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

Epigenetics. Jan-Feb 2020;15(1-2):161-173. doi: 10.1080/15592294.2019.1656158. Epub 2019 Aug 26.

Abstract

Parental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.

Keywords: Cannabis; DNA methylation; autism; heritability; sperm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Autistic Disorder / genetics
  • Cannabinoid Receptor Agonists / pharmacology
  • CpG Islands
  • DNA Methylation*
  • Dronabinol / pharmacology
  • Humans
  • Introns
  • Male
  • Marijuana Abuse / genetics*
  • Nerve Tissue Proteins / genetics*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Spermatozoa / drug effects
  • Spermatozoa / metabolism*

Substances

  • Cannabinoid Receptor Agonists
  • DLGAP2 protein, human
  • Nerve Tissue Proteins
  • Dronabinol

Grant support

This research was supported in part by the John Templeton Foundation under Grant 60564.