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TRIADIMEFON INDUCES RAT THYROID TUMORS THROUGH A NON-TSH MEDIATED MODE OF ACTION
Citation:
Wolf, D C., J W. Allen, G. Sun, J R. Thibodeaux, M H. George, S D. Hester, S. F. Thai, D. A. Delker, G M. Nelson, E. Winkfield, B C. Roop, S. A. Leavitt, W. O. Ward, AND S. C. Nesnow. TRIADIMEFON INDUCES RAT THYROID TUMORS THROUGH A NON-TSH MEDIATED MODE OF ACTION. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 6-10, 2005.
Description:
Conazoles are a class of fungicides used as agricultural and pharmaceutical products which inhibit ergosterol biosynthesis. Members of this class are hepatotoxic and cause mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. Triadimefon-induced rat thyroid tumors may arise through increased TSH secretion after induction of thyroxine metabolizing enzymes. Male Wistar rats treated with triadimefon (TRID, 100, 500, 1800 ppm), propiconazole (PROP, 100. 500, 2500 ppm), or myclohutanil (MYCL, 100, 500, 2000 ppm) in feed for 4, 30, or 90d were evaluated for clinical signs, body and liver wt, histopathology of thyroid and liver, metabolizing enzyme activity, and serum T3, T4, and TSH levels. There was a dose-dependent increase in liver wt but body wts were not different from control for all treatments. Pentoxyresorufin O-dealkylation (PROD) activities had a dose-related increase at all time points for all three conazoles. UGT activities were induced to the same extent after 30- and 90d treatments for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4d of treatment, while only TRID and PROP treated rats had hepatocyte hypertrophy after 30d, and only TRID treated rats had hepatocyte hypertrophy after 90d. Thyroid follicular cell hypertrophy and colloid depletion was present only after 30d TRID treatment. A dose-dependent decrease in T4 was present after 4d of treatment with all 3 compounds but only the high doses of PROP and TRID after 30d. T3 was decreased in the high dose group of TRID after 4d and in a dose-dependent manner for all compounds after 30d. Thyroid hormone levels did not differ from control values after 90d of treatment and TSH was not different from control in any exposure group. Although this group of conazoles does transiently perturb thyroid function, these data suggest that thyroid tumors arising after TRID treatment are not a result of persistent increases in TSH.