Determining the effects of prenatal THC use on offspring lung development and function

About This Grant

PROJECT SUMMARY Cannabis is currently the most commonly used federally illicit drug during pregnancy. It is often used to alleviate symptoms of nausea, insomnia, pain and stress during pregnancy, especially in the first trimester when the fetus is most sensitive to environmental exposures. The high prevalence of use is partly because safety data is substantially lacking. Thus, individuals continue to use cannabis when trying to conceive or 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 low birth weight infants, preterm delivery, stillbirth and infant mortality, and have focused largely on impact to offspring neurodevelopment. Our group has recent preliminary data that shows that chronic prenatal delta-9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) exposure in pregnant rhesus macaques negatively affects offspring lung development, including decreased infant lung volumes and gas exchange, and transcriptional and epigenetic changes. As THC can readily cross the placenta and bind to cannabinoid receptors expressed in the fetal lung, there is concern that prenatal THC exposure can adversely affect offspring lung development and function. As this has not been previously studied, it is crucial to study the influence of THC on offspring respiratory health. The lack of understanding regarding the effects of prenatal THC use on offspring lung development is partly due to the paucity of relevant preclinical models for mechanistic studies with strong translation to human health. Lung development is structurally and cellularly different in primates than rodents. To address this critical knowledge gap, our proposed study will leverage our translational rhesus macaque model of chronic prenatal edible THC consumption. Edibles are the second most common mode of cannabis delivery amongst pregnant individuals and allow rigor and reproducibility in dosing. The objective of our study is to determine the impact of in utero THC exposure on offspring lung development and function. To do this we will integrate advanced imaging techniques, pulmonary function testing and lung stereology to first determine the effects on lung structure and function. Then we will analyze gene expression and alterations in DNA methylation utilizing spatial transcriptomics, whole genome bisulfite sequencing and confocal microscopy to determine underlying molecular mechanisms. The successful completion of our study will result in: 1) new insights into the effects of chronic maternal THC use in pregnancy on offspring lung development and function, 2) defining the effect of in utero THC exposure on the newborn and infant lung epigenome and transcriptome, and 3) the creation of a publicly-available non-human primate tissue bank of comprehensive biological samples and offspring tissues (control and THC-exposed). Results from our proposed work will inform future studies and guide patient counseling on maternal cannabis use.