Toxicological Sciences 62, 166-175 (2001)
Copyright © 2001 by the Society of Toxicology
SAFETY EVALUATION |
Hepatic Vitamin A Depletion Is a Sensitive Marker of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Exposure in Four Rodent Species
Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, S-171 77 Stockholm, Sweden
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-treated animals show altered retinoid homeostasis and exhibit signs of toxicity similar to those of vitamin A–deficient animals. In this study we established dose-response curves for sublethal oral doses of TCDD and hepatic vitamin A gain in four rodent species. This was done to evaluate any potential correlation between decreased hepatic vitamin A gain and other TCDD-induced effects, particularly depressed body weight gain and hepatic CYP1A induction. Young Hartley guinea pigs, Sprague-Dawley rats, C57BL/6 mice, and Golden Syrian hamsters were given single oral doses of TCDD at up to 2.5, 100, 1000, and 1000 µg/kg bw, respectively, and killed 28 days after treatment. Hepatic vitamin A gain was decreased 25% compared to controls at estimated doses of 0.1, 0.9, 1.1 and 3.6 µg/kg bw in guinea pigs, hamsters, rats, and mice, respectively. CYP1A induction and hepatic vitamin A gain were affected at similar dose levels and showed similar, but inverse dose-response curves in each of the four species, consistent with the hypothesis that altered vitamin A homeostasis is Ah-receptor mediated. In addition, there was an apparent correlation between the dose-response curves for decreased hepatic vitamin A gain and decreased body weight gain in all species. Taken together with the known importance of vitamin A in body weight regulation, this result was consistent with a contributing role for altered retinoid homeostasis in the wasting syndrome induced by TCDD.
Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD, vitamin A; retinoids; wasting; EROD; species; hepatic; renal.
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