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DNA MICROARRAY ANALYSIS OF RAT BRAIN TO ASSESS CHANGES IN GENE EXPRESSION AND NEUROTOXICITY OF FOUR CONAZOLES.
Citation:
White, L. D., D B. Tully, W Bao, J E. Schmid, A K. Goetz, G. Sun, S Nesnow, D J. Dix, AND S Barone. DNA MICROARRAY ANALYSIS OF RAT BRAIN TO ASSESS CHANGES IN GENE EXPRESSION AND NEUROTOXICITY OF FOUR CONAZOLES. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
Conazoles are a class of azole fungicides widely used both pharmaceutically and agriculturally. This study focused on four conazoles that exhibit a range of cancer and non-cancer effects, to ascertain if any neurotoxic effects are present and to identify possible common and unique modes of action. Conazoles target cytochrome P450s (CYPs), and the inhibition and induction of various CYP activities may be part of the toxic modes of action in brain. We used gene expression profiling to characterize a broader range of conazole effects and to identify additional, potential modes of action. Adult male Sprague-Dawley rats were dosed by gavage for 14 days with fluconazole, propiconazole, myclobutanil or triadimefon (three doses per chemical). Liver weights increased relative to body weight following exposure to all chemicals. All four conazoles induced cytochrome 2B and/ or 3A CYPs in liver microsomes. Spotted oligonucleotide microarrays utilizing cy3/cy5 labeling interrogated the expression of over 4000 genes in brains from control and conazole-treated rats. Log-transformed data were normalized using an intensity dependent local (Lowess) regression model. Genes expressed consistently in at least one treatment group were analyzed individually using a one-way anova. The analysis was repeated with various modifications to the data or analysis: with and without local background subtraction, with and without a range normalization, and with and without a random predictor for date of array experiment added to the anova. Gene expressions consistently different for at least one treatment versus control were selected for further analysis. Comparison of brain expression profiles between control and fluconazole-, myclobutanil-, propiconazole-, and triadimefon-treatment identified 107, 71, 138, and 130 differentially expressed genes, respectively, including genes involved in programmed cell death and neurotrophic factor production. This abstract does not necessarily reflect EPA policy.