The aim of this research is to gain a better understanding of the mechanisms involved in the expression of dioxin induced toxicity. We want to expand our ongoing investigations which use congenic haired and hairless HRS/J mice to study the regulatory mechanisms which control the expression of cutaneous toxicity following topical treatment with dioxin. The work in this proposal is based on the hypothesis formulated as a result of studies completed in our laboratory during the present funding period. That is, that epidermal cells of haired as well as hairless HRS/J mice have the potential to express dioxin induced hyperplasia and terminal differentiation (as demonstrated by in vitro studies), but that this response is inhibited in haired mice in vivo, while still being expressed in the hairless animals. Our studies are designed to determine the site of the regulatory mechanisms of the cutaneous response. Since haired and hairless HRS/J mice are congenic animals with identical histocompatibility genes, they are ideal models in which to study this problem by skin grafting experimentation. By grafting skin and skin components from responsive hr/hr mice to unresponsive +/+ animlas, and vice versa, and treating the grafted skin in the new host, the patterns of response in different host/graft combinations should elucidate the relative importance of each component (i.e. epidermal, dermal or humoral factors) in influencing the cutaneous response to dioxin. Once this is localized, it will be possible to further dissect the possible regulatory mechanisms in the specific component. In adddition to the skin grafting experiments which form the primary direction of our work, we also want to pursue the recent finding from our laboratory, that Langerhans cells are increased in dioxin treated hairless mouse skin and may be specifically involved in expressing the dioxin induced cutaneous response to dioxin. Studies elucidating the role of these cells are also outlined in this proposal.
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| Connor, M J; Nanthur, J; Puhvel, S M (1994) Influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on TNF-alpha levels in the skin of congenic haired and hairless mice. Toxicol Appl Pharmacol 129:12-5 |
| Puhvel, S M; Connor, M J; Sakamoto, M (1991) Vitamin A deficiency and the induction of cutaneous toxicity in murine skin by TCDD. Toxicol Appl Pharmacol 107:106-16 |
| Puhvel, S M; Sakamoto, M; Reisner, R M (1989) Effect of TCDD on the density of Langerhans cells in murine skin. Toxicol Appl Pharmacol 99:72-80 |
