In Utero Exposure to Δ9-Tetrahydrocannabinol Leads to Postnatal Catch-Up Growth and Dysmetabolism in the Adult Rat Liver.

Shelby L Oke,Kendrick Lee,Steven R Laviolette,Rosemary Papp,Daniel B Hardy

doi:10.3390/ijms22147502

Abstract

The rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to Δ9-tetrahydrocannabinol (Δ9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that Δ9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg Δ9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to Δ9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, Δ9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACCα, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, were also observed in these Δ9-THC-exposed offspring. Collectively, these findings indicate that prenatal Δ9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

Highlights

Cannabis is the most commonly used recreational drug among individuals of reproductive age
By three weeks of age, these offspring had exhibited hepatic catch-up growth, as there were no significant differences between liver to-body-weight ratios of ∆9-THC-exposed offspring and control offspring
Our results suggest that these changes in lipid metabolism occur in a sex-specific manner, as hepatic triglyceride levels were unchanged in adult female offspring exposed to gestational ∆9-THC

Summary

Introduction

Cannabis is the most commonly used recreational drug among individuals of reproductive age. The American College of Obstetricians and Gynecologists has further found that 2–5% of individuals use cannabis during pregnancy, and this was increased to 15–28% among young women who lived in urban settings and whom were socioeconomically disadvantaged [2]. Gestational exposure to cannabis can increase the risk for adverse neonatal outcomes, including low birth weight and preterm delivery [6,7,8]. These studies are confounded by that fact that cannabis users are more likely to concurrently abuse other drugs, such as alcohol and tobacco [9], highlighting the need for animal studies that focus on the effects of specific constituents of cannabis (i.e., ∆9-tetrahydrocannabinol [∆9-THC] and cannabidiol [CBD])

Methods

Results

Conclusion