Subchronic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and their reversibility in male Sprague-Dawley rats.
The hypothesis tested in this experiment is that effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) show identical dose-responses after subchronic as after acute exposure when the dose is corrected for toxicokinetics. Groups of male Sprague-Dawley (S-D) rats were administered orally a total dose of 0, 0.2, 2.3, 11.5, 35, 70 or 115 micrograms/kg of TCDD over a period of 10 weeks at 4 ml/kg of vehicle. Body weight was recorded weekly. One week after the last dose of TCDD one half of the rats was killed and tryptophan 2,3-dioxygenase (TdO), 7-ethoxyresorufin-O-deethylase (EROD) and phosphoenolpyruvate carboxykinase (PEPCK) activities were measured in livers, whereas tryptophan and total T4 (TT4) were determined in serum. The results show that the dose-response for decreased TdO and PEPCK activity and elevated serum tryptophan levels are similar if not the same as the dose-response for subchronic retardation of body weight increase. They also demonstrate that the dose-responses for the induction of EROD activity and the reduction of serum TT4 occurred at much lower doses than those for decreased TdO and PEPCK activities or elevated tryptophan levels and mortality. After a 6-week recovery period, PEPCK and TdO activities in liver as well as tryptophan in serum returned to near control values, whereas EROD activity and serum TT4 still displayed a dose-dependent induction and reduction, respectively, albeit both shifted to the right in accordance with toxicokinetics. These data support the notion that subchronic dose-responses of TCDD are similar to acute dose-responses when corrected for toxicokinetics and that at least some TCDD-induced effects are reversible also in accordance with toxicokinetics.
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Rozman
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D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013974:Thyroxine / Q000097:blood; D014366:Tryptophan Oxygenase / Q000378:metabolism
D000072317:Polychlorinated Dibenzodioxins; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D014366:Tryptophan Oxygenase; D019363:Cytochrome P-450 CYP1A1; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D013974:Thyroxine