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Extrathyroidal Effects of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on Thyroid Hormone Turnover in Male Sprague-Dawley Rats¹

Department of Toxicology, Agricultural University Wageningen (A.G.S., F.M.B., A.B.), Wageningen; and the Department of Internal Medicine III, Erasmus University Medical School (T.J.V.), Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. A. G. Schuur, Department of Toxicology, Agricultural University Wageningen, P.O. Box 8000, 6700 EA Wageningen, The Netherlands. E-mail: Gerlienke.Schuur{at}algemeen.tox.wau.nl

Treatment of rats with different polyhalogenated aromatic hydrocarbons strongly decreases plasma T₄, with little or no decrease in plasma T₃. 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 µg TCDD/kg BW or vehicle (corn oil) to euthyroid (Eu) rats, thyroidectomized (Tx) rats, and Tx rats infused with 1 µg T₄ (Tx+T₄) or 0.4 µg T₃ (Tx+T₃)/100 g BW·day by osmotic minipumps. Tx rats showed decreased plasma T₄ and T₃ 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+T₄ rats and, except for plasma T₄ and brain D2 activity, in Tx+T₃ rats, validating the thyroid hormone-replaced Tx rats as models to study the peripheral effects of TCDD. Three days after TCDD administration, plasma T₄ and free T₄ levels were significantly reduced in Eu and Tx+T₄ rats, and plasma T₃ was significantly reduced in Tx+T₃, but not in Eu or Tx+T₄ rats. Plasma TSH was not affected by TCDD in any group. Hepatic T₄ UDP-glucuronyltransferase (UGT) activity was induced approximately 5-fold by TCDD, whereas T₃ 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 T₄ UGT activity.

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