title: Cutaneous exposure to vesicant phosgene oxime: Acute effects on the skin and systemic toxicity.
abstract: Phosgene Oxime (CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical warfare and terrorist weapon. Its exposure can result in widespread and devastating effects including high mortality due to its fast penetration and ability to cause immediate severe cutaneous injury. It is one of the least studied chemical warfare agents with no effective therapy available. Thus, our goal was to examine the acute effects of CX following its cutaneous exposure in SKH-1 hairless mice to help establish a relevant injury model. Results from our study show that topical cutaneous exposure to CX vapor causes blanching of exposed skin with an erythematous ring, necrosis, edema, mild urticaria and erythema within minutes after exposure out to 8h post-exposure. These clinical skin manifestations were accompanied with increases in skin thickness, apoptotic cell death, mast cell degranulation, myeloperoxidase activity indicating neutrophil infiltration, p53 phosphorylation and accumulation, and an increase in COX-2 and TNFα levels. Topical CX-exposure also resulted in the dilatation of the peripheral vessels with a robust increase in RBCs in vessels of the liver, spleen, kidney, lungs and heart tissues. These events could cause a drop in blood pressure leading to shock, hypoxia and death. Together, this is the first report on effects of CX cutaneous exposure, which could help design further comprehensive studies evaluating the acute and chronic skin injuries from CX topical exposure and elucidate the related mechanism of action to aid in the identification of therapeutic targets and mitigation of injury.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: Neera.tewari-singh@ucdenver.edu.
authors.forename: Neera
authors.initials: N
authors.lastname: Tewari-Singh
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Dinesh G
authors.initials: DG
authors.lastname: Goswami
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Kant
authors.affiliation: MRIGlobal, Kansas City, MO 64110, USA.
authors.forename: Claire R
authors.initials: CR
authors.lastname: Croutch
authors.affiliation: MRIGlobal, Kansas City, MO 64110, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Casillas
authors.affiliation: Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004890:Erythema / Q000139:chemically induced / Q000473:pathology; D007509:Irritants / Q000633:toxicity*; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D010091:Oximes / Q000633:toxicity*; D010705:Phosgene / Q000633:toxicity*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced* / Q000473:pathology*
chemical_list: D007509:Irritants; D010091:Oximes; D010705:Phosgene; C038629:dichloroformoxine
keywords: Mast cells; Nettle agent; Phosgene oxime; SKH-1 hairless mouse; Skin injury; Systemic toxicity