Abstract
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 μg/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 T4 (TT4) and total T3 (TT3) levels were determined in serum, whereas the activities of ethoxyresorufin-O-deethylase (EROD), phosphoenolpyruvate carboxykinase (PEPCK), γ-glutamyl transpeptidase (γ-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 γ-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.
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References
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein dye binding. Anal Biochem 72: 248–254
Christian BJ, Inhorn SL, Peterson RE (1986) Relationship of the wasting syndrome to lethality in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 82: 239–255
Debas HT, Farooq O, Grossman MI (1975) Inhibition of gastric emptying is a physiologic action of cholecystokinin. Gastroenterology 68: 1211–1217
Dutton DR, Parkinson K (1989) Reduction of 7-alkoxyresorifins by NADPH-cytochrome P450 reductase and its differential effects on their O-dealkylation by rat liver microsomal cytochrome P450. Arch Biochem Biophys 268: 617–629
Fan F, Lebofsky M, Rozman KK (1994) Short- and long-term biochemical effects of TCDD in female Long-Evans rats. Toxicologist 14: 272
Gad S, Weil CS (1986) Modeling. In: Gad S, Weil CS (eds.) Statistics and experimental design for toxicologists. Telford Press, Caldwell, New Jersey, pp 93–110
Kimbrough RD (1974) The toxicity of polychlorinated polycyclic compounds and related chemicals. Crit Rev Toxicol 2: 445–498
McConnell EE, Moore JA, Haseman JK, Harris MW (1978) The comparative toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs. Toxicol Appl Pharmacol 44: 335–356
Meister A, Tate SS, Griffith OW (1981) γ-Glutamyl transpeptidase. In: Jakoby WB (ed) Methods in enzymology, Vol 77. Academic Press, New York, pp 237–253
Metzler H, Gebhardt R, Oberrauch W, Mecke D (1982) A convenient and highly sensitive spectrophotometric assay for tryptophan 2,3-dioxygenase, Anal Biochem 121: 10–16
Petrescu I, Bojan O, Saied M, Barzu O, Schmidt F, Kuhnle HF (1979) Determination of phosphoenolpyruvate carboxykinase activity with deoxyguanosine 5′-diphosphate as nucleotide substrate. Anal Biochem 96: 279–281
Pohjanvirta R, Tuomisto J, Vartiainen T, Rozman K (1987) Han/Wistar rats are exceptionally resistant to TCDD. J Pharmacol Toxicol 60: 145–150
Pohjanvirta R, Unkila M, Tuomisto J (1993) Comparative acute lethality of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin in the most TCDD-susceptible and the most TCDD-resistant rat strain. Pharmacol Toxicol 73: 52–56
Rothman DL, Magnusson I, Katz LD, Shulman RG, Shulman GI (1991) Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science 254: 573–576
Rozman K (1989) A critical view of the mechanism(s) of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Dermato Beruf Umwelt 37: 81–92
Rozman K, Pfeifer B, Kerecsen L, Alper RH (1991) Is a serotonergic mechanism involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced appetite suppression in the Sprague-Dawley rat? Arch Toxicol 65: 124–128
Stahl BU, Kettrup A, Rozman K (1992) Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture. Part I: Acute toxicity and toxic equivalency factors (TEFs). Arch Toxicol 66: 471–477
Vos JG (1978) 2,3,7,8-Tetrachlorodibenzo-para-dioxin: effects and mechanism. In: Ramel C (Ed) Chlorinated phenoxy acids and their dioxins. Ecol Bull, Stockholm, pp 165–176
Weber LWD, Lebofsky M, Greim H, Rozman K (1991) Key enzymes of gluconeogenesis are dose-dependently reduced in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats. Arch Toxicol 65: 119–123
Weber LWD, Lebofsky M, Stahl BU, Kettrup A, Rozman K (1992a) Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture. Part II: Structure-activity relationship with inhibition of hepatic phosphoenolpyruvate carboxykinase, pyruvate carboxylase and γ-glutamyl transpeptidase activities. Arch Toxicol 66: 478–483
Weber LWD, Lebofsky M, Stahl BU, Kettrup A, Rozman K (1992b) Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture. Part III: Structure-activity relationship with increased plasma tryptophan levels, but no relationship to hepatic ethoxyresorufin o-deethylase activity. Arch Toxicol 66: 484–488
Weber LWD, Palmer CD, Rozman K (1994) Reduced activity of tryptophan 2,3-dioxygenase in the liver of rats treated with chlorinated dibenzo-p-dioxins (CDDs): dose-responses and structure activity relationship. Toxicology 86: 63–69
Yamuda J, Sugimoto Y, Horisaka K (1983) Simultaneous determination of tryptophan and its metabolites in mouse brain by high performance liquid chromatography with fluorometric detection. Anal Biochem 129: 460–463
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Fan, F., Rozman, K.K. Relationship between acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and disturbance of intermediary metabolism in the Long-Evans rat. Arch Toxicol 69, 73–78 (1994). https://doi.org/10.1007/s002040050140
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DOI: https://doi.org/10.1007/s002040050140