Abstract

The aim of this research is to gain a better understanding of the mechanisms involved in the expression of dioxin induced toxicity. Our ongoing investigations 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 that epidermal cells of haired as well as of 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. Skin grafting experiments have demonstrated that this difference in response to dioxin is controlled at the cutaneous level, and is not dependent on circulatory factors. The present proposal outlines in vitro experiments which will examine the role of dermal cells in regulating the keratinocyte response to dioxin. In vivo and in vitro experiments will analyse the role of specific growth factors (EGF, TGFalpha, and TGFbeta) in mediating the effect of dioxin on murine skin in vivo, and on epidermal keratinocytes in vitro.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003597-08
Application #
3251030
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1985-02-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

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