Mechanism of trifluralin-induced thyroid tumors in rats

Trifluralin, an herbicide, has been reported to cause a significant increase in thyroid follicularcell tumors in male Fischer 344 rats. This study was designed to determine the mechanism ofthyroid hyperactivity after trifluralin exposure. A group of 15 male Fischer 344 rats were exposed to trifluralin-fortified (6500 ppm) diet for 2 weeks. The time weighted average daily intake oftrifluralin was 441 77 mg/kg/day. Ten rats of the group were sacrificed and the sera analyzed for T3, T4, and TSH levels. The livers were also analyzed for selected T4-specific UGT gene expression and total UGT enzyme activity. In the trifluralin treated rats, the serum T3 and T4 levels decreased by 17% and 90%, respectively and TSH increased by 37% more than the control rats. Trifluralin-inclUced total hepatic UGT enzymes (2.4-fold) and mRNA expression of selected hepatic UGT isozymes (UGT1 Al, 1.4-fold; UGTlA6,6.4-fold; UGT2BI, 3.7-fold). For the remaining 5 rats in the group, bile was collected for 2 h and analyzed for free and conjugated T3 and T4 The total. amount of T4 in bile more than doubled in trifluralin treated rats. Trifluralin treatment increased bile flow, caused a 3.2-fold increase in biliary elimination ofconjugated T4 and 63% increase in conjugated T3. Based on these data, the decrease in total serum T3 and T4 levels in the trifluralin treated rats was due to enhanced peripheral metabolism and an increase in bile flow that results in a compensatory increase in TSH synthesis and secretion. The increased levels ofTSH with chronic exposure to trifluralin would exert a continuous stimulation ofthe thyroid gland leading to cellular hypertrophy and proliferation predisposing to the development of follicular cell tumors in rats. (c) 2008 Published by Elsevier Ireland Ltd.