Immediate-Early Gene Expression Responses to Sulfur Mustard Exposure

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Authors
  1. Ford, B.N.
  2. Shei, Y.
  3. Nelson, P.
  4. McWilliams, M.
  5. Weiss, T.
  6. Sawyer, T.W.
Corporate Authors
Defence R&D Canada - Suffield, Ralston ALTA (CAN)
Abstract
Sulfur mustard (bis-(2-chloroethyl) sulphide, HD) is a well-known chemical warfare agent which causes skin blisters, respiratory tract injury, and systemic toxic effects. The underlying molecular basis of HD toxicity is not well understood. Multiple hypotheses attempting to improve understanding of this problem have been proposed, including DNA damage and repair, inflammation, aberrant cytokine expression, direct protein modification to keratin fibres, and combinations of these effects. Despite such efforts, there is little consensus on the biological basis for the profound observed toxicity of HD. A particularly puzzling aspect is the terminal arrest of cultured cells at concentrations of HD substantially lower than those at which cytotoxic effects are seen, suggesting there may be multiple pathways through which HD can exert its biological effects. Previously, Sawyer and others have proposed receptor-based interactions as being at the root of HD induced cytotoxic effects. In order to explore this hypothesis, gene expression profiles of first passage cultures of human keratinocytes were developed using an oligonucleotide microarray platform. Analysis of data from six independent donors at multiple concentrations of HD and varying time points revealed a complex response. Combined data at adjacent time points enabled the identification of the mitogen-activated protein kinase (MAPK) network and genes associated with it, as primary functions responding to sulfur mustard. Publish

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Keywords
microarray;sulfur mustard;MAPK pathway;therapeutics;Gene expression;HD agent;Human Keratinocytes
Report Number
DRDC-SUFFIELD-TM-2007-290 — Technical Memorandum
Date of publication
01 Dec 2007
Number of Pages
34
DSTKIM No
CA030775
CANDIS No
529416
Format(s):
CD ROM

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