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.

Fig. 1. Gestational exposure to Δ9-THC leads to decreased heart weights at birth followed by postnatal catch-up growth at 3 weeks.

a, b Body weights, c, d heart-to-body weight ratios. All values are expressed as means ± SEM, an average of 4 pups/dam from N = 7–8 dams/group (i.e., N = 1 represents pups from a single dam). Significant differences between groups were determined using Student’s unpaired t test (*p < 0.05, **p < 0.001).

Fig. 2. Representative echocardiogram from 3-week vehicle and 3-week-old rat offspring exposed to Δ9-THC.

All animals were measured at postnatal day 21. LVAW left ventricular anterior wall, LVID left ventricular interior diameter, LVPW left ventricular posterior wall, d diastole, s systole.

Fig. 3. Maternal exposure to 3 mg/kg Δ9-THC i.p. daily from gestational days 6 to 22 results in increased expression of cardiac remodelling markers associated with hypertrophy and collagen deposition.

Transcript abundance of a collagen I and b collagen III. Protein abundance of c collagen 1 and d collagen III e Phosphorylated GSK-3β-to-total GSK-3β ratio and f MMP-2. g Representative Western blot displaying all the cardiac markers with associated Ponceau staining. All protein levels were expressed as means normalized to total protein (using Ponceau staining), ±SEM, N = 7–8 offsprings/group (each offspring was taken from a different dam’s litter). Significant differences between groups were determined using Student’s unpaired t test (*p < 0.05, **p < 0.01).