Microarray analysis of mouse ear tissue exposed to bis-(2-chloroethyl) sulfide: gene expression profiles correlate with treatment efficacy and an established clinical endpoint.
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.
Dillman
James F
JF
Cell and Molecular Biology Branch, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. james.dillman@us.army.mil
Hege
Alison I
AI
Phillips
Christopher S
CS
Orzolek
Linda D
LD
Sylvester
Albert J
AJ
Bossone
Carol
C
Henemyre-Harris
Claudia
C
Kiser
Robyn C
RC
Choi
Young W
YW
Schlager
John J
JJ
Sabourin
Carol L
CL
D000287:Administration, Topical; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004431:Ear, External / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009151:Mustard Gas / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002619:Chemical Warfare Agents; D009151:Mustard Gas