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Title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure of normal human dermal fibroblasts results in AhR-dependent and -independent changes in gene expression

Abstract

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a variety of lesions in mammals including severe skin lesions. The majority of TCDD's biological effects are mediated through activation of the aryl hydrocarbon receptor (AhR). We have chosen to examine the effect of TCDD and the AhR pathway on dermal fibroblasts because this cell type plays an integral role in skin homeostasis through the production of cytokines and other factors that regulate epidermal proliferation and differentiation. Our data show that normal human dermal fibroblasts (NHDFs) are responsive to TCDD, as demonstrated by induction of cytochrome p450 1B1 (CYP1B1) expression. Further, our data demonstrate that TCDD treatment of NHDFs results in significant (75-90%) decrease in expression of Id-1 and Id-3, proteins that are involved in regulation of cell proliferation and differentiation. The Id (Inhibitor of DNA binding) proteins are transcriptional inhibitors that function by forming inactive heterodimers with other HLH proteins. TCDD-repression of Id-1 and -3 is independent of de novo protein synthesis; co-treatment with cycloheximide has no effect on TCDD inhibition of Id-1 and Id-3. Co-treatment with the AhR antagonist {alpha}-naphthoflavone also does not block inhibition of Id-1 and Id-3 by TCDD, suggesting that TCDD inhibition of Id-1 and Id-3 is, at leastmore » in part, mediated independently of the AhR pathway. Our data also show that TCDD inhibits expression of the cell cycle regulatory gene p16{sup ink4a}, which is often linked to Id expression. TCDD-induced reduction of p16{sup ink4a} expression is also independent of protein synthesis and the AhR pathway.« less

Authors:
 [1];  [2];  [3]
  1. Department of Biochemistry and Microbiology, 76 Lipman Dr., Rutgers, State University of NJ, New Brunswick, NJ 08901 (United States)
  2. Joint Graduate Program in Toxicology, Rutgers, State University of New Jersey, New Brunswick, NJ 08901 (United States)
  3. Department of Biochemistry and Microbiology, 76 Lipman Dr., Rutgers, State University of NJ, New Brunswick, NJ 08901 (United States). E-mail: lawhite@aesop.rutgers.edu
Publication Date:
OSTI Identifier:
20976893
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 220; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2006.12.002; PII: S0041-008X(06)00468-6; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL EFFECTS; BIOSYNTHESIS; CELL CYCLE; CELL PROLIFERATION; CYCLOHEXIMIDE; DIOXIN; DNA; FIBROBLASTS; GENES; HOMEOSTASIS; HUMAN POPULATIONS; HYDROCARBONS; INHIBITION; LYMPHOKINES; MAMMALS; RECEPTORS; SKIN

Citation Formats

Akintobi, A.M., Villano, C.M., and White, L.A. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure of normal human dermal fibroblasts results in AhR-dependent and -independent changes in gene expression. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.12.002.
Akintobi, A.M., Villano, C.M., & White, L.A. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure of normal human dermal fibroblasts results in AhR-dependent and -independent changes in gene expression. United States. doi:10.1016/j.taap.2006.12.002.
Akintobi, A.M., Villano, C.M., and White, L.A. Sun . "2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure of normal human dermal fibroblasts results in AhR-dependent and -independent changes in gene expression". United States. doi:10.1016/j.taap.2006.12.002.
@article{osti_20976893,
title = {2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure of normal human dermal fibroblasts results in AhR-dependent and -independent changes in gene expression},
author = {Akintobi, A.M. and Villano, C.M. and White, L.A.},
abstractNote = {Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a variety of lesions in mammals including severe skin lesions. The majority of TCDD's biological effects are mediated through activation of the aryl hydrocarbon receptor (AhR). We have chosen to examine the effect of TCDD and the AhR pathway on dermal fibroblasts because this cell type plays an integral role in skin homeostasis through the production of cytokines and other factors that regulate epidermal proliferation and differentiation. Our data show that normal human dermal fibroblasts (NHDFs) are responsive to TCDD, as demonstrated by induction of cytochrome p450 1B1 (CYP1B1) expression. Further, our data demonstrate that TCDD treatment of NHDFs results in significant (75-90%) decrease in expression of Id-1 and Id-3, proteins that are involved in regulation of cell proliferation and differentiation. The Id (Inhibitor of DNA binding) proteins are transcriptional inhibitors that function by forming inactive heterodimers with other HLH proteins. TCDD-repression of Id-1 and -3 is independent of de novo protein synthesis; co-treatment with cycloheximide has no effect on TCDD inhibition of Id-1 and Id-3. Co-treatment with the AhR antagonist {alpha}-naphthoflavone also does not block inhibition of Id-1 and Id-3 by TCDD, suggesting that TCDD inhibition of Id-1 and Id-3 is, at least in part, mediated independently of the AhR pathway. Our data also show that TCDD inhibits expression of the cell cycle regulatory gene p16{sup ink4a}, which is often linked to Id expression. TCDD-induced reduction of p16{sup ink4a} expression is also independent of protein synthesis and the AhR pathway.},
doi = {10.1016/j.taap.2006.12.002},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 220,
place = {United States},
year = {Sun Apr 01 00:00:00 EDT 2007},
month = {Sun Apr 01 00:00:00 EDT 2007}
}