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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003597-05
Application #
3251028
Study Section
Toxicology Study Section (TOX)
Project Start
1985-02-01
Project End
1991-04-30
Budget Start
1989-05-01
Budget End
1990-04-30
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Connor, M J; Sidell, N (1997) Retinoic acid synthesis in normal and Alzheimer diseased brain and human neural cells. Mol Chem Neuropathol 30:239-52
Ajie, H O; Connor, M J; Lee, W N et al. (1995) In vivo study of the biosynthesis of long-chain fatty acids using deuterated water. Am J Physiol 269:E247-52
Connor, M J; Puhvel, S M; Sakamoto, M et al. (1994) The hr locus and the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in newborn mice. Arch Toxicol 69:87-90
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