The transcriptional effects of the vesicants lewisite and sulfur mustard on human epidermal keratinocytes.
Sulfur mustard (SM) injury is a complex process that begins with extensive alkylation of critical cellular components and culminates in cell death and skin vesication. The mechanism of toxicity is not well understood since SM broadly alkylates cellular nucleophiles. However, two events appear integral-the formation of DNA cross-links and the release of proteases into the extracellular matrix. To identify genes directly involved in vesication, the transcriptional profile of SM was compared to the vesicant lewisite (L). Similarly, to identify genes directly involved in DNA damage, the transcriptional profile of SM was compared to the genotoxic agent cisplatin (c-Pt). Microarrays containing 7,075 sequence-verified human cDNAs were screened with mRNA from human epidermal keratinocytes treated with 200 mu M agent for 2 h. A large number of differentially expressed genes were identified, with many similarities observed between agents. Many genes not previously associated with SM and L injury were also identified, including a large percentage of unknown function. A comparison of the differential expression profiles revealed that L had the broadest and most robustly altered expression. Apoptotic transcripts were clearly evident in L but not in SM, suggesting a late stage in L injury.
Platteborze
Peter L
PL
Pharmacology Division, USAMRICD, Aberdeen Proving GroundMaryland, USA.