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

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.

Metabolic Consequences of Gestational Cannabinoid Exposure

“…Oke et al further elucidated that higher hepatic expression of p66shc in ∆9-THCexposed offspring might also be regulated via epigenetic mechanisms. ∆9-THC offspring exhibited decreased expression of the hepatic microRNAs, miR-203a-3p and miR-29a/b/c [104]. Collectively, these microRNAs can influence the expression of p66Shc and long-term liver health [111][112][113][114].…”

“…in rats leads to liver growth deficits at birth followed by complete catchup growth by 3 weeks whereby exposed offspring caught-up in body and liver weight relative to control [81]. In a follow-up study, Oke et al demonstrated for the first time that ∆9-THC-induced FGR led to male-specific augmentation of hepatic lipid synthesis (e.g., DGAT2, ACCa, FABP1, and SCD) as early as 3 weeks [104]. This was partially sustained (DGAT2) in adulthood, culminating to increased hepatic triglycerides and visceral adiposity [104].…”

“…In a follow-up study, Oke et al demonstrated for the first time that ∆9-THC-induced FGR led to male-specific augmentation of hepatic lipid synthesis (e.g., DGAT2, ACCa, FABP1, and SCD) as early as 3 weeks [104]. This was partially sustained (DGAT2) in adulthood, culminating to increased hepatic triglycerides and visceral adiposity [104]. These metabolic deficits observed in adult rats (6 months) were associated with increased expression of p66shc [104], which targets the mitochondria and leads to pro-apoptotic reactive oxygen species (ROS) release [105], as well as induces intracellular lipid accumulation [106].…”

“…This was partially sustained (DGAT2) in adulthood, culminating to increased hepatic triglycerides and visceral adiposity [104]. These metabolic deficits observed in adult rats (6 months) were associated with increased expression of p66shc [104], which targets the mitochondria and leads to pro-apoptotic reactive oxygen species (ROS) release [105], as well as induces intracellular lipid accumulation [106]. These mitochondrial defects are believed to be potentiated by catch-up growth [107], which is known to further increase the long-term risk of metabolic disease [108,109].…”

“…In astrocytes, activation of mtCB 1 leads to decrease in mitochondrial complex I, leading to a reduction of ROS, alterations in the redox state, and ultimately impacting behavioral outcomes [110]. While the expression of mtCB 1 has not be examined in peripheral tissues, it is tempting to speculate that if there is a loss of mtCB 1 signaling by exogenous cannabinoids after birth, this could further contribute to the observed increase in complex I and ROS in the livers of ∆9-THC exposed rat offspring [104].…”