Genomic analysis of rodent pulmonary tissue following bis-(2-chloroethyl) sulfide exposure.
Bis-(2-chloroethyl) sulfide (sulfur mustard, SM) is a carcinogenic alkylating agent that has been utilized as a chemical warfare agent. To understand the mechanism of SM-induced lung injury, we analyzed global changes in gene expression in a rat lung SM exposure model. Rats were injected in the femoral vein with liquid SM, which circulates directly to the pulmonary vein and then to the lung. Rats were exposed to 1, 3, or 6 mg/kg of SM, and lungs were harvested at 0.5, 1, 3, 6, and 24 h postinjection. Three biological replicates were used for each time point and dose tested. RNA was extracted from the lungs and used as the starting material for the probing of replicate oligonucleotide microarrays. The gene expression data were analyzed using principal component analysis and two-way analysis of variance to identify the genes most significantly changed across time and dose. These genes were ranked by p value and categorized based on molecular function and biological process. Computer-based data mining algorithms revealed several biological processes affected by SM exposure, including protein catabolism, apoptosis, and glycolysis. Several genes that are significantly upregulated in a dose-dependent fashion have been reported as p53 responsive genes, suggesting that cell cycle regulation and p53 activation are involved in the response to SM exposure in the lung. Thus, SM exposure induces transcriptional changes that reveal the cellular response to this potent alkylating agent.
Dillman
James F
JF
Applied Pharmacology and Neurotoxicology Branches, U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400, USA. James.Dillman@apg.amedd.army.mil
Phillips
Christopher S
CS
Dorsch
Linda M
LM
Croxton
Matthew D
MD
Hege
Alison I
AI
Sylvester
Albert J
AJ
Moran
Theodore S
TS
Sciuto
Alfred M
AM
D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D018816:Genes, cdc; D016158:Genes, p53; D023281:Genomics; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002619:Chemical Warfare Agents; D012333:RNA, Messenger; C031278:2-chloroethyl ethyl sulfide; D009151:Mustard Gas