Induction of hepatocellular carcinoma in B6C3 (F1) mice chronicly exposed to trichloroethylene with enhanced acetylation of histone H2AK9ac and SET expression in the liver tissue

Abstract

Objective: To establish an animal model of trichloroethylene (TCE) -induced liver cancer following chronic exposure and to understand the changes in SET expression and histone acetylation, potentially serving as a molecular mechanism for TCE-induced hepatocarcinogenesis. Methods: B6C3 mice at 6 weeks were treated with TCE at a series of doses (500, 1000 and 2000 mg/kg) by gastric gavage, with corn oil used as the negative control and carbon tetrachloride (CCl(4)) as the positive control. The serum and liver were sampled for the determination of biochemical indexes and pathological examination after 56 weeks of chemical exposure. Western blot was used to determine the levels of SET, H2AK9ac and HDAC1 expression. Results: The overall survival rate of the mice in various groups was 90.4% (141/156) , with no statistical difference between groups (P>0.05) . Compared with the negative control, the organ coefficient for the liver in the high dose TCE group and the positive control group were significantly increased (P<0.05) . The levels of ALT, AST, LDH and BUN in the all the three TCE groups and the positive control were significantly higher than those in the negative control (P<0.01) . CREA levels in the 1000 and 2000 mg/kg TCE groups were significantly higher than those in the negative control (P<0.05) . Statistical increases in the incidence of hepatocellular carcinoma and the activities of ALT and AST in various doses of TCE-exposed mice as compared with the control were observed (P<0.01) , in a dose-dependent manner. In the 1000 and 2000 mg/kg of TCE treated mice, levels of SET and H2AK9ac were increased (P<0.05) , while HDAC1 was decreased (P<0.05) , Compared to the tissue adjacent to liver cancer, in the 1000 and 2000 mg/kg TCE groups, the levels of SET were increased (P<0.05) , while HDAC1 was decreased (P<0.05) , and H2AK9ac increased in the 2000 mg/kg group. Conclusion: The hepatocellular carcinoma mouse model induced by chronic exposure to trichloroethylene was successfully established, with enhanced SET protein expression and H2AK9ac in the hepatic tissue.