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ASSESSING MOLECULAR MECHANISMS OF THREE TOXICOLOGICALLY DIFFERENT CONAZOLES BASED ON PATHWAY ANALYSIS OF MOUSE LIVER TRANSCRIPTOMES
Citation:
WARD, W. O., S. D. HESTER, S. Y. THAI, D. A. DELKER, B. ROOP, J. W. ALLEN, C. JONES, DOUG C. WOLF, AND S. NESNOW. ASSESSING MOLECULAR MECHANISMS OF THREE TOXICOLOGICALLY DIFFERENT CONAZOLES BASED ON PATHWAY ANALYSIS OF MOUSE LIVER TRANSCRIPTOMES. Presented at Keystone Symposium: Systems Biology: Integrating Biology, Technology and Computation , Taos, NM, March 05 - 10, 2006.
Description:
The present study was designed to identify the underlying molecular mechanism for the induction of mouse liver tumors by structurally-related conazoles. CD-1 mice were treated with the tumor producing conazoles, triadimefon (1800, 500, or 100 ppm), or propiconazole (2500, 500, or 100 ppm), or the non-tumorigenic, myclobutanil (2000, 500, 100 ppm) for 4, 30, or 90 days in the feed. Hepatic gene expression changes, identified using Affymetrix Mouse genome 430 2.0 arrays, were analyzed for patterns associated with potential modes of tumorigenic action. Gene expression measures were obtained from Robust Multiarray Analysis (RMA). Differential expression was assessed using a Cross Gene Error Model and 1 Way ANOVA with a 5% False Discovery Rate. Fold change was calculated and functional groupings were made using annotations from KEGG, BioCarta and Mouse Genome Informatics. Notably arachidonic acid and sterol metabolizing gene expression were altered by all conazoles. Liberation of arachidonic acid through cell membrane hydrolysis can generate biologically active lipid mediators that have been associated with enhanced cell proliferation and cancer. In addition, numerous cytochromes had altered expression after 90-days of conazole treatment. Based on a functional pathway analysis of differentially expressed genes, triadimefon and propiconazole had a much broader effect on liver cell function than myclobutanil and their expression changes resembled each other more closely than either resembled myclobutanil. After 90 days at the highest dose, propiconazole and triadimefon had impacts on gene expression for a number of biological pathways associated with tumorigenesis. Those pathways included steroid metabolism, steroidigenesis, anti-apoptosis, energy metabolism, the actin cytoskeleton, and cell adhesion. Thus pathway analysis can distinguish molecular mechanisms of structurally-related conazoles.