Bioassay of mannitol and caprolactam and assessment of response to diethylnitrosamine in heterozygous p53-deficient (+/-) and wild type (+/+) mice

Alternative bioassays of mannitol (MAN) and caprolactam (CAP) were conducte d in transgenic p53-deficient mice. Also, to assess the sensitivity of the transgenic mice to a model DNA-reactive carcinogen, the hepatic effects of diethylnitrosamine (DEN) were compared in the wild type background strain o f mouse and in the transgenic derivative. Fifty-one male wild type strain C 57BL/6 mice p53 (+/+), 8 weeks old, and 51 heterozygous p53 (+/-) C57BL/6 T ac-[KO] Trp53 NS mice. 8 weeks old. were allocated to six experimental grou ps as follows: groups 1 (wild type +/+) and 2 (p53 +/-) served as room cont rols, groups 3 (+/+ and 4 (+/-) were exposed orally (gavage) to 50 mu mol:k g body weight DEN weekly for a total of ten doses during the first 10 weeks of the study. group 5 (+/-) was exposed to 15.000 ppm CAP in the diet for up to 26 weeks, and group 6 (+/-) was exposed to 50.000 ppm MAN in the diet for up to 26 weeks. After 10 weeks, liver from control and DEN-exposed mic e was used for O-4-ethylthymidine (O-4-EtT) DNA adduct analysis by the immu noslot blot method. The cell replicating fraction (RF) in the liver was det ermined by quantification of the percentage of immunohistochemically staine d hepatocytes positive for proliferating cell nuclear antigen. No significa nt or consistent body or liver weight changes were present in any of the tr eatment groups. No consistent and pertinent changes in RF values were prese nt in any of the treatment groups. None of the tested substances produced n eoplasms of any type in p53 (+/-) mice. DEN induced comparable levels of O- 4-EtT adducts in the liver in both wild type and p53 +/- genotypes, but no morphologic changes were evident in the livers of either genotype. The lack of response to DEN, in spite of formation of DNA adducts, may reflect the resistance to hepatocarcinogenesis of the background C57BL/6 strain of the transgenic, and calls into question the general sensitivity of this transge nic for detection of carcinogenic effects.