RELATIONSHIP BETWEEN ACUTE TOXICITY OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) AND DISTURBANCE OF INTERMEDIARY METABOLISM IN THE LONG-EVANS RAT

The aim of this study was to examine the acute toxicity of 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a rat strain other than the Sprague-Dawley (S-D) rat, for which most of our data have been generated thus far. Doses for the biochemical study were selected based on an acute range-finding study, which indicated that Long-Evans (L-E) rats are somewhat less susceptible to TCDD toxicity than are S-D rats. Male L-E rats were dosed orally with 10, 20, 45, 67, 100 and 150 mu g/kg TCDD. Body weight and feed intake were dose-dependently decreased prior to killing of the animals. Eight days after dosing, animals were killed and tryptophan, total T-4 (TT4) and total T-3 (TT3) levels were determined in serum, whereas the activities of ethoxy-resorufin-O-deethylase (EROD), phosphoenolpyruvate carboxykinase (PEPCK), gamma-glutamyl transpeptidase (gamma-GT) and tryptophan 2,3-dioxygenase (TdO) were measured in liver. EROD activity was fully induced at all doses studied, indicating that as in S-D rats, Ah-receptor-mediated effects do not seem to play any major role in the acute toxicity of TCDD in this rat strain either. Hepatic PEPCK activity was dose-dependently decreased in a similar dose range as in S-D rats, indicating inhibition of gluconeogenesis. Feed intake was dose-dependently decreased as a result of a dose-dependent elevation in serum tryptophan levels, which in turn were related to reduced liver TdO activity. Hepatic gamma-GT activity was also dose-dependently reduced. However, unlike in S-D rats, these dose-responses occurred in a higher dose range than the reduction of PEPCK activity which appears to be the explanation for the decreased susceptibility of L-E rats to TCDD. Serum TT4 levels were significantly decreased at all doses, whereas the serum concentration of TT3 appeared unaffected. The results of this study suggest that subtle differences in the regulation of intermediary metabolism between these two strains of rats are responsible for strain differences in the susceptibility to TCDD.