Maternal edible THC consumption alters offspring neurodevelopment and emotional behavior in rhesus macaques

BACKGROUND: Prenatal cannabis exposure is associated with adverse offspring outcomes including altered neurodevelopment. However, there is insufficient evidence to establish a direct association. We sought to determine the impact of chronic prenatal delta-9-tetrahydrocannabinol (THC) exposure on offspring neurodevelopment and emotional behavior in a translational rhesus macaque model. METHODS: Animals were divided into two groups, control and THC-exposed, with both groups receiving a daily edible (placebo or THC) pre-conception, throughout pregnancy, and postnatally. MRI was performed longitudinally across gestation and infancy to assess volumetric and microstructural brain development. Serial behavioral testing, including motor and emotional assessments, was performed postnatally. At 6 months of age, brain tissue was collected for histology, immunohistochemistry (IHC), whole genome bisulfite sequencing (WGBS), and bulk RNA-sequencing. FINDINGS: Analysis of the MRI images showed white matter changes with higher fractional anisotropy in the corpus callosum (CC) and centrum semiovale in THC-exposed infants. However, there were no significant differences in regional brain volumes. Behavioral testing demonstrated that THC-exposed infants displayed increased vocalizations and decreased independence. WGBS identified differentially methylated regions (DMRs) associated with THC exposure in the cerebellum and prefrontal cortex, annotated to genes involved in synaptic organization and brain development. RNA-sequencing confirmed differential expression of genes related to axon development and glutamatergic synapse, with expression correlating with methylation levels. INTERPRETATION: Chronic prenatal edible THC exposure in the rhesus macaque was associated with changes in white matter development, effects on infant behavior with signs of increased stress and anxiety, and brain DNA methylation and expression of genes involved in neurodevelopment.