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Quantitative changes in endogenous DNA damage correlate with conazole mutagenicity and tumorigenicity.
Citation:
NELSON, G. B., S. A. LEAVITT, AND J. A. ROSS. Quantitative changes in endogenous DNA damage correlate with conazole mutagenicity and tumorigenicity. Presented at American Association for Cancer Resaerch (AACR) Meeting, San Diego, CA, January 30 - February 02, 2011.
Impact/Purpose:
We therefore measured the spectra of endogenous DNA damage in the livers of mice from these studies to determine if there were quantitative or qualitative differences between mice receiving tumorigenic or non-tumorigenic conazoles comRared to concurrent control animals.
Description:
The mouse liver tumorigenic conazolefungicides triadimefon and propiconazole have previously been shown to be in vivo mouse liver mutagens in the Big Blue" transgenic mutation assay when administered in feed at tumorigenic doses, whereas the nontumorigenic conazole myclobutanil was not mutagenic. DNA sequencing of the mutants recovered from each treatment group as well as from animals receiving control diet revealed that propiconazole and triadimefon induced mutations do not represent clonal expansion of background mutations, and support the hypothesis that they arise from the accumulation of reactive electrophilic metabolic intermediates within the liver in vivo. We therefore measured the spectra of endogenous DNA damage in the livers of mice from these studies to determine if there were quantitative or qualitative differences between mice receiving tumorigenic or non-tumorigenic conazoles comRared to concurrent control animals. We resolved and quantitated 16 individual adduct spots by 3 P postlabeling and thin layer chromatography using 3 solvent systems. Qualitatively, we observed the same DNA adducts in control mice as in mice receiving conazoles. However, the 13 adducts with the highest chromatographic mobility were, as a group, present at significantly higher amounts in the livers ofmice treated with propiconazole and triadimefon than in their concurrent controls, whereas this same group of DNA adducts in the myclobutanil-treated mice was not different from controls. We hypothesize that this treatment-related increase in endogenous DNA damage may explain the observed increased in vivo mutation frequencies previously reported to be induced by treatment with propiconazole and triadimefon. This abstract does not necessarily reflect EPA policy