The Effects of Gestational Cannabinoid Exposure on the Postnatal Cardiac Outcomes in the Offspring
Abstract
Clinical studies suggest that cannabis use in pregnancy leads to low-birth-weight outcomes. This is concerning given fetal growth deficits increase the risk of cardiovascular disease later in life. Despite this, prior to the work in this thesis, there were no studies examining the effects of gestational exposure to the major constituents in cannabis, Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD), on postnatal cardiac outcomes in offspring. In this thesis, I aimed to characterize the effects of THC and CBD on postnatal cardiac function and elucidate the underlying mechanisms involved in any associated perturbations. Additionally, I explored the potential cardioprotective effects of maternal supplementation of omega-3 fatty acids on THC-induced fetal growth restriction and associated postnatal cardiac deficits. To execute this, we utilized three rodent models: (1) Maternal exposure to THC (2) maternal exposure to CBD and (3) maternal exposure to THC with a maternal omega-3 fatty acid-enriched diet. To date, we demonstrated that while only THC resulted in significant decreases in birthweight, both THC and CBD led to reduced cardiac function at three-weeks of age in male offspring. Mechanistically, THC-exposed offspring demonstrated complete catch-up growth along with an increase in markers of cardiac remodeling. On the other hand, transcriptomic analysis revealed CBD-exposed offspring exhibited significant alterations in cardiac mitochondrial metabolism. Moreover, these CBD offspring also demonstrated a “rewired” cardiac endocannabinoid system, known to be associated with diminished cardioprotection. Most recently, we discovered that a maternal omega-3 enriched diet ameliorates both fetal growth deficits and reduced cardiac function in offspring exposed to THC in utero. These benefits are likely owed to the diet (1) significantly increasing cardiac and hepatic Docosahexaenoic acid (DHA) while reducing arachidonic acid (AA), (2) decreasing gene expression of pro-inflammatory cytokines (3) and significantly reducing markers of cardiac remodeling (Collagen type 1 and type 3) – all of which can explain the marked improvement in cardiac function. In conclusion, our studies demonstrate that although maternal THC and CBD exposure results in different fetal growth and mechanistic outcomes, both compromises the heart early in life. Moreover, our study offers a potential dietary intervention that can ameliorate postnatal cardiac deficits in THC-exposed offspring.