Abstract
Bis-(2-chloroethyl) sulfide (sulfur mustard; SM) is a potent alkylating agent. Three treatment compounds have been shown to limit SM damage in the mouse ear vesicant model: dimercaprol, octyl homovanillamide, and indomethacin. Microarrays were used to determine gene expression profiles of biopsies taken from mouse ears after exposure to SM in the presence or absence of treatment compounds. Mouse ears were topically exposed to SM alone or were pretreated for 15 min with a treatment compound and then exposed to SM. Ear tissue was harvested 24 h after exposure for ear weight determination, the endpoint used to evaluate treatment compound efficacy. RNA extracted from the tissues was used to generate microarray probes for gene expression profiling of therapeutic responses. Principal component analysis of the gene expression data revealed partitioning of the samples based on treatment compound and SM exposure. Patterns of gene responses to the treatment compounds were indicative of exposure condition and were phenotypically anchored to ear weight. Pretreatment with indomethacin, the least effective treatment compound, produced ear weights close to those treated with SM alone. Ear weights from animals pretreated with dimercaprol or octyl homovanillamide were more closely associated with exposure to vehicle alone. Correlation coefficients between gene expression level and ear weight revealed genes involved in mediating responses to both SM exposure and treatment compounds. These data provide a basis for elucidating the mechanisms of response to SM and drug treatment and also provide a basis for developing strategies to accelerate development of effective SM medical countermeasures.
Footnotes
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In conducting the research described in this report, the investigators adhered to the Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. The data discussed in this publication have been deposited in the National Center for Biotechnology Information's Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession number GSE2950.
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doi:10.1124/jpet.105.097014.
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ABBREVIATIONS: SM, sulfur mustard; OHV, octyl homovanillamide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RMA, robust multiarray averaging; PCA, principal component analysis; Q-PCR, quantitative real-time polymerase chain reaction; CEES, chloroethyl ethyl sulfide; ANOVA, analysis of variance.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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↵1 Current affiliation: Biosciences and Protection Division, Human Effectiveness Directorate, Wright-Patterson AFB, Ohio.
- Received October 25, 2005.
- Accepted December 22, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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