title: DNA damage in internal organs after cutaneous exposure to sulphur mustard.
abstract: Sulphur mustard (SM) is a chemical warfare agent that attacks mainly skin, eye and lungs. Due to its lipophilic properties, SM is also able to diffuse through the skin and reach internal organs. DNA represents one of the most critical molecular targets of this powerful alkylating agent which modifies DNA structure by forming monoadducts and biadducts. These DNA lesions are involved in the acute toxicity of SM as well as its long-term carcinogenicity. In the present work we studied the formation and persistence of guanine and adenine monoadducts and guanine biadducts in the DNA of brain, lungs, kidneys, spleen, and liver of SKH-1 mice cutaneously exposed to 2, 6 and 60mg/kg of SM. SM-DNA adducts were detected in all studied organs, except in liver at the two lowest doses. Brain and lungs were the organs with the highest level of SM-DNA adducts, followed by kidney, spleen and liver. Monitoring the level of adducts for three weeks after cutaneous exposure showed that the lifetime of adducts were not the same in all organs, lungs being the organ with the longest persistence. Diffusion from skin to internal organs was much more efficient at the highest compared to the lowest dose investigated as the result of the loss of the skin barrier function. These data provide novel information on the distribution of SM in tissues following cutaneous exposures and indicate that brain is an important target.
authors.affiliation: Laboratoire « Lésions des Acides Nucléiques », Université Joseph Fourier - Grenoble 1/CEA/Institut Nanoscience et Cryogénie/SCIB, UMR-E3, Grenoble, France; Département de Toxicologie et Risques Chimiques; Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Batal
authors.affiliation: Département de Toxicologie et Risques Chimiques; Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boudry
authors.affiliation: Département de Toxicologie et Risques Chimiques; Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mouret
authors.affiliation: Département de Toxicologie et Risques Chimiques; Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Cléry-Barraud
authors.affiliation: Département de Toxicologie et Risques Chimiques; Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Wartelle
authors.affiliation: Laboratoire « Lésions des Acides Nucléiques », Université Joseph Fourier - Grenoble 1/CEA/Institut Nanoscience et Cryogénie/SCIB, UMR-E3, Grenoble, France.
authors.forename: Izabel
authors.initials: I
authors.lastname: Bérard
authors.affiliation: Laboratoire « Lésions des Acides Nucléiques », Université Joseph Fourier - Grenoble 1/CEA/Institut Nanoscience et Cryogénie/SCIB, UMR-E3, Grenoble, France. Electronic address: thierry.douki@cea.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Douki
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001822:Body Burden; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002619:Chemical Warfare Agents / Q000378:metabolism / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D012869:Skin Absorption; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D002619:Chemical Warfare Agents; D018736:DNA Adducts; D009151:Mustard Gas
keywords: Brain; DNA damage; DNA repair; Lungs; Mass spectrometry; Sulphur mustard