(L-452) In utero exposure of Delta-9-tetrahydrocannabinol (THC) impacts the endothelial transcriptome in rhesus macaques

Introduction:: Cannabis is the most frequently used federally illicit drug by pregnant individuals in the United States, in part due to recent legalization trends that have resulted in increased availability and a decreased perception of harm. It is commonly used in pregnancy for symptoms of nausea and pain, especially in the first trimester during organogenesis. Of concern is that delta-9-tetrahydrocannabinol (THC, the main active component of cannabis) can cross the placenta and bind to cannabinoid receptors (CB1 and CB2) on the fetus, including the brain and heart. Studies on the impact of prenatal THC exposure largely focus on offspring neurodevelopment. However, as CB1 receptors have been demonstrated on endothelial cells and blood vessels, this suggests that THC exposure may also adversely impact fetal cardiovascular development.


Materials and Methods:: Rhesus macaques were divided into two groups, control (CON, n=5) and THC-exposed (THC, n=5). THC-exposed animals received a THC edible (2.5mg/7kg/day, equivalent of a heavy medical cannabis dose) daily pre-conception and throughout pregnancy. Dams were underwent c-section delivery and fetal necropsy at gestational day 155 (term is ~168 days). The fetal cardiac tissue and umbilical cord were collected for further studies. Endothelial cells were isolated from the fetal aorta, umbilical vein, and umbilical artery using a Trizol flush. RNA was then converted to cDNA and underwent bulk RNA-sequencing. The heart and vessels were fixed, embedded, and stained for collagen and elastin.


Results, Conclusions, and Discussions:: There was no significant difference in fetal weight between THC-exposed and control fetuses, but a significant decrease in heart to body ratio (p=0.05) in the THC-treated animals was present. RNA sequencing showed the greatest differentially expressed genes (DEGs) in the fetal aorta (Figure 1A) compared to the umbilical vein (Figure 1B). Additionally, the DEGs clustered by THC and control treatment in both the fetal aorta and umbilical vein transcriptome. The pathways affected by in utero THC exposure included metabolism and extracellular matrix (ECM) production. Interestingly, there were trends of sex differences; males had increased metabolic and ECM production pathways, but in females these pathways were decreased. Lastly, perivascular, fibrillary collagen and elastin of the heart and aorta demonstrated no statistically significant differences. There continues to be a paucity of safety data despite the rising prevalence of maternal cannabis use; thus, it is critical to study the impact of prenatal cannabis exposure on the fetus. Our study did not demonstrate significant changes in birth weight nor the amount of collagen or elastin in the heart or aorta, but was notable for alterations in the endothelial transcriptome. This warrants further investigation of pre-natal cannabis exposure. In addition, our study’s findings suggest the possibility for underlying sex differences in the response to in utero THC exposure, but larger future studies are needed to increase the power of analysis.

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