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

Schrott, Rose; Acharya, Kelly S.; Itchon-Ramos, Nilda; Hawkey, Andrew; Pippen, Erica; Mitchell, John T.; Kollins, Scott H.; Levin, Edward D.; Murphy, Susan K.

doi:10.1080/15592294.2019.1656158

Cited by 71 publications

(81 citation statements)

References 47 publications

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“…Dlgap2 has also been shown by others to be differentially methylated in the nucleus accumbens of rats born to parents with adolescent THC exposure 51 . We found that methylation of DLGAP2 in human brain tissue at the same region altered in sperm was inversely related to expression of this gene, supporting that altered DNA methylation has functional consequences for the levels of gene product produced 17 .…”

Section: Discussionsupporting

confidence: 55%

“…We observed significant differences in sperm DNA methylation following THC and nicotine exposure at an overlapping group of neurodevelopmentally important genes and the literature describes multiple exposures as being implicated in autism and autism-like phenotypes 7,9,25 . The abundance of genes that are important mediators of early growth and development identified by others [26][27][28][29] and our group 16,17,[30][31][32][33][34] that exhibit altered methylation resulting from environmental exposures suggests they may share common features that render them vulnerable. Many genes that are involved in early development require activation in a highly regulated temporal manner and are associated with the presence of bivalent chromatin marks.…”

mentioning

confidence: 73%

“…We recently demonstrated that methylation of another PSD gene, DLGAP2 50 , is significantly altered in the sperm of human cannabis users as compared to controls 17 . We also showed that Dlgap2 was hypomethylated in sperm of THC exposed rats compared to controls, and that this change persisted in the nucleus accumbens of pups born to THC exposed fathers 17 . Dlgap2 has also been shown by others to be differentially methylated in the nucleus accumbens of rats born to parents with adolescent THC exposure 51 .…”

Section: Discussionmentioning

confidence: 99%

“…We were surprised to find that a large number were implicated in neurodevelopment and neuronal processes. Given our previous demonstration that paternal cannabis use is associated with altered methylation of autism candidate DLGAP2 and our findings of effects on genes involved in neurodevelopment 17 , we focused on genes previously reported in the literature to play a role in autism and for which there was a greater than 10% difference in sperm Figure 6. Significant overlap between SFARI autism genes, genes with bivalent chromatin, and genes from human RRBS study that are differentially methylated in sperm between cannabis users and non-user controls.…”

Section: Discussionmentioning

confidence: 99%

“…We were particularly intrigued by the significant enrichment of genes involved in neurodevelopmental and regulatory processes because of our recent finding that methylation of autism candidate gene DLGAP2 is significantly altered in sperm from men who use cannabis relative to controls, as well as in the sperm of rats exposed to THC 17 . Furthermore, our results suggested the potential for intergenerational transmission of this methylation change in rats 17 . There were 19 GO terms identified (including 79 unique gene names) that are involved in neuronal development and synaptic plasticity.…”

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confidence: 99%

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

Schrott

Rajavel

Acharya

et al. 2020

Sci Rep

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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.

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Section: Discussionsupporting

confidence: 55%

mentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Schrott

Rajavel

Acharya

et al. 2020

Sci Rep

Self Cite

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Subacute cannabidiol alters genome‐wide DNA methylation in adult mouse hippocampus

Wanner

Colwell

Drown

et al. 2020

Environ and Mol Mutagen

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Use of cannabidiol (CBD), the most abundant non-psychoactive compound found in cannabis (Cannabis sativa), has recently increased as a result of widespread availability of CBD-containing products. CBD is FDA-approved for the treatment of epilepsy and exhibits anxiolytic, antipsychotic, prosocial, and other behavioral effects in animal studies and clinical trials, however, the underlying mechanisms governing these phenotypes are still being elucidated. The epigenome, particularly DNA methylation, is responsive to environmental input and can govern persistent patterns of gene regulation affecting phenotype across the life course. In order to understand the epigenomic activity of cannabidiol exposure in the adult brain, 12-week-old male wild-type a/a Agouti viable yellow (A vy) mice were exposed to either 20 mg/kg CBD or vehicle daily by oral administration for 14 days. Hippocampal tissue was collected and reduced-representation bisulfite sequencing (RRBS) was performed. Analyses revealed 3,323 differentially methylated loci (DMLs) in CBD-exposed animals with a small skew toward global hypomethylation. Genes for cell adhesion and migration, dendritic spine development, and excitatory postsynaptic potential were found to be enriched in a gene ontology term analysis of DML-containing genes, and disease ontology enrichment revealed an overrepresentation of DMLs in gene sets associated with autism spectrum disorder, schizophrenia, and other phenotypes. These results suggest that the epigenome may be a key substrate for CBD's behavioral effects and provides a wealth of gene regulatory information for further study.

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Are cannabidiol (CBD) levels in consumer food products well tested?—A review

Siddiqui,

Fidan,

Stankov

et al. 2023

Food Frontiers

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There are differing views on cannabis and phytocannabinoid usage in diverse domains of application. This review explores the advantages and drawbacks of using cannabis and phytocannabinoids, including their effects on human health, in addition to highlighting the need for precise and repeatable analytical methods for quantifying controlled phytocannabinoids in consumer cannabidiol (CBD) products and foods. The composition and characteristics of the phytochemicals found in cannabis, the advantages and disadvantages of controlled and uncontrolled phytocannabinoids, and the need for regulation and standardization in the use of cannabis and products containing phytocannabinoids are all covered in this review of the pertinent literature. Cannabinoids used illegally can have negative consequences, but controlled phytocannabinoids found in consumer CBD products are relatively safe and unlikely to cause any adverse effects. It is necessary to restrict the amount of CBD in foods and consumer products in order to ensure safety. To measure the amount of restricted phytocannabinoids in these products, accurate analytical techniques are also required. In order to increase the use of cannabis among consumers, more research is needed to improve our understanding of the bioavailability and metabolic pathways of these compounds. Furthermore, consumers want clear and uniform federal rules governing the amount of CBD in food products in order to ensure correct dosing. To promote safe and responsible use, cannabis and phytocannabinoids must be carefully considered, regulated, and standardized. It is necessary for consumers to have clear, consistent standards governing the percentage of CBD in their food products. As a result, they would know the exact amount of CBD in their products.

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

Cited by 71 publications

References 47 publications

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

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

Subacute cannabidiol alters genome‐wide DNA methylation in adult mouse hippocampus

Are cannabidiol (CBD) levels in consumer food products well tested?—A review

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