Molecular Pathophysiological Mechanism of Arsenic Intoxication-Toward Molecular Forensic Toxicology-

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To clarify the molecular mechanisms of pathogenesis of arsenic intoxication, we have studied pathogenic roles of IFN-γ in arsenate-induced renal injury using IFN-γ deficient mouse in 2005. We found that IFN-γ played a protective role in arsenate-induced renal injury. The intrarenal arsenic concentration was significantly higher in IFN-γ deficient mice later than 10 hours after NaAs treatment, with attenuated intrarenal expression of multidrug resistance-associated protein (MRP) 1, a main transporter for NaAs efflux, compared with WT mice. NF-E2-related factor (Nrf) 2 protein, a transcription factor crucial for MRP1 gene expression, was similarly increased in the kidneys of both strains of mice after NaAs treatment. In contrast, the absence of IFN-γ augmented transforming growth factor-β-Smad3 signal pathway and eventually enhanced the expression of activating transcription factor 3, which is presumed to repress Nrf2-mediated MRP1 gene expression. Thus, IFN-γ can protect against NaAs-in … More duced acute renal injury, probably by maintaining Nrf2-mediated intrarenal MRP1 gene expression. In 2006, we have studied sex-based differences in susceptibility to arsenate-induced renal injury. In this study, we found that female mice were more susceptible to arsenate-induced renal injury. Moreover, we examined the effects of ovariectomy on susceptibility to arsenate-induced renal injury in female mice, and the effects of fltamide, an androgen receptor antagonist, on susceptibility to arsenate-induced renal injury in male mice. In this experiment, ovariectomy attenuated arsenate-induced renal injury, suggesting that estrogen was involved in pathogenesis of arsenate-induced renal injury. We further studied pathogenic roles of IL-6 in arsenate-induced renal injury. In this study, we found that IL-6 played a protective role in arsenate-induced renal injury. Interestingly, there was no sex-based difference of susceptibility to arsenate-induced renal injury in IL-6 deficient mice, which suggested that estrogen acts detrimentally in arsenate-induced renal injury through IL-6 signaling. In the next project, we will clarify the action mechanism of estrogen and IL-6 in arsenate-induced renal injury. Less