Liver tumorigenicity of trimethylarsine oxide in male Fischer 344 rats--association with oxidative DNA damage and enhanced cell proliferation

Arsenic is a notorious environmental toxicant known to be carcinogenic for the skin, lung and urinary bladder in human beings. The carcinogenicity of trimethylarsine oxide (TMAO), one organic metabolite of inorganic arsenics in humans and experimental animals, was investigated here in male Fischer 344 rats in a 2-year carcinogenicity test. TMAO was administered to a total of 129 male rats ad libitum at concentrations of 0 (Control), 50 or 200 p.p.m. in the drinking water. In animals that died or were killed from the 87th week until the end of 104th week, incidences of hepatocellular adenomas were 14.3, 23.8 and 35.6% in the 0, 50 and 200 p.p.m.-treated groups, respectively; the multiplicities were 0.21, 0.33 and 0.53. Both were significantly increased in the 200 p.p.m.-treated group. While a variety of other tumors developed in various organs, they were present in all groups, including the controls, and were histologically diagnosed as those known to occur spontaneously in F344 rats. To test the contribution of reactive oxygen species (ROS) to TMAO tumorigenicity in the liver, 8-hydroxydeoxyguanosine (8-OHdG) formation was assessed by high performance liquid chromatography. The 8-OHdG values for the 200 p.p.m. TMAO group were significantly higher than those for the control group. Furthermore, as assessed by the proliferating cell nuclear antigen index, cell proliferation in the normally appearing parenchyma was elevated by the TMAO treatment. These results indicate that TMAO exerts liver tumorigenicity with possible mechanistic roles for oxidative DNA damage and enhanced cell proliferation.