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 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 i.p. administration of a single dose of 10 microg TCDD/kg BW or vehicle (corn oil) to euthyroid (Eu) rats, thyroidectomized (Tx) rats, and Tx rats infused with 1 microg T4 (Tx+T4) or 0.4 microg T3 (Tx+T3)/100 g BW x 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.
Schuur
A G
AG
Department of Toxicology, Agricultural University Wageningen, The Netherlands. Gerlienke.Schuur@algemeen.tox.wau.nl
Boekhorst
F M
FM
Brouwer
A
A
Visser
T J
TJ
D000818:Animals; D001921:Brain / Q000201:enzymology; D014453:Glucuronosyltransferase / Q000378:metabolism; D007453:Iodide Peroxidase / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008291:Malate Dehydrogenase / Q000378:metabolism; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013965:Thyroidectomy; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000008:administration & dosage / Q000097:blood*; D014284:Triiodothyronine / Q000008:administration & dosage / Q000097:blood*
D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D014284:Triiodothyronine; D013972:Thyrotropin; D008291:Malate Dehydrogenase; D007453:Iodide Peroxidase; D014453:Glucuronosyltransferase; D013974:Thyroxine