Subchronic exposure to arsenic decreased Sdha expression in the brain of mice.
Exposure of arsenic (As) elevates reactive oxygen species (ROS) level, which is supposed to be a molecular mechanism of As neurotoxicity. Mitochondria are the major source of ROS. However, the mechanism of the ROS generation induced by As remains unclear. To provide target evidence for exploring the molecular mechanism of As-induced neurotoxicity, 8-hydroxy-2-deoxyguanosine (8-OHdG) as an oxidative damage biomarker was examined, and the critical gene expression profiles related to mitochondrial respiratory chain were analyzed by GeneChip in mice exposed to As(2)O(3) subchronically. Our results showed that immunoreactivity of 8-OHdG increased remarkably. Succinate dehydrogenase subunit A (Sdha), ubiquinol-cytochrome c oxidoreductase gene (Uqcr), cytochrome oxidase genes (Cox6a2, Cox17) and ATP Synthase genes (Atp5a1, Atp5g1, Atpif1) were down-regulated in brain cells of mice exposed to As. We further analyzed the influence of As on brain Sdha expression using Western blot method. The quantity of Sdha band and the corresponding succinate dehydrogenase (SDH) activity in the group exposed to 4ppm As(2)O(3) significantly decreased compared to the 1ppm or control group, agreeing well with the gene microarray result. These results indicate that subchronic exposure to As induces down-regulation of Sdha expression and inhibition of SDH activity in brain tissue. They also suggest that the Sdha as complex II subunit may be a molecular target for As in mitochondria. Furthermore, the intervening experiment showed that the coadministered antioxidants taurine or vitamin C scavenging ROS in vivo partly rescued Sdha expression. It implies that the increased level of ROS by As may also be a factor in the disrupting Sdha expression in brain tissue of mice exposed to As.
Hong
Yan
Y
Department of Occupational and Environmental Health, Dalian Medical University, No 9 Western Section of Lushun South Road, Dalian, Liaoning 116044, China.
Piao
Fengyuan
F
Zhao
Yufeng
Y
Li
Sheng
S
Wang
Yanyan
Y
Liu
Peng
P
D000080242:8-Hydroxy-2'-Deoxyguanosine; D025181:ATP Synthetase Complexes / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001205:Ascorbic Acid / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D019295:Computational Biology; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006131:Growth Inhibitors / Q000633:toxicity*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010087:Oxides / Q000633:toxicity*; D013385:Succinate Dehydrogenase / Q000378:metabolism*; D013654:Taurine / Q000008:administration & dosage
D000975:Antioxidants; D001152:Arsenicals; D045222:Electron Transport Chain Complex Proteins; D006131:Growth Inhibitors; D010087:Oxides; D013654:Taurine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045304:Cytochromes c; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D025181:ATP Synthetase Complexes; D014450:Electron Transport Complex III; D003849:Deoxyguanosine; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide