Mechanism of Phosgene Oxime Induced Skin Toxicity in C57BL/6 Mouse Model

Abstract

Phosgene Oxime (CX) is a potent chemical warfare agent. It is grouped with vesicants; however, its effect resembles of an urticant or nettle agent. CX has faster penetration compared to other vesicating chemical warfare agents and causes erythema, urticaria, blanching, itching hives, necrosis, and systemic toxic effects upon exposure. The mechanism of CX induced toxicity is not known and there are no approved therapies. We have shown that dermal CX exposure in SKH‐1 hairless mice causes clinical lesions, epidermal cell death, mast cell degranulation, infiltration of immune cells, and increase in the level of DNA damage and inflammatory markers. In this study we examined the mechanism of CX‐induced inflammatory response in C57BL/6 mice. Dorsal skin of mice was exposed to neat CX for 0.5 or 1.0 min using two 12 mm vapor caps at MRI Global. CX exposure caused decrease in heart rate and breath rate with significant mortality (50%) after 1.0 min CX exposure. CX exposure caused erythema, and edema at the exposure site and led to increase in epidermal thickness. Significant mast cell degranulation was observed within 2h of CX exposure in male and female mice at both the exposure durations. The increase in mast cell degranulation was associated with increased tryptase and chymase levels in the mouse skin. CX exposure also led to increased expression of inflammatory mediators, cyclooxygenase‐2 (COX‐2), matrix metallopeptidase‐9 (MMP‐9), myeloperoxidase (MPO), and MAP kinases JNK. Inflammatory cytokines and chemokines were analyzed in the skin tissue lysates using cytokine array. CX exposure caused increases in several pro‐inflammatory cytokines and chemokines including IL‐6 and TNF‐α, and a decrease in anti‐inflammatory cytokines IL‐4 and IL‐10. Together, these results suggest mast cells as important contributors of CX induced dermal inflammation and toxicity. Further studies are being carried out using WT (C57BL/6) and mast cell deficient mice to evaluate the role of mast cells in CX‐induced toxicity.