ToxSci Advance Access published online on October 15, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp253
Mechanisms Mediating the Vesicant Actions of Sulfur Mustard after Cutaneous Exposure
1 Department of Environmental Health Science, School of Health Sciences and Practice, Institute of Public Health , New York Medical College, Valhalla, NY 2 Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 3 Department of Science, United States Coast Guard Academy, New London, CT 4 Department of Pharmaceutics, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 5 Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 6 Battelle Memorial Institute, Columbus, OH 7 Department of Chemistry, Lehigh University, Bethlehem, PA 8 Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ
jlaskin{at}eohsi.rutgers.edu
Received October 3, 2009; revision received October 3, 2009; accepted October 11, 2009
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Abstract |
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Sulfur mustard, a chemical weapon first employed during World War I, targets the skin, eyes, and lung. It remains a significant military and civilian threat. The characteristic response of human skin to sulfur mustard involves erythema of delayed onset, followed by edema with inflammatory cell infiltration, the appearance of large blisters in the affected area, and a prolonged healing period. Several in vivo and in vitro models have been established to understand the pathology and investigate the mechanism of action of this vesicating agent in the skin. Sulfur mustard is a bifunctional alkylating agent which reacts with many targets including lipids, proteins and DNA, forming both intra- and intermolecular cross-links. Despite the relatively non-selective chemical reactivity of this agent, basal keratinocytes are more sensitive, and blistering involves detachment of these cells from their basement membrane adherence zones. The sequence and manner in which these cells die and detach is still unresolved. Much has been discovered over the past two decades with respect to the mechanisms of sulfur mustard-induced cytotoxicity, and the intracellular and extracellular targets of this vesicant. In this review, the effects of sulfur mustard exposure on the skin are described, as well as potential mechanisms mediating its actions. Successful therapy for sulfur mustard poisoning will depend on following new mechanistic leads to develop drugs that target one or more of its sites of action.
Key Words: chemical & biological weapons; Agents, alkylating agents; Agents, cutaneous or skin toxicity; Systems Toxicology.