455. Effects of adolescent cannabinoid exposure on DNA methylation in Erbb4 conditional knockout and wild-type mice

Abstract

Abstract Background Adolescent cannabis use is associated with an increased risk of psychosis, yet the underlying molecular mechanisms remain poorly understood. Emerging evidence also pointed to genetic liability shaping individual risk of cannabis-induced psychosis. The neuregulin–ErbB4 signalling pathway, implicated in schizophrenia-related neurodevelopment, may modulate individual susceptibility to cannabis exposure. Aims & Objectives This study aimed to identify potential epigenetic biomarkers of exposure to different cannabinoid compounds, explore possible gene–environment interactions via DNA methylation, and investigate affected biological pathways relevant to psychosis. Method We examined the effects of chronic adolescent exposure (postnatal days 35–44) to 5 mg/kg Δ9-tetrahydrocannabinol (THC), 20 mg/kg cannabidiol (CBD), or their combination on DNA methylation in the prefrontal cortex, dorsal striatum, and blood of ErbB4 conditional knockout and wildtype C57BL/6 mice (N = 30 per drug group, sex and genotype balanced). Genome-wide methylation profiling was conducted using the Illumina Mouse Methylation BeadChip. Epigenome-wide association analyses were performed in R using a linear model that included drug group, genotype, sex, a sex × genotype interaction term, and principal components to account for batch effects. Results Preliminary analyses suggested extensive DNA methylation differences associated with genotype and sex, reflecting strong intrinsic epigenetic effects. Drug-related effects at individual CpG sites were nuanced, with no sites reaching genome-wide significance when comparing cannabinoid-exposed groups to vehicle. However, analysis of differentially methylated regions (DMRs) revealed numerous tissue-specific alterations associated with each cannabinoid exposure, indicating coordinated epigenetic changes beyond single CpG sites. Functional annotation and Gene Ontology analyses indicated enrichment in pathways related to neurodevelopment, synaptic signalling, and transcriptional regulation across the prefrontal cortex, dorsal striatum, and blood. Discussion & Conclusions Together, these findings provide new insight into the molecular consequences of adolescent cannabinoid exposure. By integrating genotype, sex, and drug exposure in a single epigenome-wide model, this study highlights both genetic and environmental contributions to epigenetic variation in neurodevelopmentally relevant brain regions. While drug-induced changes at individual CpG sites were subtle, tissue-specific DMRs enriched in neurodevelopmental and synaptic pathways suggest potentially meaningful effects of cannabinoids in the context of psychosis.