title: Impact of topical application of sulfur mustard on mice skin and distant organs DNA repair enzyme signature.
abstract: Sulfur mustard (SM) is a chemical warfare agent that, upon topical application, damages skin and reaches internal organs through diffusion in blood. Two major toxic consequences of SM exposure are inflammation, associated with oxidative stress, and the formation of alkylated DNA bases. In the present study, we investigated the impact of exposure to SM on DNA repair, using two different functional DNA repair assays which provide information on several Base Excision Repair (BER) and Excision/Synthesis Repair (ESR) activities. BER activities were reduced in all organs as early as 4h after exposure, with the exception of the defense systems against 8-oxo-guanine and hypoxanthine which were stimulated. Interestingly, the resulting BER intermediates could activate inflammation signals, aggravating the inflammation triggered by SM exposure and leading to increased oxidative stress. ESR activities were found to be mostly inhibited in skin, brain and kidneys. In contrast, in the lung there was a general increase in ESR activities. In summary, exposure to SM leads to a significant decrease in DNA repair in most organs, concomitant with the formation of DNA damage. These synergistic genotoxic effects are likely to participate in the high toxicity of this alkylating agent. Lungs, possibly better equipped with repair enzymes to handle exogenous exposure, are the exception.
authors.affiliation: LXRepair, Grenoble, France. Electronic address: sylvie.sauvaigo@lxrepair.com.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Sauvaigo
authors.affiliation: LXRepair, Grenoble, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Sarrazy
authors.affiliation: University Grenoble Alpes, INAC, LCIB, LAN, F-38000 Grenoble, France; CEA, INAC, SCIB, LAN, F-38000 Grenoble, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Batal
authors.affiliation: University Grenoble Alpes, INAC, LCIB, LAN, F-38000 Grenoble, France; CEA, INAC, SCIB, LAN, F-38000 Grenoble, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Caillat
authors.affiliation: LXRepair, Grenoble, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Pitiot
authors.affiliation: Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mouret
authors.affiliation: Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Cléry-Barraud
authors.affiliation: Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boudry
authors.affiliation: University Grenoble Alpes, INAC, LCIB, LAN, F-38000 Grenoble, France; CEA, INAC, SCIB, LAN, F-38000 Grenoble, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Douki
mesh_terms: D000287:Administration, Topical; D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004260:DNA Repair / Q000187:drug effects*; D003875:Drug Eruptions / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D019271:Hypoxanthine / Q000494:pharmacology; D008297:Male; D051379:Mice; D009151:Mustard Gas / Q000008:administration & dosage* / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000477:Alkylating Agents; D015415:Biomarkers; D002619:Chemical Warfare Agents; D009153:Mutagens; D019271:Hypoxanthine; C024829:8-hydroxyguanine; D006147:Guanine; D009151:Mustard Gas
keywords: DNA adducts; DNA repair; Exposure biomarker; Inflammation; Oxidative stress; Sulfur mustard