Epigenetic alterations in cytochrome P450 oxidoreductase (Por) in sperm of rats exposed to tetrahydrocannabinol (THC)
Open Access
- 23 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 10 (1), 1-11
- https://doi.org/10.1038/s41598-020-69204-7
Abstract
As marijuana legalization is increasing, research regarding possible long-term risks for users and their offspring is needed. Little data exists on effects of paternal tetrahydrocannabinol (THC) exposure prior to reproduction. This study determined if chronic THC exposure alters sperm DNA methylation (DNAm) and if such effects are intergenerationally transmitted. Adult male rats underwent oral gavage with THC or vehicle control. Differentially methylated (DM) loci in motile sperm were identified using reduced representation bisulfite sequencing (RRBS). Another cohort was injected with vehicle or THC, and sperm DNAm was analyzed. Finally, THC-exposed and control adult male rats were mated with THC-naïve females. DNAm levels of target genes in brain tissues of the offspring were determined by pyrosequencing. RRBS identified 2,940 DM CpGs mapping to 627 genes. Significant hypermethylation was confirmed (p < 0.05) following oral THC administration for cytochrome P450 oxidoreductase (Por), involved in toxin processing and disorders of sexual development. Por hypermethylation was not observed after THC injection or in the subsequent generation. These results support that THC alters DNAm in sperm and that route of exposure can have differential effects. Although we did not observe evidence of intergenerational transmission of the DNAm change, larger studies are required to definitively exclude this possibility.Funding Information
- John Templeton Foundation (60564)
This publication has 28 references indexed in Scilit:
- Acute Illness Associated With Cannabis Use, by Route of ExposureAnnals of Internal Medicine, 2019
- Hyper-methylation of the upstream CpG island shore is a likely mechanism of GPER1 silencing in breast cancer cellsGene, 2017
- Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER studyClinical Epigenetics, 2016
- Genetic and Epigenetic Variation, but Not Diet, Shape the Sperm MethylomeDevelopmental Cell, 2015
- Association Between Use of Marijuana and Male Reproductive Hormones and Semen Quality: A Study Among 1,215 Healthy Young MenAmerican Journal of Epidemiology, 2015
- Parental THC Exposure Leads to Compulsive Heroin-Seeking and Altered Striatal Synaptic Plasticity in the Subsequent GenerationNeuropsychopharmacology, 2014
- Proximal Promoter of the Cytochrome P450 Oxidoreductase Gene: Identification of Microdeletions Involving the Untranslated Exon 1 and Critical Function of the SP1 Binding SitesJournal of Clinical Endocrinology & Metabolism, 2011
- Cytochrome P450 Oxidoreductase Deficiency: Identification and Characterization of Biallelic Mutations and Genotype-Phenotype Correlations in 35 Japanese PatientsJournal of Clinical Endocrinology & Metabolism, 2009
- Targeted and genome-scale strategies reveal gene-body methylation signatures in human cellsNature Biotechnology, 2009
- Marihuana: Studies on the Disposition and Metabolism of Delta-9-Tetrahydrocannabinol in ManScience, 1970