Persistent DNA Damage after High Dose In Vivo Gamma Exposure of Minipig Skin 英文参考文献.docVIP

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Persistent DNA Damage after High Dose In Vivo Gamma Exposure of Minipig Skin 英文参考文献.doc

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Persistent DNA Damage after High Dose In Vivo Gamma Exposure of Minipig Skin 英文参考文献

PersistentDNADamageafterHighDoseInVivoGamma ExposureofMinipigSkin EmadA.Ahmed1,DianeAgay2,GerritSchrock1,MichelDrouet2,ViktorMeineke1,HarryScherthan1* 1Institutfu¨rRadiobiologiederBundeswehrinVerbindungmitderUniversita¨t Ulm,Mu¨nchen,Germany,2IRBA-antenneLaTronche-CRSSA,LaTronche,France Abstract Background:Exposuretohighdosesofionizingradiation(IR)canleadtolocalizedradiationinjuryoftheskinandexposed cellssufferdsDNAbreaksthatmayelicitcelldeathorstochasticchanges.LittleisknownabouttheDNAdamageresponse after high-dose exposure of the skin. Here, we investigate the cellular and DNA damage response in acutely irradiated minipigskin. Methods and Findings: IR-induced DNA damage, repair and cellular survival were studied in 15cm2 of minipig skin exposedinvivoto,50Co-60crays.Skinbiopsiesofcontroland4hupto96dayspostexposurewereinvestigatedfor radiation-inducedfoci(RIF)formationusingc-H2AX,53BP1,andactiveATM-pimmunofluorescence.High-doseIRinduced massivec-H2AXphosphorylationandhigh53BP1RIFnumbers4h,20hafterIR.AstimeprogressedRIFnumbersdropped to a low of ,1% of keratinocytes at 28–70 days. The latter contained large RIFs that included ATM-p, indicating the accumulationofcomplexDNAdamage.At96daysmostofthecellswithRIFshaddisappeared.Thefrequencyofactive- caspase-3-positiveapoptoticcellswas17-foldincreased3daysafterIRandremained.3-foldelevatedatallsubsequent timepoints.Replicatingbasalcells(Ki67+)werereduced3dayspostIRfollowedbyincreasedproliferationandrecoveryof epidermalcellularityafter28days. Conclusions: Acute high dose irradiation of minipig epidermis impaired stem cell replication and induced elevated apoptosisfrom3daysonward.DNArepairclearedthehighnumbersofDBSsinskincells,whileRIFsthatpersistedin,1% cells marked complex and potentially lethal DNA damage up toseveral weeks after exposure. An elevated frequency of keratinocyteswithpersistentRIFsmaythusserveasindicatorofpreviousacuteradiationexposure,whichmaybeusefulin thefollowupofnuclearorradiologicalaccidentscenari