A model of chronic hepatitis in mice expressing a truncated XRCC1 protein

F our-month-old C57BL/6 mice expressing a truncated protein of the DNA repair gene Xrcc1 (1) were treated with the aklyating carcinogen azoxymethane (AOM). Six months later, when tested, more than 90% of XRCC1 mutant mice treated with AOM had abnormal-appearing livers (Fig. 1b), whereas more than 80% of wild-type littermates had normal-appearing livers (Fig. 1a). The livers of the mutant mice had a shrunken appearance with a mild to severe irregular surface characterized by nodular lesions uniformly distributed throughout the parenchyma (Fig. 1b), compared to the appearance of livers from wild-type littermates (Fig. 1a). Microscopic features of livers from XRCC1 mutant mice treated with AOM were compatible with hepatic lesions associated with chronic toxicity and generally manifested necrosis, hepatocellular hyperplasia, biliary hyperplasia and hypertrophy, and perivascular inflammation (Fig. 1c). These observations suggest that XRCC1 is a critical protein for responding to alkylating agents and that the XRCC1 mutant mouse would be a good model to study liver disease in association with epigenetic factors such as environmental exposure and diet.