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

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 (alpha-KG), an important mitochondrial metabolite during the citric acid cycle, in fetal livers. Further, gestational supplementation of alpha-KG alleviated hepatic lipid deposition caused by early-life exposure to iAs(III). This beneficial effect was particularly pronounced in female offspring. alpha-KG partially restored the beta-oxidation process in hepatic tissues by hydroxymethylation modifications of carnitine palmitoyltransferase 1a (Cpt1a) gene during fetal development. Insufficient beta-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 alpha-KG. These results suggest that gestational administration of alpha-KG can ameliorate hepatic lipid deposition caused by iAs(III) in female adult offspring partially through epigenetic reprogramming of the beta-oxidation pathway. Furthermore, alpha-KG shows potential as an interventive target to mitigate the harmful effects of arsenic-induced hepatic developmental toxicity.