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. © 2004 Wiley‐Liss, Inc.