Gestational α-ketoglutarate supplementation ameliorates arsenic-induced hepatic lipid deposition via epigenetic reprogramming of β-oxidation process in female offspring

Abstract

Inorganic trivalent arsenic (iAs^Ⅲ) at environmentally relevant levels has been found to cause developmental toxicity. Maternal exposure to iAs^Ⅲ leads to enduring hepatic lipid deposition in later adult life. However, the exact mechanism in iAs^Ⅲ induced hepatic developmental hazards is still unclear. In this study, we initially found that gestational exposure to iAs^Ⅲ at an environmentally relevant concentration disturbs lipid metabolism and reduces levels of alpha-ketoglutaric acid (α-KG), an important mitochondrial metabolite during the citric acid cycle, in fetal livers. Further, gestational supplementation of α-KG alleviated hepatic lipid deposition caused by early-life exposure to iAs^Ⅲ. This beneficial effect was particularly pronounced in female offspring. α-KG partially restored the β-oxidation process in hepatic tissues by hydroxymethylation modifications of carnitine palmitoyltransferase 1a (Cpt1a) gene during fetal development. Insufficient β-oxidation capacities probably play a crucial role in hepatic lipid deposition in adulthood following in utero arsenite exposure, which can be efficiently counterbalanced by replenishing α-KG. These results suggest that gestational administration of α-KG can ameliorate hepatic lipid deposition caused by iAs^Ⅲ in female adult offspring partially through epigenetic reprogramming of the β-oxidation pathway. Furthermore, α-KG shows potential as an interventive target to mitigate the harmful effects of arsenic-induced hepatic developmental toxicity.

Keywords: Arsenite; CPT1A; Developmental toxicology; Epigenetic modifications; Hydroxymethylation; β-oxidation.