title: Sulfur mustard analog, 2-chloroethyl ethyl sulfide-induced skin injury involves DNA damage and induction of inflammatory mediators, in part via oxidative stress, in SKH-1 hairless mouse skin.
abstract: Bifunctional alkyalating agent, sulfur mustard (SM)-induced cutaneous injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-1 hairless mouse skin. To further establish a link between CEES-induced DNA damage and signaling pathways and inflammatory responses, skin samples from mice exposed to 2 mg or 4 mg CEES for 9-48 h were subjected to molecular analysis. Our results show a strong CEES-induced phosphorylation of H2A.X and an increase in cyclooxygenase-2 (COX-2), inducible NOS (iNOS), and matrix metalloproteinase-9 (MMP-9) levels, indicating the involvement of DNA damage and inflammation in CEES-induced skin injury in male and female mice. Since, our recent studies showed reduction in CEES-induced inflammatory responses by glutathione (GSH), we further assessed the role of oxidative stress in CEES-related DNA damage and the induction of inflammatory molecules. Oral GSH (300 mg/kg) administration 1h before CEES exposure attenuated the increase in both CEES-induced H2A.X phosphorylation (59%) as well as expression of COX-2 (68%), iNOS (53%) and MMP-9 (54%). Collectively, our results indicate that CEES-induced skin injury involves DNA damage and an induction of inflammatory mediators, at least in part via oxidative stress. This study could help in identifying countermeasures that alone or in combination, can target the unveiled pathways for reducing skin injury in humans by SM.
authors: Department of Pharmaceutical Sciences, University of Colorado Denver School of Pharmacy, Aurora, CO 80045, USA. Anil.Jain@ucdenver.edu
authors: Anil K
authors: AK
authors: Jain
authors: Neera
authors: N
authors: Tewari-Singh
authors: Mallikarjuna
authors: M
authors: Gu
authors: Swetha
authors: S
authors: Inturi
authors: Carl W
authors: CW
authors: White
authors: Rajesh
authors: R
authors: Agarwal
mesh_terms: D000477:Alkylating Agents / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D000931:Antidotes / Q000378:metabolism / Q000627:therapeutic use; D001768:Blister / Q000139:chemically induced; D002619:Chemical Warfare Agents / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004249:DNA Damage; D003877:Dermatitis, Contact / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D005978:Glutathione / Q000378:metabolism / Q000627:therapeutic use; D006657:Histones / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000477:Alkylating Agents; D000931:Antidotes; D002619:Chemical Warfare Agents; D051546:Cyclooxygenase 2; D005978:Glutathione; D006657:Histones; D018836:Inflammation Mediators; D020780:Matrix Metalloproteinase 9; D009151:Mustard Gas; D052247:Nitric Oxide Synthase Type II; C031278:2-chloroethyl ethyl sulfide; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; C501830:Mmp9 protein, mouse; C475961:gamma-H2AX protein, mouse