L.L. Lanning, M.L. Wenk, C.E. Bentley, and T.C. Dailey
BioRelianceSM Rockville, MD
The use of genetically altered mouse models has become an important tool in the detection of carcinogens after short-term chemical exposure. In particular, the p53-deficient mouse, which has one functional wild-type p53 allele and one inactivated allele in its DNA composition, has been used extensively. The p53 gene is critical to cell cycle control and DNA repair and is often found to be mutated or lost in human and rodent tumors. Mice with a single copy of the wild-type p53 allele offer a single target for mutagens which should increase the probability for either loss of a p53 tumor suppressor function or gain of transforming activity by requiring only a single mutation. Recently, data has been collected during the 26-week studies of over 20 chemicals, which cover the major endpoints commonly used in assessment of toxicity in the heterozygous p53-deficient mouse.
The data presented includes information from untreated control animals (n=139) and the p-cresidine positive control model (n=45). Survival was excellent for the untreated controls (96% in both males and females). Weight gain was steady over the 26-week testing period in these animals. Terminal body weights were 29.5 +/- 4.40 grams for females and 36.7 +/- 6.78 grams for males. Spontaneous proliferative lesions (tumors) in untreated control mice included skin/subcutis sarcoma (1.4% in males and 3.6% in females), malignant lymphoma (1.4% in males and 1.4% in females), osteosarcoma (1.4% in males and 0 in females), granulocytic leukemia (0.7% in males and 0 in females), meningeal sarcoma (0 in males and 0.7% in females), lung adenoma (0 in males and 0.7% in females) and urinary bladder sarcoma (0.7% in males and 0 in females). P-cresidine is often utilized as a positive control chemical for the p53-deficient mouse model. In these studies, the animals received p-cresidine at 400 mg/kg daily by oral gavage for 7 days per week over a 6-month period. Survival was 77% for the males and 87% for the females. These animals experienced minimal body weight gain over the 26-week treatment period. Terminal body weights were 21.1 +/-1.63 grams for the females and 24.6 +/- 18.8 grams for the males. Organ weights, especially kidney weights, were decreased in a statistically and biologically significant manner. Proliferative lesions of the urinary bladder were found in these animals (indicating success of the positive control material) and included transitional cell papilloma (29% of males and 13% of females), transitional cell carcinoma (24% of males and 16% of females), carcinoma, in situ (2 males and 9% of females) and submucosal mesenchymal tumor (2% of males and 0 female). These data provide a comprehensive profile of baseline data for this genetically altered mouse strain.