Maternal exposure to Δ9-tetrahydrocannabinol impairs female offspring glucose homeostasis and endocrine pancreatic development in the rat

Recent reports indicate that 7% of pregnant mothers in North America use cannabis. This is concerning given that in utero exposure to Delta 9-tetrahydrocannabinol (Delta 9-THC), the main psychoactive component in cannabis, causes fetal growth restriction and may alter replication and survival of pancreatic beta-cells in the offspring. Accordingly, we hypothesized that maternal exposure to Delta 9-THC during pregnancy would impair postnatal glucometabolic health of offspring. To WA this hypothesis, pregnant Wistar rats were treated with daily intraperitoneal injections of either 3 mg/kg Delta 9-THC or vehicle from gestational day 6 to birth. Offspring were subsequently challenged with glucose and insulin at 5 months of age to assess glucose tolerance and peripheral muscle insulin sensitivity. Female offspring exposed to Delta 9-THC in utero were glucose intolerant, associated with blunted insulin response in muscle and increased serum insulin concentration 15 min after glucose challenge. Additionally, pancreata from male and female offspring were harvested at postnatal day 21 and 5 months of age for assessment of endocrine pancreas morphometry by immunostaining. This analysis revealed that gestational exposure to Delta 9-THC reduced the density of islets in female, but not male, offspring at postnatal day 21 and 5 months, culminating in reduced beta-cell mass at 5 months. These results demonstrate that fetal exposure to Delta 9-THC causes female-specific impairments in glucose homeostasis, raising concern regarding the metabolic health of offspring, particularly females, exposed to cannabis in utero.