate gene Disks-Large Associated Protein 2 ( DLGAP2 ) and demonstrated in rats that paternal THC exposure showed heritable methylation changes at Dlgap2 [ 2 ]. We found that THC and nicotine both independently impact rat sperm DNA methylation at a select group of the same CpG sites of multiple neuroactive genes, and that these genes are enriched for bivalent chromatin as are the Simons Foundation for Autism Research curated list of autism candidate genes [ 18 ]. Recent reports have shown compelling associations between early-life exposure to cannabis and increased incidence of autism and neurodevelopmental delays in offspring [ 6–9 ].…”

Simulated Wildfire Smoke Significantly Alters Sperm DNA Methylation Patterns in a Murine Model

“…The GO terms associated with the genes ( Figure 3 ) and DMRs ( Supplementary Table S1 ) identified in this study include many developmental processes. While this is the first time that sperm DNA methylation patterns have been examined following wildfire smoke exposure, our results are consistent with GO term results from an existing study assessing tobacco and cannabis smoke exposure, including gene networks important for neuronal development and neuronal processes [ 30 ]. Notably, these sources of air pollution PM likely differ in toxic potential, which the authors posit warrants the continued assessment of wildfire smoke separately from the existing works.…”