Host: The Japanese Society of Toxicology
The phosphorylated form of histone variant H2AX at Ser 139, called γ-H2AX, is strongly induced by DNA double-strand breaks (DSB) and is widely used as a biomarker of DNA damage. We have found that the increase of γ-H2AX-positive cells could be a useful marker of urinary bladder carcinogenicity of chemicals. On the other hand, hepatocarcinogens that do not exhibit hepatocyte proliferative stimuli were not efficiently detected by the increase of γ-H2AX-positive hepatocytes as an index. In this study, we sought novel biomarkers that can detect liver carcinogenicity of test chemicals, and found the increases of EpCAM- and cytoplasmic CD13 positive hepatocytes in the liver specimen of male F344 rats administrated with hepatocarcinogens for 4 weeks. Hepatocytes expressing EpCAM and CD13 were increased in the rats treated with hepatocarcinogens o-aminoazotoluene, 2-nitropropane, 3,3′-dimethylbenzidine, N-nitrosomorpholine, and thioacetamide. Moreover, EpCAM-positive hepatocytes was also increased in N-bis(2-hydroxypropyl)nitrosamine, p-cresidine, and di(2-ethylhexyl)phthalate treated groups. On the other hand, there were no increase of neither EpCAM- nor CD13-positive hepatocytes in N-nitrosodiethylamine and 1,4-dioxane, which increases γ-H2AX-positive hepatocytes. For non-hepatocarcinogenic carcinogens, neither EpCAM, CD13 nor γ-H2AX positive cells were increased in 4-chloro-o-phenylendiamine and N-ethyl-N-nitrosourea treated groups. These results suggest that EpCAM and/or CD13 could be useful biomarkers for the early detection of hepatocarcinogenicity in combination with γ-H2AX.
