Impact of prenatal THC exposure on offspring neurodevelopment

About This Grant

PROJECT SUMMARY Cannabis is now the most commonly used federally illegal drug during pregnancy, where it is often used to alleviate symptoms of nausea, insomnia, pain and stress. The high prevalence of use is partly because safety data is substantially lacking, especially on the developing fetal brain. Thus, individuals continue to use cannabis when trying to conceive, or even during pregnancy, because it is perceived as harmless. The available studies are often limited by self-reported cannabis intake and other confounding variables, including polysubstance use, but suggest that prenatal cannabis use is associated with an increased risk of offspring neurodevelopmental deficits. Babies prenatally exposed to cannabis display an exaggerated response to stimuli, sleep disruption, and a high-pitched cry, indicative of adverse neurological development. Our group also has recent preliminary data that shows that chronic prenatal 9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) exposure in pregnant rhesus macaques negatively affects offspring brain development, including decreased brain volume, and transcriptional and epigenetic changes. The central hypothesis is that maternal prenatal cannabis use adversely impacts offspring neurodevelopment and emotional behavior. At present, there is insufficient evidence to establish a direct association between maternal cannabis use and later child outcomes. This gap in knowledge is due to the lack of relevant preclinical models that have strong translation to human health. Brain development is different in rodents than primates, including cortical expansion, neurogenesis, and brain size. We propose to address this knowledge gap by leveraging our first-in-kind translational rhesus macaque model of chronic edible THC use to fundamentally understand how maternal cannabis use shapes offspring brain and behavioral development. Edibles are the second most common mode of cannabis delivery amongst pregnant individuals, and allow rigor and reproducibility in dosing. The objective of this study is to examine the impact of chronic (e.g., daily use) maternal prenatal THC use on neonatal and infant neurodevelopment and behavior. This comprehensive study will bridge the gap in knowledge regarding how maternal cannabis use impacts offspring health. The successful completion of our study will result in: 1) new insights into the direct impact of chronic maternal THC use during pregnancy on offspring neurodevelopment, sensorimotor development and emotional behavior, 2) defining the effect of in utero THC exposure on the infant brain epigenome and transcriptome, and cannabinoid receptor expression and localization, and 3) the creation of a publicly-available non-human primate tissue bank of comprehensive biological samples and offspring tissues (control and THC- exposed) that can be used as a reference for other environmental exposures and can be accessed by other substance use researchers. Results from our proposed work will guide patient counseling, be used for harm reduction, and inform future studies focused on maternal cannabis use.