Exposure to Δ9-tetrahydrocannabinol during rat pregnancy leads to impaired cardiac dysfunction in postnatal life

Abstract

Background Cannabis use in pregnancy leads to fetal growth restriction (FGR), but the long-term effects on cardiac function in the offspring are unknown, despite the fact that fetal growth deficits are associated with an increased risk of developing postnatal cardiovascular disease. We hypothesize that maternal exposure to Δ9-tetrahydrocannabinol (Δ9-THC) during pregnancy will impair fetal development, leading to cardiac dysfunction in the offspring. Methods Pregnant Wistar rats were randomly selected and administered 3 mg/kg of Δ9-THC or saline as a vehicle daily via intraperitoneal injection from gestational days 6 to 22, followed by echocardiogram analysis of cardiac function on offspring at postnatal days 1 and 21. Heart tissue was harvested from the offspring at 3 weeks for molecular analysis of cardiac remodelling. Results Exposure to Δ9-THC during pregnancy led to FGR with a significant decrease in heart-to-body weight ratios at birth. By 3 weeks, pups exhibited catch-up growth associated with significantly greater left ventricle anterior wall thickness with a decrease in cardiac output. Moreover, these Δ9-THC-exposed offsprings exhibited increased expression of collagen I and III, decreased matrix metallopeptidase-2 expression, and increased inactivation of glycogen synthase kinase-3β, all associated with cardiac remodelling. Conclusions Collectively, these data suggest that Δ9-THC-exposed FGR offspring undergo postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function early in life. Impact To date, the long-term effects of perinatal Δ9-THC (the main psychoactive component) exposure on the cardiac function in the offspring remain unknown. We demonstrated, for the first time, that exposure to Δ9-THC alone during rat pregnancy results in significantly smaller hearts relative to body weight. These Δ9-THC-exposed offsprings exhibited postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function. Given the increased popularity of cannabis use in pregnancy along with rising Δ9-THC concentrations, this study, for the first time, identifies the risk of perinatal Δ9-THC exposure on early postnatal cardiovascular health.

In Utero Exposure to 9-Tetrahydrocannabinol Leads to Postnatal Catch-up Growth and Dysmetabolism in the Adult Rat Liver

“…While much remains unknown about the role of prenatal cannabinoids on offspring outcomes, it is clear that long-term metabolic health becomes compromised as a result. We have previously shown that exposure to 9-THC specifically has effect on glucose tolerance and cardiovascular function [63,92], and our current study demonstrates that it further contributes to dyslipidemia. Overall, these data provide great insight into the effects of gestational 9-THC exposure on the development and function of the liver, as well as the fundamental molecular mechanisms that underlie the metabolic dysfunction of growth-restricted offspring.…”

The Impact of Early Life Exposure to Cannabis: The Role of the Endocannabinoid System

“…However, as mentioned before, the ECS is also involved in peripheral organogenesis and is present in multiple systems throughout development. While there is evidence that suggests that fetal ECS disruption may affect immune function [173,174], cardiac function [175] and liver development [61], for the purpose of this review only neurological, metabolic and reproductive impacts will be addressed.…”

Metabolic Consequences of Gestational Cannabinoid Exposure

“…These elevated markers of cardiac hypertrophy and fibrosis have been previously demonstrated in IUGR models of maternal nicotine, hypoxia, and protein restriction [141,142,144]. While these aforementioned studies observed these effects around adulthood (3-7 months old), it is noteworthy that the ∆9-THC offspring began to exhibit deficits at 3 weeks [148]. Unfortunately, our study did not examine effects in the females, and further studies should investigate whether these cardiac deficits persist later in life.…”

“…Yet almost all animal studies primarily examine the effects of ∆9-THC alone. Nonetheless, emerging pre-clinical data suggest that ∆9-THC leads to placental insufficiency, early cardiac deficits, dysglycemia (i.e., glucose intolerance, blunted insulin signaling) and dyslipidemia (i.e., augmented hepatic triglycerides, and visceral adiposity) in adult offspring [81,82,104,131,148] (Figure 3). Furthermore, these data indicate that catchup growth may be playing a major role in exacerbating these observed deficits.…”

“…Recently, we demonstrated that rat offspring exposed to ∆9-THC in utero resulted in cardiac growth deficits at birth (Figure 2) [148], followed by cardiac remodeling and impaired cardiac function at 3 weeks [148]. Specifically, at 3 weeks of age, ∆9-THC-exposed pups exhibit complete catch-up growth concomitant with early signs of ventricular hypertrophy and increased fibrotic markers, namely collagen type 1 and 3 [148]. This was associated with lower stroke volume and cardiac output.…”