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In vivo mutagenicity of conazole fungicides correlates with tumorigenicity
Citation:
ROSS, J. A., T. MOORE, AND S. A. LEAVITT. In vivo mutagenicity of conazole fungicides correlates with tumorigenicity. Presented at American Association for Cancer Research Annual Meeting 2008, San Diego, CA, April 12 - 16, 2008.
Impact/Purpose:
This work was undertaken to establish whether mutagenicity is a key event in the hepatotumorigenic MOA of conazole fungicides.
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. Mice were fed either control diet, diet containing 1800 ppm triadimefon, diet containing 2500 ppm propiconazole, or diet containing 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 mutated in the lacI gene were detected by plating on XGAL indicator plates, and mutant frequencies determined from the ratio of blue plaques to white plaques. Propiconazole induced a 1.9-fold increase in mutant frequency compared to concurrent control (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 = 0.414). These results provide the first evidence that these hepatotumorigenic conazoles are capable of inducing mutations in liver in vivo, and this may represent a key event in their mode of action.