MUTAGENESIS AND CARCINOGENESIS STUDIES IN P53 (+/-) OR LACI:P53 (+/-) MICE

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Mice with only a single wild type p53 allele provide a distinct target for mutagens and are analogous to humans at risk due to heritable forms of cancer, e.g., the Li-Fraumeni syndrome. The reduction in p53 gene by this "germline first hit" increases the probability that a second mutagenic event will cause either loss of p53 tumor suppressor function or gain of transforming activity by requiring (at minimum) only a single mutation. Using the same route and dose-regiment as 104-week chronic NTP bioassays of benzene, p-cresidine (aromatic amine), p-anisidine, 4-vinyl-1-cyclohexene diepoxide (VCD), N-methyl-o-acrylamide (NMOA), and reserpine, we exposed p53 (+/-) or lacIq:p53 (+/-) F1 C57Bl/6 mice in order to determine the sensitivity of p53 deficient mice to mutagenic carcinogens. Benzene, p-cresidine, and VCD (trans-species mutagenic carcinogens) were positive. Chemical- and tissue-specific tumors were observed after 24 weeks of exposure. Confirmation of tissue-specificity and mutagenicity was determined using the rescued lacIq gene and determining the in vivo mutant frequency. Extensive evaluation of control and benzene, p-cresidine, or VCD induced tumors have or are in the process of being examined for p53 mutations or LOH. (2) Acute and sub-chronic exposures (oral) of the aromatic amine, p-cresidine, or benzene, will be used to induce pre-neoplastic lesions and tumors in target tissues for sampling over time to determine early genetic lesions using DNA and RNA analyses (p53 mutations and/or LOH). In addition, lacI mutant frequency will be used to determine chemically induced genetic stress in the target tissues.