Impact of prenatal THC exposure on lipid metabolism and microbiota composition in rat offspring

Objective: Recent studies have demonstrated that prenatal exposure to the psychoactive ingredient of cannabis that is tetrahydrocannabinol (THC) disrupts fatty acid (FA) signaling pathways in the developing brain, potentially linking to psychopathologic consequences. Our research aims to investigate whether changes in midbrain FA metabolism are linked to modifications in peripheral metabolism of FAs and shifts in microbiota composition. Methods: In order to model prenatal exposure to THC (PTE) in rats, Sprague Dawley dams were systemically administered with THC (2 mg/kg, s.c.) or vehicle once daily from gestational day 5-20. To evaluate the metabolic impact of PTE in the offspring during preadolescence (postnatal day, PND, 25-28), we analyzed FA profiles and their bioactive metabolites in liver and midbrain tissues, and microbiota alterations. Results: Our findings indicate that PTE leads to sex-specific metabolic changes. In both sexes, PTE resulted in increased liver de novo lipogenesis (DNL) and alterations in FA profiles, as well as changes in N-acylethanolamines (NAEs), ligands of peroxisome proliferator-activated receptor alpha (PPAR-alpha). In females only, PTE influenced gene expression of PPAR-alpha and fibroblast growth factor 21 (Fgf21). In male offspring only, PTE was associated with significantly reduced fasting glycaemia and with alterations in the levels of midbrain NAEs. Our analysis of the progeny gut microbiota revealed sex-dependent effects of PTE, notably an increased abundance of Ileibacterium in PTE-exposed male offspring, a change previously associated with the long-term effects of a maternal unbalanced diet. Conclusions: Our data suggest that in male PTE offspring a reduced fasting glycaemia, resulting from increased liver DNL and the absence of a compensatory effect by Ppar-alpha and FGF21 on glycemic homeostasis, are associated to alterations in midbrain NAEs ligands of PPAR-alpha. These metabolic changes within the midbrain, along with Ileibacterium abundance, may partly elucidate the heightened susceptibility to psychopathologic conditions previously observed in male offspring following PTE.