Extrathyroidal effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on thyroid hormone turnover in male Sprague-Dawley rats

Treatment of rats with different polyhalogenated aromatic hydrocarbons strongly decreases plasma T-4, with little or no decrease in plasma T-3. The extrathyroidal effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thyroid hormone turnover were studied by ip administration of a single dose of 10 mu g TCDD/kg BW or vehicle (corn oil) to euthyroid (Eu) rats, thyroidectomized (Tx) rats, and Tx rats infused with 1 mu g T-4 (Tx+T-4) or 0.4 mu g T-3 (Tx+T-3)/100 g BW.day by osmotic minipumps. Tx rats showed decreased plasma T-4 and T-3 and increased plasma TSH levels, decreased hepatic type I deiodinase (D1) and malic enzyme activities, and increased brain type II deiodinase (D2) activities. All parameters were largely restored to Eu levels in Tx+T-4 rats and, except for plasma T-4 and brain D2 activity, in Tx+T-3 rats, validating the thyroid hormone-replaced Tx rats as models to study the peripheral effects of TCDD. Three days after TCDD administration, plasma T-4 and free T-4 levels were significantly reduced in Eu and Tx+T-4 rats, and plasma T-3 was significantly reduced in Tx+T-3, but not in Eu or Tx+T-4 rats. Plasma TSH was not affected by TCDD in any group. Hepatic T-4 UDP-glucuronyltransferase (UGT) activity was induced approximately 5-fold by TCDD, whereas T-3 UGT activity was only increased by about 20% (P = NS) in the different groups. TCDD produced an insignificant decrease in liver D1 activity in Tx rats and an insignificant increase in brain D2 activity in Tx rats and hormone-replaced Tx rats. Hepatic malic enzyme activity was significantly increased by TCDD in all groups, except Tx rats. These results strongly suggest that the thyroid hormone-decreasing effects of TCDD are predominantly extrathyroidal and mediated by the marked induction of hepatic T-4 UGT activity.