Effect of α-ketoglutarate on maternal lipid homeostasis and mitochondrial status perturbed by gestational arsenic...

Arsenic is a common environmental toxicant with known hepatotoxic effects, yet its impact on maternal lipid metabolism during pregnancy remains poorly understood. In this study, we established a pregnant mouse model to investigate the effects of gestational arsenic exposure and the potential protective role of α-ketoglutarate (α-KG), a key tricarboxylic acid (TCA) cycle intermediate. In the first experiment, arsenic exposure led to significant disruptions in maternal serum and hepatic lipid profiles. Mechanistically, arsenic reduced hepatic α-KG concentrations, impaired mitochondrial ultrastructure, altered mitochondria-related gene expression, induced oxidative stress, and decreased multiple TCA cycle intermediates, collectively indicating compromised mitochondrial function. In the second experiment, α-KG supplementation during gestation effectively restored hepatic α-KG levels and reversed arsenic-induced lipid metabolic imbalances. Moreover, α-KG preserved mitochondrial morphology, normalized the expression of mitochondrial genes, alleviated oxidative stress, and partially rescued the levels of disrupted TCA intermediates. These results suggest that arsenic disrupts maternal lipid homeostasis primarily through mitochondrial dysfunction and oxidative stress, and that α-KG supplementation can alleviate these disturbances by supporting mitochondrial function. Although the exact molecular mechanisms require further clarification, our findings highlight the potential therapeutic role of α-KG in maintaining maternal lipid metabolic health during arsenic exposure during pregnancy.