Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Physiology and Pharmacology
Supervisor
Hardy, Daniel B.
Affiliation
Lawson Health Research Institute
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.
Summary for Lay Audience
Studies have shown that the rate of cannabis use during pregnancy is approximately 7%. This is concerning given that using cannabis during pregnancy can lead to low birthweight babies. Epidemiological studies suggest that these low-birth-weight individuals will age with an increased risk of heart disease later in life. In cannabis there are two major constituents, (1) Delta-9-tetrahydrocannabinol (THC) which is the main chemical in cannabis that gives users the "high" and (2) Cannabidiol (CBD) a non-euphoric chemical that has skyrocketed in popularity. Currently, exposure to THC and CBD during pregnancy and its impacts on the offspring’s cardiovascular health is unknown. To test this, we used pregnant rats and exposed them to THC and CBD during pregnancy to assess if there are deficits in heart function and signs of heart damage present in the pups early in life. In our first study we showed that maternal THC exposure leads to smaller hearts and decreases in birthweight. By the time these animals are weaned (3-weeks-old) they demonstrated reduced heart function and increased proteins that are associated with injury (collagen). On the other hand, when pregnant animals were exposed to CBD, the pup’s birthweight did not change, however, they still demonstrated decreases in heart function at 3-weeks. We think this deficit in heart function is due to alterations in mitochondrial gene expression for energy production in the heart. Next, we sought to explore the therapeutic potential of omega-3s to mitigate the effects of cannabinoids on the offspring. Interestingly, when we gave the pregnant rats both THC and the omega-3 enriched diet, we saw improvements in birthweight. We also saw significant increases in cardiac function in male offspring. We believe this occurs because the beneficial omega-3s were elevated directly in the heart and that this was associated with a decrease in protein levels of collagen. Collectively, our studies provide novel evidence to suggest that both THC and CBD alone in pregnancy compromises the heart in young offspring. Fortunately, our work also presents a promising intervention that may be beneficial for the cardiovascular health of offspring exposed to cannabinoids in pregnancy.
Recommended Citation
Lee, Kendrick, "The Effects of Gestational Cannabinoid Exposure on the Postnatal Cardiac Outcomes in the Offspring" (2024). Electronic Thesis and Dissertation Repository. 10487.
https://ir.lib.uwo.ca/etd/10487