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MUTATIONS INDUCED BY BENZO[ A ]PYRENE AND DIBENZO[ A,L ]PYRENE IN LACI TRANSGENIC B6C3F1 MOUSE LUNG RESULT FROM STABLE DNA ADDUCTS
Citation:
ROSS, J. A., T. MOORE, M. H. GEORGE, AND S. A. LEAVITT. MUTATIONS INDUCED BY BENZO[ A ]PYRENE AND DIBENZO[ A,L ]PYRENE IN LACI TRANSGENIC B6C3F1 MOUSE LUNG RESULT FROM STABLE DNA ADDUCTS. Presented at 21st International Symposium for Polycyclic Aromatic Compounds (ISPAC), Trondheim, NORWAY, August 05 - 10, 2007.
Description:
Dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P) are carcinogenic polycyclic aromatic hydrocarbons (PAH) that are each capable of forming a variety of covalent adducts with DNA, some of which spontaneously depurinate, producing apurinic (AP) sites. The role of the formation of AP sites in the induction of mutations and tumors by PAH has been under investigation. Because cells have efficient and accurate mechanisms for repairing background levels of AP sites, the contribution of PAH induced AP sites to mutagenesis is expected to be maximal at doses where the induced AP sites are produced in significant excess of the endogenous AP sites. We have investigated the effect of two dosing regimens on the mutagenicity of DB[a,l]P and B[a]P in vivo using the Big Blue® transgenic mouse system. We compared administration of a single highly tumorigenic dose of PAH (200 mg/kg B[a]P or 6 mg/kg DB[a,l]P) with fractionated delivery of the same total doses (40 mg/kg B[a]P or 1.2 mg/kg DB[a,l]P per day for 5 days). Because the fractionated dose regimen allows time for AP site repair between doses, PAH induced AP sites, if produced, would attain a greater level above background in the case of the high single dose than in the case of the fractionated doses. Mutations in the lacI gene in DNA extracted from the lungs were analyzed after allowing 31 days for mutation fixation. Solvent treated control mice had a mutant frequency of 3.18 x 10-5, but treatment with single and fractionated doses of DB[a,l]P yielded 2.5- and 3-fold increases in mutant frequencies compared to controls. Both B[a]P treatment regimens induced about 15-fold increases in mutant frequencies. Mutant frequencies induced by the high single doses were no higher than those induced by the fractionated doses for either PAH. DNA sequencing revealed that the types and distribution of mutations resulting from each PAH treatment were consistent with the distribution of stable covalent DNA adducts, but were not consistent with the pattern predicted by unstable DNA adducts. Taken together, these mutation results are consistent with stable DNA adducts being the primary promutagenic lesions induced by these two PAH, and do not support a major role for depurinating adducts contributing to PAH-induced mutagenesis in mouse lung in vivo.