Stockpiled during World War II, Phosgene Oxime (CX; dichloroform oxime) is a potent chemical weapon that poses a threat of exposure; both, alone and with other chemical agents. It is an urticant or nettle agent grouped with vesicating agents due to similar damaging properties; although, it causes more severe damage than other vesicants due to its highly reactive nature. Even though it is the most notorious vesicant with special military and terrorist interests, it is one of the least studied chemical warfare agents with no specific antidote available. Information on its effect on human dermal tissue and absorption is limited, and its mechanism of action is unknown. Well defined animal models of exposure to CX are thus essential to study its skin toxicity and for the development of effective treatments. Thus, the ultimate goal of this proposal is to develop a relevant cutaneous CX exposure mouse injury model to elucidate mechanisms of skin damage by CX and examine its systemic toxic effects with the objective of identifying novel targets for therapeutic intervention and drug development. Our preliminary data show that cutaneous CX vapor exposure (4 min) on to the SKH-1 hairless mouse skin causes edema, erythema, blanching, urticaria and necrosis within 30 min with sustained effects till 8 h post- exposure. The rapid onset of these clinical lesions from cutaneous CX exposure were associated with: a) an increase in apoptotic cell death and p53 phosphorylation indicating a DNA damaging response, b) an inflammatory response associated with i) mast cell degranulation and increase in pro-inflammatory cytokine tumor necrosis factor-? and cyclooxygenase-2, and ii) neutrophil infiltration and an increase myeloperoxidase levels. These results suggest that CX possesses alkylating and nucleophilic properties resembling mustard vesicants that can cause DNA damage and an inflammatory response. The skin urticaria from CX resembles urticaria from frequently caused allergic and non-allergic reactions involving an inflammatorily response mainly via histamine release from mast cells. Additionally, the CX-exposure effects were accompanied with dilatation of peripheral vessels with a robust surge in RBCs in vessels of all the major internal organs, which could cause sudden blood pressure fall, hypoxia and death. Based on these findings, our hypothesis is that CX activates inflammatory and p53-DNA damaging pathways that are potential major contributors of CX-induced skin toxic lesions, and that it causes vasculature dilation and blood congestion in multiple organs resulting in systemic toxicity and mortality.
Specific aims proposed to test this hypothesis are: 1) Characterize and establish CX- induced in vivo rodent skin injury model following its cutaneous exposure, and identify associated mechanism/s of action; and 2) examine systemic toxic effects and related mortality from CX cutaneous exposure. We anticipate that our studies would establish skin and systemic injury biomarkers of acute CX exposure that can be employed for screening therapies for the rescue of skin injuries and mortality by CX.
Phosgene oxime (dichloroform oxime, CX; Cl2CNOH), classified as a vesicating agent, is a potent urticant chemical weapon which was first synthesized in 1929 and stored during World War II. Compared to other vesicants, CX causes bewilderingly rapid effects on the skin, eye and mucus membranes including instant pain and prompt penetration. Even though it is considered the most harmful vesicant with real military and terrorist threat potential that can be used for rapid incapacitation and death, very little is known regarding the toxic effects of CX following its cutaneous exposure and its mechanism of action is unknown. Studies are proposed in this application to address that CX activates inflammatory and p53-DNA damaging pathways that are potential major contributors of CX-induced skin toxic lesions, and that it causes vasculature dilation and blood congestion in multiple organs resulting in systemic toxicity and mortality. Completion of our studies would potentially have a profound impact on understanding the molecular mechanism of CX cutaneous toxicity with significant translational implications towards designing therapeutic intervention strategies.
|Goswami, Dinesh Giri; Agarwal, Rajesh; Tewari-Singh, Neera (2018) Phosgene oxime: Injury and associated mechanisms compared to vesicating agents sulfur mustard and lewisite. Toxicol Lett 293:112-119|