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

Ryan Gillies,Kendrick Lee,Sebastian Vanin,Steven R Laviolette,Alison C Holloway,Edith Arany,Daniel B Hardy

doi:10.1016/j.reprotox.2020.04.070

Abstract

Recent reports indicate that 7% of pregnant mothers in North America use cannabis. This is concerning given that in utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive component in cannabis, causes fetal growth restriction and may alter replication and survival of pancreatic β-cells in the offspring. Accordingly, we hypothesized that maternal exposure to Δ9-THC during pregnancy would impair postnatal glucometabolic health of offspring. To test this hypothesis, pregnant Wistar rats were treated with daily intraperitoneal injections of either 3 mg/kg Δ9-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 Δ9-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 Δ9-THC reduced the density of islets in female, but not male, offspring at postnatal day 21 and 5 months, culminating in reduced β-cell mass at 5 months. These results demonstrate that fetal exposure to Δ9-THC causes female-specific impairments in glucose homeostasis, raising concern regarding the metabolic health of offspring, particularly females, exposed to cannabis in utero.

Highlights

Recent reports indicate that 7% of pregnant mothers in North America, and 19 % of those aged 18–24, use cannabis [1]
We previously demonstrated that 3 mg/kg Δ9-THC given from GD6 to GD22 does not cause fetal demise, alterations in litter size, gestational length, or maternal weight gain [7]
By PND21, Δ9-THC-exposed offspring recovered in terms of both bodyweight and pancreatic weight (Fig. 1 B, E), and thereafter maintained comparable weights to that of their sex-matched controls (Fig. 1 C, F)

Summary

Introduction

Recent reports indicate that 7% of pregnant mothers in North America, and 19 % of those aged 18–24, use cannabis [1] Much of this use may be motivated by the belief that cannabis eases nausea, vomiting, and lost appetite during pregnancy [2], in conjunction with media portrayals of cannabis as a natural alternative to pharmaceuticals [3,4]. We and others have recently demonstrated in rodents that Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive component of cannabis, leads to fetal growth restriction, in part, due to placental insufficiency [6,7]. This is pertinent because since 1995, selective breeding has increased Δ9-THC content in cannabis from 4% to 12 % [8]. Δ9-THC may directly influence development of the fetal pancreas, through its interaction with the cannabinoid 1 receptor (CB1R)

Results

Discussion

Conclusion