Effects of maternal edible THC consumption on offspring lung growth and function in a rhesus macaque model

Prenatal cannabis use is rising, in part due to legalization and perceptions of safety. The impact of prenatal cannabis exposure on offspring development, especially respiratory health, remains largely unknown. The objective of this study was to determine whether in utero exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, is deleterious to offspring lung development and function using a rhesus macaque model. Female rhesus macaques received a daily edible containing either THC (2.5 mg/7 kg/day, equivalent to a heavy medical cannabis dose) or placebo during gestation and postnatally. Serial in utero magnetic resonance imaging (MRI) was performed during pregnancy at approximately gestational days (G)110 and G150. At 6 mo of age, infants underwent pulmonary function testing, followed by tissue collection for molecular analysis (bulk RNAseq, whole genome bisulfite sequencing, and spatial RNAseq). THC-exposed infants displayed significantly reduced forced residual capacity, which correlated with nonsignificant decreases in total lung capacity, lung diffusion capacity and lower fetal lung perfusion, oxygen availability, and lung volume measured by MRI. Consistent with these decreases in volume indices, levels of pulmonary growth factors were decreased in bronchial alveolar lavage at 6 mo. Molecular analysis of infant lungs revealed altered epigenetic regulation of gene expression, including at genes involved in extracellular matrix organization and lung development, and activation of immune signaling. Our study suggests that exposure to prenatal edible THC alters epigenetic regulation of lung gene expression and may negatively affect offspring lung development and function. Data from this study will help guide healthcare provider counseling on cannabis use in pregnancy.<b>NEW & NOTEWORTHY</b> In a translational rhesus macaque model, chronic prenatal delta-9-tetrahydrocannabinol exposure resulted in decreased lung volumes in offspring measured at 6 mo of age. These decreases correlated with altered DNA methylation in the lung, including at genes involved in extracellular matrix organization, lung development, and activation of immune signaling, and changes in lung cell composition as measured by spatial transcriptomics. These findings add to the growing evidence that prenatal cannabis exposure may adversely affect offspring development.