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Quantitative changes in endogenous DNA adducts correlate with conazole mutagenicity and tumorigenicity in mouse liver.**
Citation:
ROSS, J. A., S. A. LEAVITT, J. E. SCHMID, AND G. B. NELSON. Quantitative changes in endogenous DNA adducts correlate with conazole mutagenicity and tumorigenicity in mouse liver.**. Presented at American Association of Cancer Research, Chicago, IL, March 30 - April 04, 2012.
Impact/Purpose:
We hypothesize that this treatment-related increase in endogenous DNA adducts may explain the observed increased in vivo mutation frequencies previously reported to be induced by treatment with propiconazole and triadimefon.
Description:
We have previously shown that the conazole fungicides triadimefon and propiconazole, which are tumorigenic in mouse liver, are in vivo mouse liver mutagens in the Big Blue" transgenic mutation assay when administered in feed at tumorigenic doses. The nontumorigenic conazole myclobutanil was not mutagenic under the same conditions. DNA sequencing of the mutants recovered from each treatment group and from untreated control animals revealed that the mutations induced by propiconazole and triadimefon do not result from clonal expansion of background mutations. We hypothesized that these mutations arise from the accumulation of reactive electrophilic metabolic byproducts within the liver in vivo. We therefore measured the spectra of endogenous DNA adducts in the livers of mice from these studies in order to determine if quantitative or qualitative differences in DNA adducts correlated with mutagenicity and tumorigenicity. We resolved and quantitated 16 individual adduct spots by 32p 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 of mice 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 adducts 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.