Subchronic Exposure To Arsenic Decreased Sdha Expression In The Brain Of Mice

Objective:To examine the influence of subchronic exposure arsenic (As) on expression of Sdha protein in the brain of mice so as to provide the evidence of molecular target for exploring mechanism of As neurotoxicity.Methods: 50 mice were divided into 5 groups with 10 for each, Group 1 received drinking distilled water alone (control). Group 2 and 3 received 1 or 4 mg/L arsenic trioxide. Group 4 and 5 received both 4 mg/L arsenic trioxide and 150 mg/kg taurine or 45 mg/kg Vit C (as interfering groups), respectively. Arsenic trioxide was given through drinking water for 60 days and taurine or Vit C was poured into stomach twice a week. On the 60th day after As exposure, mice were decapitated and their brains were removed. 8-OH-dG expressions were examined by immunohistochemistry. Changes of mitochondrial ultrastructures were examined in brain subchronically exposed to arsenic by the electron microscope. Expression profiles of mitochondrial respiratory chain -related genes were examined in the brain of mice exposed to As by GeneChip. Level of Sdha protein expression and SDH activity were examined by western blot and colorimetry.Date were presented as mean±standard deviation(SD). All data were analyzed with SPSS10.0 for windows. Difference in mean values between groups was tested with the one-way ANOVA. P values less than 0.05 were considered significant.Results: Compared to control group, Intensive 8-OH-dG immunoreactivity was found in 4 ppm group. Changes of mitochondrial ultrastructures in the control group showed a double membrane of the wall and membranes of cristae were well arranged. In the mice given 4 ppm arsenic trioxide, morphological changes including swelling and vacuolus alteration were shown in mitochondria, but the double membranes of mitochondria remained in good shape. Among 11genes selected by gene chip, 10 genes were downregulated, namely, NADH dehydrogenase genes (Ndufab1, Ndufb12, and Ndufb2), succinate dehydrogenase gene (Sdha), ubiquinol-cytochrome c oxidoreductase gene (Uqcr), cytochrome oxidase genes (Cox6a2, Cox17) and ATP Synthase genes (Atp5a1, Atp5g1, Atpif1). NADH dehydrogenase gene (Ndufs4) was upregulated. The activity of SDH and level of Sdha protein expression in brain mitochondria decreased in the groups exposed to As. Especially, the SDH activity and level of Sdha protein expression were significantly lower in the group received 4 ppm As2O3 than those in controls (P <0.05). However, the activity of SDH and level of Sdha protein expression was significantly higher in interfering groups than those in the group received 4 ppm As2O3 (P <0.05). In this 4 ppm group, the SDH activity and level of Sdha protein expression were significantly lower on the 30th or 60th day after exposure than those on 0 day (P <0.05).Conclusion: Mitochondria may be a subcellular organelle of the arsenic neurotoxicity. mitochondria complexⅡmay be the most possible target site of the arsenic neurotoxicity. Sdha may be the most possible target of the arsenic neuron- toxicity. The toxic effect of As on Sdha was mitigated by the coadministration of taurine or Vit C.