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COMPARISON OF HEPATIC GENE EXPRESSION PROFILES FROM MICE EXPOSED TO THREE TOXICOLOGICALLY DIFFERENT CONAZOLES
Citation:
Ward, W. O., S D. Hester, S. F. Thai, J W. Allen, C. P. Jones, D C. Wolf, AND S. C. Nesnow. COMPARISON OF HEPATIC GENE EXPRESSION PROFILES FROM MICE EXPOSED TO THREE TOXICOLOGICALLY DIFFERENT CONAZOLES. Presented at Society of Toxicology, New Orleans, LA, March 6-10, 2005.
Description:
Conazoles comprise a chemical class of fungicides used as agricultural and pham-taceutical products. Both propiconazole and triadimefon are hepatotoxic and hepatotumorigenic in mice, while myclobutanil is not a mouse liver tumorigen. The tumorigenic activities of these conazoles are thought to be mediated through increased liver cytochrome P450 enzyme activity leading to oxidative stress, mitogenesis, and altered foci development. Our goal was to assess correlations of global gene expression in liver with the hepatocarcinogcnic responses in mice. Male CD-1 mice were treated for 4 days with feed incorporated with triadimefon (0, 500 or 1800 ppm), propiconazole (0, 500 or 2500 ppm) or myclobutanil (0, 500 or 2000 ppm). At high dose exposures, propiconazole induced more than twice the number of differentially expressed genes (Affymetrix 430 2.0 gene array) compared to triadimefon or myclobutanil. 121 genes were upregulated by 50% or more in liver tissue from mice treated with any of the three conazoles; 87 genes were upregulated in both triadimefon and propiconazole; 102 genes were upregulated exclusively in triadimefon and 328 genes were uprcgulated exclusively in propiconazole. All three conazoles increased the gene expression of a series of eytochrome P450s including, cyp2b20, cyp2c37, and cyp2c55. These P450 increases were dose responsive with more than twenty-fold induction at the high dose in some cases. Effects of global gene expression at the lower doses are also being investigated