Phosgene Oxime (dichloroform oxime; CX), an urticant categorized as a vesicating agent, is a potential chemical threat agent. Exposure causes rapid and painful dermal injury and systemic effects leading to prompt incapacitation and death; however, its mechanism of action is unknown and effective therapies have not been identified. Since exposure to mustard vesicants has been shown to cause oxidative stress, DNA damage, and apoptotic cell death, we studied these toxic effects from CX skin exposure in mice. We exposed the dorsal skin of male C57BL/6 mice to vapor generated from10 μl of liquid CX or 0.5 or 1.0 min using two 12 mm caps at MRIGlobal, MO. Results showed that CX skin exposure caused increased expression of DNA damage markers, phosphorylated H2A.X (Ser139) and p53 (Ser15), within 2h of exposure. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling showed an increase in epidermal cell death within 2h of CX exposure and increased cleaved caspase 3 and cleaved Poly (ADP-ribose) polymerase 1, suggesting apoptotic cell death and rapid skin toxicity. Further investigation showed an increase in oxidative DNA damage (8-oxo-2-deoxyguanosine), protein oxidation (carbonylation), and lipid peroxidation (4-Hydroxynonenal) in the skin of CX-exposed mice. In summary, this comprehensive study reports novel outcomes indicating that CX-induced apoptotic cell death could involve oxidative stress and programmed signaling leading to DNA damage. Oxidative damage and related signaling pathways could significantly contribute to CX-induced skin toxicity either directly and/or via inflammatory response and mast cell activation (reported in our recent studies), which is being further analyzed in our ongoing studies.
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