The role of inositol-requiring enzyme 1α in gestational arsenic-induced α-KG collapse in male offspring

Arsenic，a well-documented environmental contaminant, has been associated with hepatic metabolism dysregulation. Previous study found arsenic exposure during pregnancy induced hepatic lipid accumulation in female offspring through α-ketoglutarate(α-KG) reduction. However, the mechanism of arsenic-reduced α-KG content remains unclear. In this study, in vivo experiments were conducted to investigate endoplasmic reticulum (ER) stress activation in arsenic-exposed offspring, while experiments in vitro were to investigate the role of ER stress in arsenic-reduced α-KG content. Our findings revealed gestational arsenic exposure reduced the hepatic α-KG level in male offspring. Mechanistically, arsenic exposure triggered ER stress, as evidenced by the activation of ER stress sensor inositol-requiring enzyme 1α (IRE1α). To confirm the effect of ER stress in arsenic impeded α-KG content, 4-phenylbutyric acid (4-PBA), an accepted inhibitor of ER stress, was used to treat AML12 cells. The results showed 4-PBA pretreatment upregulated the expression of α-KG synthase and mitigated the depletion of α-KG content. Moreover, IRE1α siRNA pretreatment markedly reversed arsenic-reduced α-KG content in AML12 cells. As above, Arsenic exposure reduced α-KG content via activating IRE1α signaling. ER stress maybe the potential mechanism of arsenic exposure impaired α-KG level in male offspring. This study provided novel insights into the toxicological mechanisms whereby maternal environmental exposure programed metabolic disorders in offspring. • Arsenic exposure during pregnancy decreased hepatic α-KG content in male offspring. • Arsenic exposure during pregnancy activated the IRE1α signaling in male offspring. • ER stress inhibitor 4-PBA attenuated arsenic reduced α-KG collapse in AML12 cells. • Arsenic exposure reduced α-KG content via activating IRE1α signaling in AML12 cells.