Trifluralin, an
herbicide, has been reported to cause a significant increase in thyroid follicular cell
tumors in male Fischer 344 rats. This study was designed to determine the mechanism of thyroid 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 of
trifluralin 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-induced total hepatic UGT
enzymes (2.4-fold) and
mRNA expression of selected hepatic UGT
isozymes (UGT1A1, 1.4-fold; UGT1A6, 6.4-fold; UGT2B1, 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 of conjugated 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 of TSH with chronic exposure to
trifluralin would exert a continuous stimulation of the thyroid gland leading to cellular
hypertrophy and proliferation predisposing to the development of follicular cell
tumors in rats.