In Utero Exposure to 9-Tetrahydrocannabinol Leads to Postnatal Catch-up Growth and Dysmetabolism in the Adult Rat Liver

Abstract

Rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to 9-tetrahydrocannabinol (9-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 9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg 9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to 9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, 9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACC, 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, was also observed in these 9-THC-exposed offspring. Collectively, these findings indicate that prenatal 9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

Maternal propionate supplementation ameliorates glucose and lipid metabolic disturbance in hypoxia-induced fetal growth restriction

“…This is consistent with the previous study in which obesity was observed in adult offspring following postnatal catch-up growth. 41 In this study, we found that maternal administration of SP has beneficial effects, such as lowering the liver to body weight ratio, diminishing adipocyte size, and decreasing serum and hepatic lipid levels, indicating a hypolipidemic effect of SP. Moreover, the increased RER implies the increased availability of fat as an energy source under SP administration and also suggests a possibility that the hypolipidemic effect of SP may be partially attributed to increased energy expenditure.…”

Influence of prenatal cannabinoid exposure on early development and beyond

“…In Long Evans, Wistar, and Sprague Dawley rats, lower birth weight was associated with daily in utero exposure to 15, 30, or 150 mg/kg (oral) cannabis extracts (130,131), 50 mg/kg (s.c.) THC (132), 3 mg/kg (i.p.) THC (133)(134)(135), or smoke from cannabis extracts (400 mg/mL) (130,(136)(137)(138)(139)(140). In contrast, no effect of PCE on birth weight was observed following daily in utero exposure to 0.5-10 mg/kg (oral) THC or CE (130,139,140), 2 mg/kg (s.c.) THC (141), or smoke from CEs (100 mg/mL) (142, 143).…”