The infant mouse as a in vivo model for the detection and study of DNA damage-induced changes in the liver

The present work describes the use of the infant (4-wk-old) mouse as an animal model for the study of DNA damage-induced G(1) checkpoint response, changes in p53 protein levels, and multiple gene expression changes after DNA damage has been induced in the liver. Hepatocytes in the infant B6C3F1 mouse had a proliferation index that was 27 times greater than that of the 12-wk-old B6C3F1 mouse (57.4 vs. 2.1%, respectively). Eight hours after infant mice were exposed to the DNA damaging agents bleomycin (100 mg/kg, i.p.) or 10 Gy of whole body gamma irradiation, the G(1)/S ratio significantly increased from 21 (control) to 66 and 75, respectively, because of the induction of the G(1)/S checkpoint response. One hour after whole body irradiation of infant mice the levels of the p53 protein, phosphoserine 18-p53 and phosphoserine 23-p53 increased dramatically and tended to peak at 1 h in the liver, whereas the p21(WAF1) protein increased more slowly and tended to peak at 2 h after irradiation. The mRNA expression of the p53-response genes p21, murine double minute clone 2 (mdm2), and cyclin G was increased at 2 h after irradiation but was decreased by 8 h postirradiation, relative to the 2-h time-point. The expression of insulin-like growth factor binding protein-1 (IGFBP-1) and growth-regulated oncogene 1 (GRO1) increased at 2 and 8 h postirradiation. This work characterizes various parameters in the infant mouse, thus validating the use of this model to study in vivo DNA damage-induced cell-cycle-related changes. (C) 2004 Wiley-Liss, Inc.