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ALTERATIONS IN mRNA GENE EXPRESSION ASSOCIATED WITH CHOLESTEROL METABOLISM, CELL CYCLE, AND OXIDATIVE STRESS INDUCED BY TRIAZOLE CONTAINING CONAZOLES IN RAT LIVER
Citation:
NESNOW, S., S. Y. THAI, D. C. WOLF, C. JONES, G. M. NELSON, B. ROOP, AND S. D. HESTER. ALTERATIONS IN mRNA GENE EXPRESSION ASSOCIATED WITH CHOLESTEROL METABOLISM, CELL CYCLE, AND OXIDATIVE STRESS INDUCED BY TRIAZOLE CONTAINING CONAZOLES IN RAT LIVER. Presented at Society of Toxicology Annual Meeting, San Diego, CA, March 05 - 09, 2006.
Description:
Conazoles are fungicides used as pharmaceuticals and in agriculture. Triadimefon was hepatotoxic and induced follicular cell adenomas in the thyroid gland. In contrast,propiconazole and myclobutanil were hepatotoxic but had no effect on the thyroid gland. It was proposed that triadimefon induces thyroid tumors by induction of xenobiotic metabolizing enzymes which alter circulating T4, T3, and TSH. Serum thyroid hormone levels and UDP-glucuronyl transferase activity failed to support this hypothesis. The present study used genomic profiling to examine transcriptional alterations associated with a mode of toxic action. Male Wistar rats (3 per group) were exposed to triadimefon (1800, 500, or 100 ppm), propiconazole (2500, 500, 100 ppm), or myclobutanil (2000, 500, or 100 ppm) in the feed for 4, 30 or 90 days. Hepatic gene expression was performed using Affymetrix GeneChips (Rat 230_2) s. Differential gene expression was assessed using Robust Multichip Average Analysis (RMA) for probe level analysis. Low and mid dose exposure resulted in
the induction of phase I and phase II metabolizing enzymes, including CYP 1Al, CYP1A2, CYP 2B, CYP 3A, NADPH quinone oxidoreductase, and UGT1A6. At the high dose
additional changes were present in cell cycle control, cell signaling, lipid, carbohydrate, and nitrogen metabolism, and cytoskeletal and membrane coding proteins. Using Principle Component Analysis (PCA), all three conazoles could be discriminated from controls.
Propiconazole and myclobutanil clustered together and were distinct from triadimefon. The genes altered by any treatment were mapped to several gene networks including steroid biosynthesis, cell proliferation, and oxidative stress. [This abstract does not necessarily reflect EPApolicy].