Time- and dose-dependent analysis of gene expression using microarrays in sulfur mustard-exposed mice.

The chemical warfare agent sulfur mustard (SM) produces blister formation with a severe inflammatory reaction in skin of exposed individuals. The development of efficacious countermeasures against SM vesication requires an understanding of the cellular and molecular mechanism of SM-induced tissue injury. This study examined SM-induced alterations in gene expression using Atlas Mouse 5K DNA microarrays (5002 genes) to identify transcriptional events associated with SM skin injury. Mice (N=3) were exposed topically to SM (0.04, 0.08, and 0.16 mg; 48.8, 97.5, and 195 mM) on the inner surface of the right ear and skin tissues were harvested at 1.5, 3, 6, and 12 h. Genes were selected based on the three mice in the same dose group demonstrating a > or =2-fold increase or decrease in gene expression for the SM-exposed tissue when compared to the dichloromethane vehicle control ear at all three doses and four time points. At the 0.04 mg SM dose, the genes observed were primarily involved in inflammation, apoptosis, and cell cycle regulation. Exposure to 0.08 mg SM increased the expression of genes related to inflammation and cell cycle regulation. Exposure to 0.16 mg SM led to a total of six genes that were changed at all observed time periods; however, these genes do not appear to be directly influential in biological mechanisms such as inflammation, apoptosis, and cell cycle regulation as was observed at the lower SM doses of 0.04 and 0.08 mg. These functional categories have been observed in previous studies utilizing both in vivo and in vitro model systems of SM-induced dermal injury, suggesting that molecular mechanisms associated with inflammation, apoptosis, and cell cycle regulation may be appropriate targets for developing prophylactic/therapeutic treatments for SM skin injury.