Peripheral Blood Signatures of Lead Exposure 英文参考文献.docVIP

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Peripheral Blood Signatures of Lead Exposure 英文参考文献.doc

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Peripheral Blood Signatures of Lead Exposure 英文参考文献

PeripheralBloodSignaturesofLeadExposure HeatherG.LaBreche1,2,3*,SarahK.Meadows4,JosephR.Nevins1,2,JohnP.Chute1,4,5 1Duke Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America, 2Department of Molecular Genetics and Microbiology,DukeUniversity,Durham,NorthCarolina,UnitedStatesofAmerica,3PrograminGeneticsandGenomics,DukeUniversity,Durham,NorthCarolina,United States of America, 4Division of Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina, United States of America, 5Department of PharmacologyandCancerBiology,DukeUniversity,Durham,NorthCarolina,UnitedStatesofAmerica Abstract Background:Currentevidenceindicatesthatevenlow-levellead(Pb)exposurecanhavedetrimentaleffects,especiallyin children.WetestedthehypothesisthatPbexposurealtersgeneexpressionpatternsinperipheralbloodcellsandthatthese changesreflectdose-specificalterationsintheactivityofparticularpathways. Methodology/PrincipalFinding:UsingAffymetrixMouseGenome4302.0arrays,weexaminedgeneexpressionchangesin theperipheralbloodoffemaleBalb/cmicefollowingexposuretoperosleadacetatetrihydrateorplaindrinkingwaterfor two weeks and after a two-week recovery period. Data sets were RMA-normalized and dose-specific signatures were generated using established methods of supervised classification and binary regression. Pathway activity was analyzed usingtheScoreSignaturesmodulefromGenePattern. Conclusions/Significance:Thelow-levelPbsignaturewas93%sensitiveand100%specificinclassifyingsamplesaleave- one-out crossvalidation. The high-level Pb signature demonstrated 100% sensitivity and specificity in the leave-one-out crossvalidation.Thesetwosignaturesexhibiteddose-specificityintheirabilitytopredictPbexposureandhadlittleoverlap intermsofconstituentgenes.ThesignaturesalsoseemedtoreflectcurrentlevelsofPbexposureratherthanpastexposure. Finally,thetwodosesshoweddifferentialactivationofcellularpathways.Low-levelPbexposureincreasedactivityofthe interferon-