Title: Transcriptional profiling of mouse ears exposed to the irritant sulfur mustard with or without drug (including indomethacin) pre-treatment. [original title: Transcription profiling of mouse ears exposed to sulfur mustard alone, sulfur mustard preceded by drug treatment, or vehicle compounds to identify gene expression changes that correlate with compound efficacy]
Organism(s): Mus musculus
Description: Sulfur mustard (SM) is a potent alkylating agent. We are developing medical countermeasures to reduce the injury caused by SM exposure. Screening in the mouse ear vesicant model has identified three effective compounds: dimercaprol (British anti-lewisite), indomethacin, and octyl homovanillamide (OHV). To identify gene expression changes that correlate with compound efficacy we used oligonucleotide microarrays to compare gene expression profiles in vehicle-exposed skin, SM-exposed skin, and skin pretreated with each compound before SM exposure. Mice were topically exposed on the inner surface of the right ear to SM alone or pretreated for 15 min with one of the compounds and then exposed to SM. Left ears were vehicle-exposed. Ear tissue was harvested 24 hr later for ear weight determination (an endpoint indicating compound efficacy). The exposure groups were: methylene chloride (sulfur mustard vehicle); ethanol (drug vehicle); 0.08 mg sulfur mustard; 6.25 mg dimercaprol 15 min before 0.08 mg sulfur mustard; 1.34 mg indomethacin 15 min before 0.08 mg sulfur mustard; 0.6 mg octylhomovanillamide 15 min before 0.08 mg sulfur mustard; 6.25 mg dimercaprol alone; 1.34 mg indomethacin alone; 0.6 mg octylhomovanillamide alone. RNA was extracted from the tissues and used to generate oligonucleotide microarray probes. Principal component analysis of the gene expression data revealed partitioning of the samples based on drug treatment and SM exposure. Vehicle-exposed mouse ears clustered away from the other treatment groups. SM-exposed mouse ears pretreated with dimercaprol or OHV clustered more closely with vehicle-exposed ears, while SM-exposed mouse ears pretreated with indomethacin clustered more closely with SM-exposed ears. This clustering of the samples is supported by the ear weight data, in which the indomethacin group has ear weights closer to the SM-exposed group, whereas the dimercaprol and OHV groups have ear weights closer to the vehicle-exposed group. Correlation coefficients were calculated for each gene based on the correlation between gene expression level and ear weight. These data provide the basis for understanding what gene expression changes are important in the development of effective SM medical countermeasures. Experiment Overall Design: Exposure of mouse ears to sulfur mustard alone, sulfur mustard preceded by drug treatment, or vehicle compounds. Naive controls were also included. Biological replicates of at least n=3 were examined for each exposure condition.
Design(s): compound_treatment_design, co-expression_design, transcription profiling by array
Experimental factor(s):
10 recorded
methylene chloride dimercaprol and sulfur mustard ethanol indomethacin and sulfur mustard octylhomovanillamide and sulfur mustard indomethacin dimercaprol sulfur mustard naive octylhomovanillamide
1 recorded
outer ear
Publication(s): James F Dillman, Alison I Hege, Christopher S Phillips, Linda D Orzolek, Albert J Sylvester, Carol Bossone, Claudia Henemyre-Harris, Robyn C Kiser, Young W Choi, John J Schlager, Carol L Sabourin
Microarray analysis of mouse ear tissue exposed to bis-(2-chloroethyl) sulfide: gene expression profiles correlate with treatment efficacy and an established clinical endpoint. PubMed:16377760

Sample attribute(s):
Material Type
2 recorded
synthetic_RNA total_RNA
sulfur mustard treatment
3 recorded
vehicle only none bis(2-chloroethyl) sulfide
other pretreatment
4 recorded
none dimercaprol vehicle only N-octylhomovanillamide
2 recorded
left right
1 recorded
indomethacin pretreatment
1 recorded
1 recorded
Mus musculus
1 recorded
Contact(s): James Dillman
Release Date: 12/1/2007
Submission Date:
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transcription profiling using DNA microarray
107 assays