Vitamin A deficiency and the induction of cutaneous toxicity in murine skin by TCDD

The mechanisms involved in the induction of toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototype for a group of toxic polyhalogenated aromatic hydrocarbons, are largely unknown. To test the hypothesis that TCDD-induced toxicity involves the reduction of vitamin A levels, we investigated the role of vitamin A deficiency in modulating the cutaneous response of congenic haired (+/+) and hairless (hr/hr) mice to TCDD. Hairless mice are recognized as sensitive models for expression of TCDD-induced cutaneous toxicity. Haired mice normally do not develop a cutaneous response to TCDD. Mice raised on a vitamin A-deficient diet, and age- and sex-matched controls raised on standard chow, were treated topically with TCDD and their cutaneous responses monitored histologically. Body weights and thymus gland weights were monitored as additional parameters of toxicity. Liver and skin vitamin A levels were determined by HPLC. Vitamin A depletion by itself had no effect on the normal cutaneous histology of the haired phenotype, nor were any changes in cutaneous morphology attributable to TCDD toxicity observed in haired, TCDD-treated animals even when they were severely vitamin A depleted. On the other hand, in hairless mice, vitamin A deficiency caused a distinct increase in keratinization of dermal epithelial cysts, and an increase in the sensitivity of these cysts to TCDD-induced hyperkeratinization. TCDD-induced body weight loss and atrophy of the thymus gland were not affected by the vitamin A status of either the haired or hairless animals. Analysis of vitamin A levels in skin and liver, following topical treatment of mice with TCDD, indicated that TCDD exposure did not affect cutaneous levels, but did significantly lower liver levels of vitamin A. These experiments suggest that although systemic vitamin A deficiency may potentiate the expression of TCDD-induced toxicity in skin of hairless mice, expression of TCDD-induced toxicity probably involves more complex mechanisms than a reduction in vitamin A levels.