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IN VIVO MUTAGENICITY OF CONAZOLE FUNGICIDES CORRELATES WITH TUMORIGENICITY-JOURNAL
Citation:
ROSS, J. A., T. MOORE, AND S. A. LEAVITT. IN VIVO MUTAGENICITY OF CONAZOLE FUNGICIDES CORRELATES WITH TUMORIGENICITY-JOURNAL. MUTAGENESIS. Oxford University Press, Cary, NC, 24(2):149-152, (2009).
Impact/Purpose:
This study represents the first identification of in vivo mutagernesis as a key event in the tumorigencicity of conazole fungicides in mouse liver, suggesting an indirect genotoxic component to conazole MOA.
Description:
Triadimefon, propiconazole, and myclobutanil are conazoles, an important class of agricultural and therapeutic fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. All three conazoles are generally inactive in short-term genotoxicity tests. We studied the in vivo mutagenicity of these three conazoles using the Big Blue® mouse assay system. Groups of mice were fed either control diet, or diet containing 1800 ppm triadimefon, 2500 ppm propiconazole, or 2000 ppm myclobutanil. After 4 days of feeding, mice were euthanized, livers were removed, DNA isolated, and lacI genes recovered into infectious bacteriophage lambda particles by in vitro packaging. Bacteriophage with mutations in the lacI gene were detected by infecting into E. coli and plating on XGAL indicator plates, and mutant frequencies determined from the ratio of blue plaques to white plaques. Propiconazole induced a 1.97-fold increase in mutant frequency compared to concurrent controls (p=0.018) and triadimefon induced a 1.94-fold increase compared to concurrent controls (p=0.009). Myclobutanil did not induce any change in mutant frequency (p = 0.548). These results provide the first evidence that the hepatotumorigenic conazoles are capable of inducing mutations in liver in vivo while the nontumorigen myclobutanil is not, suggesting that mutagenicity may represent a key event in conazoles tumorigenic mode of action.
