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REVIEWOpenAccessOxidativestress-inducedtelomericerosionasamechanismunderlyingairborneparticulatematter-relatedcardiovasculardiseaseThomasJGrahame1*andRichardBSchlesinger2AbstractParticulatematter(PM)pollutionisresponsibleforhundredsofthousandsofdeathsworldwide,themajorityduetocardiovasculardisease(CVD).
Whilemanypotentialpathophysiologicalmechanismshavebeenproposed,thereisnotyetaconsensusastowhicharemostimportantincausingpollution-relatedmorbidity/mortality.
NoristhereconsensusregardingwhichspecifictypesofPMaremostlikelytoaffectpublichealthinthisregard.
OnetoxicologicalmechanismlinkingexposuretoairbornePMwithCVDoutcomesisoxidativestress,acontributortothedevelopmentofCVDriskfactorsincludingatherosclerosis.
Recentworksuggeststhatacceleratedshorteningoftelomeresand,thus,earlysenescenceofcellsmaybeanimportantpathwaybywhichoxidativestressmayacceleratebiologicalagingandtheresultantdevelopmentofage-relatedmorbidity.
ThispathwaymayexplainasignificantproportionofPM-relatedadversehealthoutcomes,sinceshortenedtelomeresacceleratetheprogressionofmanydiseases.
Thereislimitedbutconsistentevidencethatvehicularemissionsproduceoxidativestressinhumans.
Giventhatoxidativestressisassociatedwithacceleratederosionoftelomeres,andthatshortenedtelomeresarelinkedwithaccelerationofbiologicalageingandgreaterincidenceofvariousage-relatedpathology,includingCVD,itishypothesizedthatassociationsnotedbetweencertainpollutiontypesandsourcesandoxidativestressmayreflectamechanismbywhichthesepollutantsresultinCVD-relatedmorbidityandmortality,namelyacceleratedagingviaenhancederosionoftelomeres.
Thispaperreviewstheliteratureprovidinglinksamongoxidativestress,acceleratederosionoftelomeres,CVD,andspecificsourcesandtypesofairpollutants.
IfcertainPMspecies/sourcesmightberesponsibleforadversehealthoutcomesviatheproposedmechanism,perhapsthepathwaytoreducingmortality/morbidityfromPMwouldbecomeclearer.
Notonlywouldpollutionreductionimperativesbemorefocused,butinterventionswhichcouldreduceoxidativestresswouldbecomeallthemoreimportant.
Keywords:Telomere,Oxidativestress,Particulatematter,Cardiovasculardisease,Blackcarbon,VehicularemissionsIntroductionEpidemiologicalstudieshavefoundassociationsbetweenexposuretoairborneparticulatematter(PM)andad-verseeffectsonthecardiovascularsystem,aswellasincreasedincidenceorprevalenceofcardiovasculardis-ease(CVD)-relatedmorbidityandmortality[1,2].
How-ever,thepathophysiologyunderlyingthisrelationshiphasnotbeenclearlydefined.
OnemechanismunderlyingPM-relatedCVDisoxidativestress.
Thisoccurswhenthehomeostaticbalanceofoxidizingagentstoanti-oxidantsisupsettowardsanimbalanceoftheformer.
Theprimaryoxidizingagentsinthisregardarereactiveoxygenspecies(ROS),suchashydroxylradicalandsuperoxideanion.
Whilethesearenormalproductsofaerobicmetabolism,underconditionswherebyROSpro-ductionincreasesbeyondtheabilitytodetoxifythesechemicals,moleculardamagemayresultsinceROSreadilyreactswithproteins,lipidsandnucleicacids.
AnAmericanHeartAssociationScientificStatementonParticulateMatterhasproposedaroleforoxidativestressinalteringcardiacfunction[2].
Areviewofthere-lationshipbetweenoxidativestressandairpollutants*Correspondence:thomas.
grahame@hq.
doe.
gov1UnitedStatesDepartmentofEnergy,1000IndependenceAvenue,SWWashington,DC20585,USAFulllistofauthorinformationisavailableattheendofthearticle2012GrahameandSchlesinger;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
GrahameandSchlesingerParticleandFibreToxicology2012,9:21http://www.
particleandfibretoxicology.
com/content/9/1/21discussedtheroleoffinePM,andcertainmorebiologic-allyactivecomponentsthereof,incausingbothprimaryoxidizingeffectsinlungliningfluidandasecondarywaveofoxidativestressviainfluxofinflammatorycells[3].
ArecentreportfromtheHealthEffectsInstitutehypothesizedthatoxidativestressmightindeedbetheunderlyingmechanismofactionbywhichexposuretopollutantsspecificallyfromtrafficmayleadtoadversehealthoutcomes[4].
Furthermore,areviewofinvitro,invivoandepidemiologicalstudiesexaminingvehicular-derivedPMemissionsandtheirassociationwithcardio-vascularmorbidityandmortalityconcludedthatoneofthemajortoxicologicalmechanismslikelylinkedtoCVDisoxidativestress[5].
Finally,thereisincreasingevidencethatsomespecificcomponentsofairbornePMthatmaycontributelittletototalPM2.
5massmaybere-sponsibleforinducingoxidativestress[6].
Advancedageisaknownriskfactorforanumberofchronicdiseasesandfunctionalimpairment,includingthoseinvolvingthecardiovascularsystem.
However,asopposedsolelytochronologicalage,"biological"age,whichisdeterminedbothbyphysiologyaswellaschronology,appearstobeakeyfactorrelatedtodevel-opmentofultimatepathologyandthis,inturn,hasbeenrelatedtoacumulativeburdenofoxidativestress[7].
Thereisalsoincreasingevidencethatbiologicalagingisrelatedtoshorteningofchromosomaltelomeres.
Telomeresarestructuresconsistingofnoncodingnu-cleotidesequences(telomericDNA),associatedwithcer-tainproteins,foundatbothendsofchromosomalDNAmolecules.
TheyhelpprotectagainsterosionofcodingDNA,whichwouldleadtosubsequentlossofgeneticin-formationonthechromosomesduringrepetitivereplica-tioncycles.
SeveralproteinsassociatedwithtelomericDNA,in-cludingtelomerase,areversetranscriptaseenzyme,andthetelomericrepeatbindingfactors1and2(TRF1,TRF2),helpregulatetelomerelengthandstructure.
Tel-omeraseisinvolvedinthereplicationoftelomericDNAstrands,soastopreservetheirlengthwhenchromo-somalDNAisreplicated.
However,inmostmammaliansomaticcells,asopposedtogermandstemcelllines,ac-tivityoftelomeraseisverylow,orevenabsent[8,9],resultinginincompletereplicationofthetelomereandthelossofacertainnumberoftelomericDNAbasepairsduringeachdivisioncyclewithsubsequentshort-eningofthetelomereitself.
Becauseprogressiveshorten-ingoftelomeresisacrucialfactorinthenormalprocessoforganismalaging,telomericlengthcanserveasamarkerofacell'sbiologicalage,incontrasttoactualchronologicalage[10,11].
Thenaturalerosionoftelomericlengthiscumulative.
Eventually,withrepetitivecelldivisions,thetelomerereachesacriticallength,andfurthercelldivisioncannolongerproceed.
Thecellthenbecomessenescent,andeventuallyundergoesapoptosis.
Senescentcellshavebeenreportedtoaccumulateintissuesandorgans,withpotentialtointerferewithnormaltissuefunctionandstructure.
Senescencehasalsobeencausallyrelatedtothegenerationofage-relatedphenotypes,sinceremovalofsenescentcellsseemstopreventordelaytissuedys-function[12].
Itisofinteresttonotethatsignificanttelomeraseac-tivityhasbeenfoundinapproximately90%ofhumancancers,regardlessofcelltype[13,14],incontrasttonormalsomaticcellsaspreviouslynoted.
Theabnor-mallyincreasedlevelsoftelomeraseallowthesecellstocontinuetodivideratherthanbecomesenescentwithrepeatedDNAreplicationcycles[9].
However,whentel-omeraseactivityinthesecellswasinhibited,telomeresbecameshorterwitheachdivision,andeventuallycellgrowthceased.
Therateoftelomericerosionovertimeisdeterminedpartiallybygeneticfactorsandpartiallybyenvironmen-talfactors,andtheirinteractionlikelymodulatesbio-logicalaging,affectingtheriskofdevelopingage-relateddiseases[15].
Aroleforbiologicalage"advancement"inheartfailureandthepathogenesisofmyocardialinfarc-tion(MI)hasbeensuggested[16],andshortenedtelo-meresappeartoberesponsibleforacceleratingseveralimportantCVDdiseasestatesandriskfactors,includinghypertensionandatherosclerosis[17].
Thispaperreviewstherelationshipbetweentelomericlength,CVD,andoxidativestress,anddiscussesaroleforspecificPMairpollutantsandpollutantsourcesininducingoxidativestress.
Basedupontheavailableevi-dence,weproposethatapotentialmechanismunder-lyingatleastsomePMexposureassociationwithCVDinvolvesanacceleratedrateofcelltelomereerosionduetooxidativestress,resultinginanaccelerationoftherateofbiologicalaging.
ThismaybeanimportantandgeneralizedmechanismunderlyingPM-relatedincreasesinCVDmorbidityandmortality.
LinkingoxidativestressandtelomerelengthTheabilityofoxidativestresstodamageDNAprovidesapotentialmechanismbywhichitcouldinterferewithreplicationoftelomericDNA,acceleratingtherateoftelomericerosion.
Astudyexaminingtheeffectoncir-culatingleukocytetelomericlengthinpeopleinrelationtostatusoftheUCP2gene,whichisinvolvedintheregulationofmitochondrialROSproduction,foundthatthepresenceofafunctionalpromoterUCP2variantthatresultedinincreasedoxidativestressviadownregulationofgeneexpressionwasassociatedwithshortertelomericlengththanwhenthevariantwasabsent,suggestingadirectlinkbetweenROSandacceleratedtelomericero-sion[18].
TelomereDNAisverypronetosuchoxidativeGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page2of19http://www.
particleandfibretoxicology.
com/content/9/1/21damagesinceitisespeciallyrichinguanine;accumula-tionofthisdamagealongthetelomereduringthelife-spanofacellcanthenresultinenhancedtelomerelossduringeachreplicationcycle,thuscontributingtoaccel-eratedcellsenescence[19,20].
ReactiveoxygenspeciescandamageDNAeitherdir-ectlyorduringattemptedrepairofoxidation-inducedbasemodifications[20].
Inaddition,asalreadynoted,telomericDNAisinefficientinrepairofsinglestrandbreaksorotherinducedlesions,incontrasttomostgen-omicDNA,inthatrepairiseitherslowerormoreincom-plete[21].
Thisinefficiencymaybefurtherenhancedbyoxidativedamagetoanytelomerasewhichmaybepresentinthecell.
Forexample,increasedlevelsofintra-cellularROShavebeenshowntoresultinareductionoftelomeraseactivity,whichcanbepreventedbythepres-enceofROSscavengerswhichalsodelaytheonsetofcel-lularsenescence[22].
Thus,duetothesensitivityofbothtelomeraseandtelomericDNAtooxidative-induceddamageandthenormalinsufficiencyofrepairmechan-isms,telomeresareespeciallysensitivetocumulativeoxi-dativedamage[23].
Therefore,oxidativestressisalikelyenvironmentalfactoracceleratingtelomericerosionateachreplicationcycle,withresultantacceleratedcellularbiologicalaging[24].
Theextentoftelomericerosionhasbeenrelatedtothelevelofoxidativestress.
RichterandvanZglinicki[25]examinedtherateoftelomericshorteningunderconditionsofoxidativestressinducedbyvaryinglevelsofoxygeninculturesoffibroblastsobtainedfromhumanadultskin,foreskin,embryoniclungandsheepembryos.
Theinvestigatorsreportedacorrelationbe-tweenROSlevelsandtherateoftelomericshortening,whichwasindependentoftheindividualhumandonororspecificanimalspecies.
TheyfurthersuggestedthatagivenlevelofintracellularROSwouldleadtoapredict-ableaccelerationoftherateofshorteningoftelomeresoverthenorm,regardlessofanyotherdifferencebe-tweendonorsintermsofindividualgeneticswithinonespecies,orbetweenspecies.
Furthermore,highlevelsofintracellularROSandaccumulateddamagetoDNAandproteinhavebeenassociatedwiththedevelopmentofsenescentsomaticcells,comparedwithmuchlessoxida-tivedamagenotedinmore"immortal"celltypesthatcancontinuetodivideforlongerperiodsoftime[26,27].
Ifoxidativestressplaysaroleintelomericerosion,thenthepresenceofantioxidantsshouldresultinsomemodulationofthiseffect.
Overexpressionofextracellularsuperoxidedismutaseresultedinadecreaseinboththeperoxidecontentofhumanfibroblasts,andtherateoftelomericshortening[28].
Anassociationbetweenoxi-dativestressandincreasedrateoftelomericshortening,likelyduetodirectROS-induceddamagetotelomericDNA,andthepreventativeroleofantioxidantsindeceleratingthisrate,hasbeenshowninanumberofotherinvitrostudiesaswell[19,21,29,30].
Theroleofoxidativestressasanenvironmentalfactormodulatingtelomericlengthhasalsobeensuggestedbyepidemiologicalstudies.
Mostoftheseinvolvedassess-mentofCVD,andarediscussedinsubsequentsections.
Accelerationoftheappearanceofage-relatedpathologyissupportedbyastudythatfoundleukocytetelomerelengthassociatedwithage-relateddiseaseburdensacrossmultiplephysiologicalsystems,andthatwasindepend-entofitsassociationwithactualchronologicalage[31].
Thisprovideddirectevidencethatmechanismswhichshortentelomerelength,suchasoxidativestress,willlikelycauseprogressionofavarietyofdiseases,includ-ingCVD.
LinkingCVDandtelomerelengthAnumberofepidemiologicalstudiesinvolvingdiversepopulationshaveconsistentlyshowanassociationbe-tweenshortertelomericlengthincellsobtainedfrompatientswithCVDcomparedtohealthypeople.
OnesuchstudyexaminedtherelationshipbetweentelomericlengthincirculatingleukocytesandvariousindicesorriskfactorsforclinicalCVDinagroupof419adultsagedover65yrs(meanage74.
2yr)[32].
Itnotedasta-tisticallysignificanttoborderlinesignificantinverserela-tionshipbetweentelomerelengthandC-reactiveprotein,IL-6,carotidarteryintimamediathickness,andanklebrachialindex,butonlyinthoseaged73yrsoryounger.
Itappearsthattheeffectofshortertelomerelengthondiseaseoutcomeattenuatesaboveacertainchronologicalage.
Inanotherstudy,leukocytemeantelomerelengthwasexaminedinagroupofpeoplehav-ingmeanageof78yr,andtheninsurvivingmembersofthisgroupsevenyearslaterandhavingmeanageof83yr[33];shorterlengthwaspredictiveofCVD-relatedmortalityonlyformenunder80yrsofage.
Ontheotherhand,somestudieshavefoundnoassociationbetweentelomerelengthandcarotidarterymediathickness[34,35].
Thereasonsfortheapparentinconsistencyareunclear,butmaybeafunctionofthespecificpopula-tionsexaminedinthisregard.
Anotherstudycomparedleukocytetelomerelengthinapopulationof484men(age45-65yr)whosubse-quentlydevelopedcoronaryheartdiseasewiththatfrom1058matchedcontrolswhodidnothaveanyCVDevents[36].
Thoseinthemidandlowesttertilesoftelo-mericlengthatthetimeofrecruitmentintothestudyhadapproximatelyatwofoldgreaterriskofdevelopingsomeformofcoronaryheartdiseaseoverthenext4.
9yrthandidthoseinthehighesttertile.
Thisstudy,similartothestudynotedabove[33],stronglysuggestedthatmeanleukocytetelomerelengthwasapredictoroffu-tureCVD,andthattherelationshipbetweentelomericGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page3of19http://www.
particleandfibretoxicology.
com/content/9/1/21lengthandCVDwasnotaconsequenceofthediseasebut,rather,afactorinitsdevelopment.
Similarly,astudyof143peopleovertheageof60yrsfoundthatthepresenceofshorterthanpopulationaver-agetelomerelengthwasassociatedwithagreaterthanthreefoldincreaseincardiacmortalityoverapproxi-matelythefollowing9years[37].
Anassociationofreducedtelomerelengthwithincreasedriskofmyocar-dialinfarction(MI)andothercardiacdiseases,andwithgreatermortalityrate,hasalsobeenfound[38];theriskofMI,consideredasprematureMI,inpeopleunderage50washigherforthosewithshortertelomerelengthscomparedtothosewithlengthsinthehighestquartile.
Attritionoftelomerelengthhasalsobeennotedinpeopleshowingage-relatedcardiomyopathy[39].
Telo-mereshorteninghasalsobeenlinkedtoCVDviaim-pairmentofcardiacstemcell-mediatedmyocardialregeneration,andmayalsocontributetoCVDbyindu-cingmyocardialcellapoptosisapartfromanyeffectonstemcells[40,41].
ApotentialfamilialpredispositiontoCVD,perhapsrelatedtotelomericlength,wasdescribedbyWongetal.
[42].
Theymeasuredleukocytetelomericlengthinpatientshavingischemicheartfailureandintheirhighriskchildren,andnotedthatlengthwasshorterincellsfrompatientsandtheirchildrencomparedtohealthycontrolsandtheirchildren.
Astudyusingbiopsymater-ial[39]foundthatmyocytesfromheartsofdiseasedeld-erlypeopleshoweda39%reductioninaveragetelomericlength,andahigherdegreeofnecrosisandapoptosis,thandidcomparablecellsfromhealthycontrols.
An-otherstudy[41]notedthattelomericlengthinleuko-cytesofpeoplewithdilated,failinghearts,comparedwiththosefromaged-matchedhealthycontrols,hadlengthsthatwere25%shorter,decreasedexpressionofTRF-2,andmarkedactivationofakinaseinvolvedinDNArepair.
Moststudiesoftelomerelengthinvivousedcirculat-ingleukocytesastheyareeasytoobtain.
Kuznetsovaetal.
[43]addressedtheissueofwhethertelomericlengthincirculatingleukocyteswasrepresentativeofthatinthecardiacmyocytesthemselves.
Itappearsthattherateoftelomericshorteningisindeedsimilarindif-ferenttissuesofanyindividualand,therefore,easilyac-cessiblecellssuchascirculatingleukocytescanindeedserveassurrogatesfortelomerelengthassessmentinthosecellsinvolvedinspecificdiseaseprocesses,suchasvesselendotheliumorcardiacmyocytes[20,44,45].
Sinceshorteningoftelomericlengthisassociatedwithcellsenescenceandbiologicalage,andwithdiseasesnormallyassociatedwithincreasingchronologicalage,oneofthewaysinwhichdifferencesintelomericlengthinpeoplewithorwithoutCVDmaybeexpressedisbythenumberofyearsofchronologicalagetowhichthisdifferenceinlengthcanbeequated[7].
Inmostsubjectsundertheageof70yrs,thereseemstobeaconsistentchronologicaltobiologicalagedifferenceequivalentofbetween8and12yrs[36,38].
Inotherwords,thosepeoplewhowillgoontodeveloporalreadyhaveCVDshowtelomereswithaveragelengthsequivalenttohealthypeoplewhoarechronologically8to12yrsolder.
SpecificriskfactorsforCVDorspecificCVD-relatedconditionshavealsobeenexaminedinrelationtotelo-merelength.
Telomerelengthinleukocyteswasfoundtoberelatedtoalteredleftventricularmass,adetermin-antofcardiacfunction,bothlongitudinallyandcross-sectionally,inastudyinvolving334peoplewithmeanageof46.
5yr[43].
Shortermeantelomerelengthinleu-kocyteshasalsobeenreportedtobeassociatedwithadecreasedleftventricularejectionfractionintheelderlywhohadnopriorevidenceofcardiacdisease[46].
Chronicheartfailure,aconditioninwhichthehearthaslosttheabilitytopumpenoughbloodtothebody'stis-sues,isoftentheresultofvalvularheartdisease,suchasaorticvalvestenosis,thatresultsinventricularhyper-trophyandresultingcompromisedcardiacfunction.
Decreasedleukocytetelomerelengthhasbeenfoundtobeassociatedwithdegenerativeaorticstenosis[47].
Increasedcardiomyocyteapoptosisisacharacteristicofchronicheartfailure[41,48].
Telomeraseknockoutmice,inwhichtelomeresshowincreasedrateofshortening,haveattenuatedmyocytedivision,increasedrateofapop-tosis,andcardiomyocytehypertrophy,allleadingtocar-diacremodelingthatmimicshumanendstagedilatedcardiomyopathy[49].
ThissuggeststhattelomeresmayplayaprimaryroleinCVDthroughtheirimpactoncel-lularsenescence,andthatshortertelomerelengthasso-ciatedwithCVDmaynotbemerelyareflectionofthegreaterextentofvascularcellturnoverthatoccursintheseconditions[7].
Ontheotherhand,theincreasedcellturnovernotedcouldresultinevenfurtherenhancedtelomereattritionthanwouldoccurnormally[50].
Telomeraseactivityhasalsobeenfoundtobesig-nificantlyreducedinpatients(medianage80–82yr)withcongestiveheartfailurecomparedtohealthycon-trols[51].
Theextentofcoronaryatherosclerosis,indicatedbytheoccurrenceandrelativeextentofcoronaryarterycal-cification,maybeapredictorofacoronaryeventandanindexofthebiologicalageoftheartery[52-55].
Across-sectionalstudyexaminedtherelationshipbetweentelo-merelengthandcalcificationinagroupof325adults(aged40-64yr)[56].
Aninverserelationshipwasnotedbetweentelomerelengthandcoronaryarterialcalcifica-tioninpeoplewithnoclinicalhistoryofcardiacdisease.
ShortermeantelomerelengthinleukocyteshasalsobeenreportedtobeassociatedwithanincreasedGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page4of19http://www.
particleandfibretoxicology.
com/content/9/1/21tendencyofcarotidarteryatherosclerosisinhypertensiveindividuals[57].
Therelationshipbetweenarterialtissueandtelomerelengthwasexaminedin84subjects(meanage69yr).
Telomerelengthwasshorterinaortictissuewhichshowedatherosclerosisthandidcorrespondingtissuewithouttheselesions[58].
Anotherstudy[59]examinedtelomerelengthinleukocytesandatheroscleroticplaquesfrompatientswithcarotidatherosclerosisandinbloodcellsofageandgender-matchedcontrolswhohadnoclinicalevidenceofatherosclerosis.
Telomerelengthwasshorterinpatientsthanincontrols,althoughlengthintheplaquecellswasonlyweaklycorrelatedwiththatinthewhitecells.
LinkingCVD,oxidativestressandtelomerelengthThediscussionintheprevioussectionsprovidedevi-dencethattelomerelengthismodulatedbyoxidativestress,andthatshortenedtelomerelengthmaybeafac-torinthepathogenesisofCVD.
Thissectionintegratestheseconcepts,discussingtherelationshipbetweenoxi-dativestress,telomerelength,andovertCVDorriskfactors.
AknownriskfactorforCVDischronicpsychologicalstress[60,61],theproposedmechanismforwhichispsy-chologicalstress-inducedoxidativestressduetoauto-nomicnervoussystemandneuroendocrineresponses[11].
Forexample,adrenalglucocorticoidhormoneshavebeenshowntoincreaseoxidativestress-relatedneuronaldamage[62,63].
Epeletal.
[11]studiedleukocytetelomerelengthinagroupof50women,20-50yrsofage(mean38yr),whowereundergoingchronicorperceivedlifestressbutwereotherwisehealthy.
Theyfoundbothperceivedandchronicstresstobepositivelycorrelatedwithoxidativestress,usingF2–isoprostaneinurine,abiomarkeroflipidperoxidation.
TheypostulatedthatpsychologicalstresscaninduceearlycellsenescenceleadingtoCVD.
Inanotherstudy,leukocytetelomerelengthwasexam-inedinasmallgroupofpeoplewithchronicdepression[64].
Variousmarkersofoxidativestresswereassessed;telomerelengthwasinverselycorrelatedwiththelevelofoxidativestressinallsubjects.
Asnotedabove,telomerelengthcanreflectbiologicalagingandtheriskofCVD.
Telomerelengthinendothe-lialprogenitorcellsfrompatientswithCVDwasfoundtobeshorter,andtelomeraseactivitylower,thaninhealthymatchedcontrols;oxidativestressintheillsubjectswasalsogreater[65].
Inalongitudinalstudyinvolvingaco-hortof2059peopleaged35-55yr(average46yrs)whowerefreeofanyovertCVD[50],baselineleukocytetelo-merelengthshowednosignificantcorrelationwithsinglemeasuresofcholesterolHDLlevelandbloodpressure,knownCVDriskfactors,butshorterlengthwassignificantlyassociatedwithincreasedlevelsofseveralmarkersofoxidativestress.
Thisstudysuggestedthattelomerelengthreflectedtheburdenofoxidativestressseeminglyindependentoflifestyle,asindicatedbytheseotherclassicalriskfactors.
However,therateofleukocytetelomereshorteninghasbeenassociatedwithlongitudinal"cumulative"levelsofcholesterolHDL[66]suggesting,asnotedabove,thattelomerelengthmaybereflectiveofanaccumulatinglifetimeburdenofoxidativestress,andthatmore"instant"markersofrisktakenatanyonetimemaynotbeasreflectiveand,therefore,mayshownoclearas-sociationwithlength.
ThereisotherevidencefortherelationbetweenCVDandoxidativestress.
Forexample,lipidperoxidationinducedbyROSisanearlyeventintheatheroscleroticprocess[67].
Hydrogenperoxideandoxidizedlowdens-itylipoproteinshavebeenfoundtoinhibitendothelialcelltelomeraseactivity[68].
Furthermore,long-termex-posureofhumanvascularendothelialcellstooxidativestressinducedbyalterationoftheglutathioneredoxcycleresultedindown-regulationoftelomeraseactivity,enhancederosionoftelomeres,andearlyonsetofcellu-larsenescence[69].
Diabetes,anotherriskfactorforCVD,isassociatedwithhighlevelsofoxidativestressresultingincellulardamageandacceleratedcellularaging[16].
Impairmentinthefunctionofcardiacprogenitorcellsinvolvedinre-generationofdamageinthecardiovascularsystemresultingfromdiabetes-enhancedoxidativestressisoneofthelikelyunderlyingcausesofdiabeticcardiomyopathy.
Type2diabeteshasalsobeenassociatedwithshortertelo-mericlengthinwhitebloodcells,anddiabetesappearstoacceleratetelomericshorteninginthesecellsinpatientshavingahistoryofMI.
Insum,theavailableevidencesupportsaroleforoxi-dativestressinacceleratingtelomereshortening,inas-muchasdiseasesinwhichchronicoxidativestressisahallmarkareassociatedwithshortenedlength.
This,inturn,providessupportforanassociationbetweenaccel-eratedrateoftelomereerosionduetooxidativestressandCVDpathophysiology.
Furthermore,differencesintelomerelengthinindividualswithorwithoutCVDcan-notbeconsistentlyexplainedmerelybydifferencesinsomeclassicalriskfactorsforCVDotherthanage,suchasobesity,BMI,smokingstatus,orcholesterollevel[32,36,38,50,70].
Atbest,thereisonlylittletomoderateassociationwithshorterlengthsandthesefactors,ifanyrelationshipisnotedatall,suggestingthatoxidativestressisapotentiallygreaterriskfactor.
Thus,areduc-tioninthecellularreplicativecapacityofcardiacorothertissueswithinthecardiovascularsystemduetooxidativestress-inducedacceleratederosionoftelomerelengthmaybedirectlyinvolvedintheprogressiontoCVD,andmayevendetermineitsseverity[43].
GrahameandSchlesingerParticleandFibreToxicology2012,9:21Page5of19http://www.
particleandfibretoxicology.
com/content/9/1/21LinkingexposuretoPM2.
5speciesorsourcesandtelomerelengthoroxidativestressLinkingwithtelomerelengthThereissome,albeitlimited,evidencethatexposuretotraffic-relatedemissionscanmodulatetelomerelength.
InastudyconductedinMilan,Italy[71],meantelomerelengthwasfoundtobesignificantlyshorterintrafficofficersthaninofficeworkercontrols,andintrafficoffi-cersworkinginhightrafficvs.
thoseworkinginlowtraf-ficareas.
Telomerelengthalsodecreasedwithincreasingchronologicalageinbothtrafficofficersandofficework-ers,butwasshorterintrafficofficersforeachagecat-egoryandwasalsodecreasedwithincreasedexposurelevelstovehicularemissions(i.
e.
,benzeneandtoluene).
Inastudyof165veteransinthegreaterBostonarea,McCrackenetal.
[17]modeledblackcarbon(BC)con-centrationsinthehomesofsubjects,andfoundthataninterquartileincreaseofBC(0.
25μg/m3)wasassociatedwithasignificantdecreaseintelomerelength;statins,whichhavebothanti-inflammatoryandantioxidantprop-erties,hadaprotectiveeffectontelomereshortening.
LinkingwithoxidativestressThissectionreviewshumanpanelstudieswhichlinktraffic-relatedemissionstoseveraldifferentmeasuresofoxidativestress.
Somestudiescomparedoxidativestressinpeopleexposedtotrafficordieselemissionsforsev-eralhoursorduringaworkshift,comparedtomatchedcontrolsnotsoexposed,whileotherslinkedlevelsofspecificPM2.
5specieswithoxidativestress.
Becauseoxi-dativestressisalsoassociatedwithtelomereshortening,asreviewedinprevioussections,thesestudieswouldthenprovidealinktotraffic-relatedemissionsgenerally,orspecificcomponentsofsuchemissions.
StudieswhichinvolvedonlymeasuresoftotalPMmasshavenotbeenincludedherein,becausetheycan-notinformusastowhichspecificPM2.
5speciesareassociatedwithhealthrisks.
Ontheotherhand,wehaveemphasizedstudieswhich:(A)assessedeitheratleasttwospecificPM2.
5speciesortotalPM2.
5massandatleastonePM2.
5speciesincludingBC/EC;and(B)haveaccurateexposureinformationforthosechemicalspe-ciesexhibitinglocalvariability.
Regarding(A),itispos-siblethatasignificantassociationforapollutantvariablemightexistonlybecauseofthelackofmeasurementofanotherimportantPM2.
5species.
Regarding(B),recentstudies[72,73]havefoundthataccuratesubjectexpos-ureaccountedforthedifferencebetweenfindingsmall,insignificanthealthriskassociationswhenacentralmonitorwasusedtocharacterizeoverallexposureforeveryonewithinalargegeographicareaandgreater,moresignificant,associationsusingamoreaccurateex-posuremetric,e.
g.
,monitorsoutsideorinsideresi-dences,orpersonalmonitors.
AsummaryofrelevanthumanpanelstudiesmeetingthecriterianotedaboveisprovidedinTable1.
Table2illustratesthedifferencesinfindingsinonestudy[72]whenexposuretoaspecificpollutant,namelyblackcarbon,wasassessedusingper-sonalmonitorscomparedtowhenexposureassessmentutilizedacentralmonitor.
StudiesprovidingdirectmeasuresofoxidativestressAsnotedpreviously,oxidativestressinthispaperhasbeendefinedasanimbalancebetweenthegenerationandremovaloffreeradicals.
Airpollutionstudieshaveusedseveraldirectmarkersofthisoxidativestressre-sponse.
Theseincludethefollowing:circulatingbiomarkersoferythrocyteantioxidantactivityinblood,suchasglutathioneperoxidase-1(GPx-1)andcopper-zincsuperoxidedismutase(Cu,Zn-SOD).
8-hydroxy-2'-deoxyguanosine(designatedaseither8-OHdGor8-oxodG)inurineorinlymphocytes,aproductofoxidationofthedeoxynucleotidepool,andofoxidationofguanineinDNA.
increasesinredox-sensitivetranscriptionfactors.
differencesinoxidativestress-relatedgeneactivityamongsubjectsexposedtopollutants.
Delfinoetal.
[74,75]examinedelderlynon-smokingretireeshavingcoronaryarterydiseaseandlivinginsev-eralcentersacrosstheLosAngelesarea.
Pollutionmoni-torswerelocatedbothinsideandoutsideresidences,andmeasuresofoxidativestressincludedcirculatingbiomarkersinblood(GPx-1,Cu,Zn-SOD).
Theseareamongthefewstudiesthatconsideredsecondaryor-ganicaerosols(SOA),whichinLosAngeleswouldmainlybeoxidationproductsofcarbonaceousgasesofvehicularorigin,amongthedifferentPM2.
5speciesbeingconsidered.
ThestudiesfoundassociationsforCu,Zn-SODwithprimaryPM2.
5speciesmainlyofvehicularori-gin(EC,BC,primaryorganiccarbon,PM0.
25),butnotSOAormixedsecondaryandprimaryorganicspecies(OC).
Inorganicsecondaryaerosols,suchassulfate,werenotmonitored,presumablybecausemajorsulfatesources,suchascoal-firedpowerplants,wereseveralhundredmilesdownwindfromthestudyarea.
Loftetal.
[77]examined8-OHdGlevelsin57busdri-versinCopenhagen,30whodroveurbanroutesand27whodroverural/suburbanroutes.
8-OHdGexcretionwassignificantlyelevatedintheformercomparedtothelatter.
Althoughurbanatmospheresappearedtobethecauseofoxidativestress,thisstudydidnotassessspe-cificvehicular-derivedemissions.
Weietal.
[79]examinedpre-andpost-workshift8-OHdGlevelsinsecurityworkersinBeijing,whoseworksitewasonaheavilytraffickedroad.
Four"clusters"ofGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page6of19http://www.
particleandfibretoxicology.
com/content/9/1/21Table1Humanpanelstudieswithgoodsubjectexposuremethodologiesassociatingmeasuresofoxidativestresswithdifferentpm2.
5speciesorspecificsourcesStudyOxidativestressmeasuresSubjectsPM2.
5species,othermeasuresofexposureAssociationsfoundAccuracyofsubjectexposuretoBC/EC1Delfinoetal.
,2008[74]CirculatingGPx-1,Cu,Zn-SOD29non-smokingelderlyw/CADinLosAngelesarea,manyonstatinsoranti-hypertensionmeds;12weeklyblooddrawsAmbientPM0.
25,PM2.
5,PN,EC,OC,BC,OCpri,SOAForCu,Zn-SOD:AssociationsfoundwithPM0.
25,PM2.
5,EC,BC,OCpri,butnotwithOC,PN,SOAVerygood:monitorsinsideandoutsideretirementcommunitiesDelfinoetal.
,2009[75]CirculatingGPx-1,Cu,Zn-SOD60non-smokingelderlyw/CADinLosAngelesarea,manyonstatinsoranti-hypertensionmeds;5-12weeklyblooddrawsAmbientPM0.
25,PM2.
5,PN,EC,OC,OCpri,SOAForCu,Zn-SOD:Associations(strongerincoolseason)withPM0.
25,PM2.
5,EC,PN,OCpri,butnotwithOC,SOAVerygood:monitorsinsideandoutsideretirementcommunitiesKimetal.
,2004[76]8-OHdG20boilermakers,average45.
5yearofage,repairingoil-firedboilersinBostonareaIndustriallevelsofPM2.
5,PM2.
5metalsV,Cr,Mn,Ni,Cu,Pb(PM2.
5=440μg/m3,V=1.
23μg/m3,othermetals<1.
0μg/m3)Postworkshift8-OHdGlevelssignificantlyhigherthanpreshift;increasedPM2.
5,V,Mn,Ni,Pbconcentrationssignificantlyassociatedwithincreased8-OHdGExcellent:personalmonitorsusedLoftetal.
,1999[77]8-oxodG57non-smokingdieselbusdriversingreaterCopenhagenAmbientairinurban(30drivers)vs.
rural/suburban(27drivers)areasSignificantlyhigher8-OHdGexcretioninurbandriversvs.
rural/suburbandriversVerygood:exposureisbaseduponcomparisonofurban(heavilytrafficked)vs.
rural/suburbanareasSauvainetal.
,2011[78]8-OHdG32SwissbusmaintenanceworkersPM4,OC,EC,PMmetal(Fe,Mn,Cu)content,PAHs(PM4between25and71μg/m3)8-OHdGexcretionssignificantlyincreasedwithineachshiftandbetweentwoconsecutiveworkdays;increasesinnon-smokersassociatedwithincreasesinOCandparticulateCuVerygood:associationsbaseduponexposuremeasuredindoors,asnearbyaspossibletoworkstationsWeietal.
,2009[79]8-OHdG2non-smokingyoungsecurityguardsworkingbyamajorroadinBeijing,noonto8PM;worksiteambientPM2.
5=243μg/m3,backgroundPM2.
5=104μg/m3Preandpost-shift8-OHdGsamplescollectedfor29days;associationswithfour"clusters"ofPM2.
5species(PM2.
5mass,PAHs,metals,polarorganicspecies)Postworkshiftincreasesin8-OHdGsignificantlyassociatedwithPM2.
5mass,PAHs,andmetals,butnotwithpolarorganicspecies,asmeasuredatworksiteVerygoodexposure:takenatworksiteLeeetal.
,2011[80]8-OHdG28dieselexhaustinspectorsinTaiwan,38ageandgendermatchedcontrolsofficeworkers,monitoredduring3consecutivedayworkperiodsDieselPM2.
5emissions(DEP2.
5),PAHcontentofDEP2.
5(personaldailyPM2.
5=86to94μg/m3,PAHs=3.
04to4.
11ng/m3)8-OHdGlevelssignificantlyhigherforinspectorsvs.
controlsondays2and3;increasedPAHconcentrationsinDEP2.
5significantlyassociatedwithincreased8-OHdGinexposedgroup,afteradjustingforsmokingstatusandBMIVerygood:personalmonitorsandambientsamplersinstalledwithinmetersofworksitesLaietal.
,2004[81]8-OHdG47femalehighwaytollworkersinTaiwan,27femaleofficeworkersascontrolsExposed(tollworkers,8hourshifts)vs.
officeworkersTollworkershadsignificantlyhigher8-OHdGlevelsthancontrols(86%higher8-OHdGcomparingnon-smokerstonon-smokers);increasesin8-OHdGalmost5timeshigherper1000trucks/busesthanper1,000cars,resultnotsignificant(separatelanesfordifferentvehicletypes)Verygood:exposuredefinedbywhetherworkingintrafficornot;forthoseworkingintraffic,furtherdefinedbycarlaneortruck/buslaneworkersandbytrafficdensityGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page7of19http://www.
particleandfibretoxicology.
com/content/9/1/21Table1Humanpanelstudieswithgoodsubjectexposuremethodologiesassociatingmeasuresofoxidativestresswithdifferentpm2.
5speciesorspecificsources(Continued)Sorensenetal.
,2005[82]8-oxodG49non-smokingstudentsinCopenhagen,medianage24,ineachoftwoseasons(summer,autumn)PM2.
5,sixmetalsinPM2.
5fraction(V,Cr,Pt,Ni,Cu,Fe);PM2.
5=20.
7μg/m3(fall),12.
6μg/m3(summer)Noassociationsfoundwithurinary8-oxodG;significantpositiveassociationsfoundforV,Crwith8-oxodGinlymphocytes.
98samplesavailableforurinary8-oxodG,52forlymphocytesExcellent;weeklypersonalmonitorsconcentrationsforeachseasonAllenetal.
,2009[83]8-OHdG,F2-isoprostanes10adults,ages18-49,withmetabolicsyndromebutnohistoryofongoingmedicalcareforheartdisease,hypertension,asthma,diabetes,orotherchroniccondition2hourexposuretoeitherdieselexhaust(200PM2.
5)fromengineoperatingat75%ofratedoutput,orfilteredairNosignificantincreasein8-OHdGorF2-isoprostaneslevelsafterexposure,indoubleblindcrossoverexperimentExcellent:exposuretodieselemissionsorfilteredairoccurredinchamberdesignedforpurposeJacobsetal.
,2011[84]OxidizedLDL79non-smokingdiabetics,averageage56.
5years,inurbanBelgiumCarbonareainairwaymacrophages,distanceofresidencesfrommajorroadsIncreaseinIQRcarbonloading,decreaseindistancefrommajorroadsbothassociatedwithincreaseinoxidizedLDLExcellent:carbonloadinginpersonalmacrophagesisaprecisemeasureofparticulatecarbon,whichinurbanareaisfromtraffic,mainlydieselsKipenetal.
,2011[85]Whitebloodcell(WBC),redbloodcell(RBC)proteasomeactivity,38healthyyoungsubjectsinNewJerseyDieselexhaust(DE),laboratory-generatedsecondaryorganicaerosol(SOA,basedupongasphasereactionsofozoneandd-limonene),both~190μg/m3Comparedtofilteredairexposure,significantdecreasesofWBCproteasomeactivityafterexposuretoeitherDEorSOA,decreaseofRBCproteasomeactivityafterexposuretoDE,"presumablyviainductionofoxidativestress"Excellent:exposurechamberusedAdaretal.
,2007[86]HRVmeasures:SDNN,r-MSSD,PNN50+1,LF,HF,LF/HF,HR44non-smokingsubjectsoverage60livingin4seniors'residencesinSt.
LouisBC,PM2.
5levelsasrecordedbymobilemonitorwhichfollowedsubjects,includingintrafficonbusFor24averageBCconcentrations,for5minuteconcentrationsondieselbusornotonbus,andfor5and24hourmeans,thegreatmajorityofmanyBCassociationsaresignificant;PM2.
5highlycorrelatedwithBCandassociationssimilartothoseforBCVerygood(monitorfollowssubjectsduringday,staysinresidenceofsubjectsatnight)Schwartzetal.
,2005[87]4measuresofHRV27subjectslivingadjacenttomajorurbanroadinBoston,age61-89BC,PM2.
5,"secondaryPM"derivedbysubtractingBCmassfromPM2.
5massBC:7of8associationssignificantVerygood(monitoradjacenttosamemajorurbanroadtowhichsubjects'residencesalsoadjacent)PM2.
5:3of8associationssignificant"SecondaryPM":nosignificantassociationsof8Ebeltetal.
,2005[88]SDNN,R-MSSDmeasuresofHRV16non-smokingpatientswithCOPDinVancouver,averageage=74PM2.
5,sulfate,estimatednon-sulfatePM2.
5Significantassociationsonlywithnon-sulfatePM2.
5Verygood(personalmonitoringinformationcombinedwithambientmonitoringinformation,toseparateeffects)GrahameandSchlesingerParticleandFibreToxicology2012,9:21Page8of19http://www.
particleandfibretoxicology.
com/content/9/1/21Table1Humanpanelstudieswithgoodsubjectexposuremethodologiesassociatingmeasuresofoxidativestresswithdifferentpm2.
5speciesorspecificsources(Continued)ForSDNN,2of2testsForR-MSSD,1of2testsCreasonetal.
,2001[89]HF,LFmeasuresofHRV56elderly,non-smokingmen,residentsofaretirementcenternearBaltimore,nearcommuterroadsPM2.
5(sulfatemonitoredbutnotusedinmodels;expressedaspercentageofPM2.
5indiscussion)Forcompletedatasetof24days,insignificantassociationswitheitherHForLF,witha"U"shapedfunctionwhereHRVmeasuresareatnormallevelsonlyatlowestandhighestPM2.
5concentrations;whenatwodayperiodwithnoeffectsonHRVisremoved,remaining22dayshaveasignificant,linearreductioninbothHFandLF,forbothindoorandoutdoorPM2.
5;twodaysremovedhadhighestand3rdhighestPM2.
5levels,werehighinsulfatebutcamefromruralareaswithnoapparenturbanorindustrialsourceofharmfulPM2.
5Reasonablygoodinthatstudywasabletodeterminebywindback-trajectoryanalysisthatfor22dayswherePM2.
5reducedHRVmeasures,airparcelspassedovereitherurbanorindustrialareas,butthatforthe2dayswithouteffectonHRV,parcelspassedovermoreruralareasSuhandZanobetti,2010[72]4measuresofHRV:SDNN,RMSSD,PNN50,HF,LF/HFSameasinWheeleretal.
(2006)EC,sulfate,PM2.
5IQRincreaseinpersonalmonitoredECsignificantlyassociatedwithdecreasesinSDNN,RMSSD,PNN50,andHF,andwithincreaseinLF/HF;IQRincreaseinambientmonitoredECnotassociatedwithchangesinanyHRVmeasures;NeithersulfatenorPM2.
5(onlypersonalmonitoredavailableforsulfate)significantlyassociatedwithanyHRVmeasuresExcellentforpersonalmonitoredEC,PM2.
5,andsulfate;Poor(horizontalexposuremisclassification;centralmonitorreadingforpeopleacrossmetroAtlantaarea)forambientECParketal.
(2007)[90]SDNN,HF,LF,LF/HF497subjectsofNormativeAgingStudylivingacrossgreaterBostonareaBC,sulfate,PM2.
5,combinedwithwindtrajectoryinformationshowingsourcedirectionsFourofsixtrajectorieshadhighandnearlyequalconcentrationsofBC,sulfate,andPM2.
5-associationsareforthesefourtrajectories.
PoorforBC(horizontalexposuremisclassification;centralmonitorreadingforpeopleacrossmetroBostonarea);however,useofwindtrajectoryanalysismitigatespoorexposurebyallowinginterpretationofruralvs.
urbansourcesForlocal(stagnant)windtrajectory:BC(2significanttestsof4);Sulfate(1of4);PM2.
5(1of4)Forlongdistanceurbanwindtrajectoryfromsouthwest(overmajorurbanareas):BC(3of4testssignificant);Fortwonon-urbantrajectories:BC,sulfate,PM2.
5(nonesignificant)GrahameandSchlesingerParticleandFibreToxicology2012,9:21Page9of19http://www.
particleandfibretoxicology.
com/content/9/1/21Table1Humanpanelstudieswithgoodsubjectexposuremethodologiesassociatingmeasuresofoxidativestresswithdifferentpm2.
5speciesorspecificsources(Continued)Langrishetal.
,2009[91]SDNN,LF15healthy,non-smokingyoungvolunteersinBeijingPersonalmonitorPM2.
5,randomizedcrossoverstudydesign:volunteerswalkedapredeterminedcitycenterroutewithorwithoutafacemask24hourSDNNsignificantlylowerwhenfacemasknotused;LFsignificantlylower(onetest)withoutmask,butinterpretationnotstraightforwardExcellent;mostimportantfindingiscorroborationthaturbanparticulatematter,notgases,drivesreductioninSDNN,suggestingassociationsinotherstudieswithBC/ECindicatedirectPMeffects,BC/ECnotaproxyforvehiculargaseousemissionsLangrishetal.
,2012[92]HF,RMSSD98patientswithcoronaryarterydisease,averageage62PersonalmonitorPM2.
5,randomizedcrossoverstudydesign:volunteerswalkedapredeterminedcitycenterroutewithorwithoutafacemaskHF,RMSSDsignificantlylowerwhenfacemasknotusedExcellent;mostimportantfindingiscorroborationthaturbanparticulatematter,notgases,drivesreductioninRMSSD,HF,suggestingassociationsinotherstudieswithBC/ECindicatedirectPMeffects,BC/ECnotaproxyforvehiculargaseousemissionsAbbreviations:GPx-1=glutathioneperoxidase-1;Cu,Zn-SOD=copper-zincsuperoxidedismutase;CAD=coronaryarterydisease;PN=particlenumber;EC=PM2.
5elementalcarbon;BC=PM2.
5blackcarbon;OC=PM2.
5organiccarbon;SOA=estimatedsecondaryorganiccarbon;OCpri=primaryOC;NAS=NormativeAgingStudy,acohortofmaleveteransacrossgreaterBostonarea,manyofwhomarepresentorformersmokers,andmanyofwhomareonanti-hypertensivemedicationsorstatins;8-OHdGor8-oxodG=8-hydroxy-2'-deoxyguanosine,aproductofoxidationofthedeoxynucleotidepoolandarepairproductofoxidationofguanineinDNA(mutagenic);IQR=interquartilerange;PAH=polycyclicaromatichydrocarbon;BMI=bodymassindex,agenerallyreliableindicatorofbodyfat;HRV=Heartratevariability,ofwhichthereareseveralmeasures;SDNN=standarddeviationofconsecutiveRRIntervals(anHRVmeasure);r-MSSDorRMSSD=root-meansquareofthedifferenceofsuccessiveR-Rintervals(anHRVmeasure);PNN50+1=numberofinstancesperhourinwhichtwoconsecutiveR-Rintervalsdifferbymorethan50msover24h(anHRVmeasure);HF=highfrequencycomponentofHRV;LF=lowfrequencycomponentofHRV;LF/HF=ratioofLFtoHF;TP=Totalpower(anHRVmeasure);COPD=ChronicObstructivePulmonaryDisease;MI=MyocardialInfarction;IQR=InterquartileRangeofpollutant.
1Accuracyofsubjectexposureisconsideredverygoodtoexcellentifassessmentofconcentrationofpollutantandactualsubjectexposurevarywelltogetherwithtimebecausemeasurementistakenincloseproximitytosubjects.
Accuracyisseemas"horizontallypoor"ifacentralmonitorisusedtocharacterizedsubjectexposureoveralargegeographicalarea,andisadditionally"verticallypoor"ifthemonitorisseveralhundredfeethigherthantheresidencesofthesubjects.
GrahameandSchlesingerParticleandFibreToxicology2012,9:21Page10of19http://www.
particleandfibretoxicology.
com/content/9/1/21PMspecieswereexamined:PM2.
5mass,PAHs,metals,andpolarorganicspecies.
Observedpost-shiftincreasesinurinary8-OHdGwereassociatedwithincreasedlevelsofPM2.
5mass,PAHs,andmetals,butnotpolarorganicspecies,attheworksite.
Leeetal.
[80]studied28dieselexhaustinspectorsinTaiwan,ageandgendermatchedwithofficeworkercon-trols,forthreeconsecutiveworkdays.
Pollutantsexam-inedweretotaldieselPM2.
5(DEP2.
5)andPAHcontent.
8-OHdGlevelsweresignificantlyhigherforinspectorsvs.
controlsondays2and3.
IncreasedPAHconcentra-tionsinDEP2.
5weresignificantlyassociatedwithincreased8-OHdGintheexposedgroupevenafteradjustingforfactorssuchassmoking.
Laietal.
[81]studied47femaletollworkersinTaiwan,matchedwithfemaleofficeworkersascontrols;pollutionconcentrationswerenotmeasured.
Non-smokingtollworkershadsignificantlyhigher8-OHdGlevelsthandidnon-smokingcontrols;increasesin8-OHdGwerealmost5timeshigherper1000trucks/busesthanper1,000cars(comparingcartolllaneswithtruck/buslanes),althoughtheseresultsdidnotreachstatisticalsignificance.
Sauvainetal.
[78]studied32Swissbusmaintenanceworkers.
PMspeciesexaminedincludedPM4,OC,EC,metals(Fe,Mn,Cu),andPAHs.
Urinary8-OHdGcon-centrationsincreasedwithineachworkshift,andbe-tweentwoconsecutiveworkdays.
Amongnon-smokers,increased8-OHdGconcentrationswereassociatedwithincreasedlevelsofOCandCu.
WhilesecondaryOCassociationswerenotfoundusingadifferentmeasureofoxidativestress(bloodlevelsofCu,Zn-SOD)intheDel-finoetal.
studies[74,75],primaryOCwassignificantlyassociatedwithoxidativestressbiomarkers,suggestingthattheOCassociationsinSauvainetal.
reflectmainlyfresh(i.
e.
,primary)dieselemissions.
Sorensenetal.
[82]usedpersonalmonitorstodeter-minelevelsofPM2.
5andsixmetals(V,Cr,Pt,Ni,Cu,Fe)inPM2.
5fractionstowhich49young,non-smokingstudentsinCopenhagenwereexposed.
Noassociationswerefoundwith8-oxodGinurine,butsignificantposi-tiveassociationswerefoundforVandCrwith8-oxodGinlymphocytes.
Kimetal.
[76]examinedassociationofurinary8-OHdGwithsixPM2.
5metalspecies(V,Cr,Mn,Ni,Cu,Pb)amongboilermakersrepairingoil-firedboilersintheBoston,MAarea.
Post-workshiftlevelsof8-OHdGweresignificantlyhigherthanpre-workshiftlevels.
Increased8-OHdGwasassociatedwithincreasesintotalPM2.
5andV,Mn,Ni,Pb,butnotCuorCr.
PMlevelswereconsiderablyhigherthanambient;forexample,thecon-centrationofVwas1.
23μg/m3,contrastedwithcontem-poraryBostonambientVlevelsof3to5nanograms/m3.
ItisinterestingthatCu,butnotMn,wasassociatedwithoxidativestressinSauvainetal.
[78],whereasoppositeassociationswereobservedforeachinKimetal.
Allenetal.
[83]studied10adults,aged18-49,withmetabolicsyndromebutnohistoryofongoingmedicalcareforheartdisease,hypertension,asthma,diabetes,orsimilarchronicconditions.
Subjectswereexposedfortwohourseithertodieselexhaust(200μg/m3PM2.
5)orfilteredair.
Nosignificantassociationswerefoundbe-tweenurinary8-OHdGanddieselexhaustexposure.
Thesefindingscontrastwithstudiesnotingincreasedurinary8-OHdGwithworkshiftexposuretodieselex-haustinTaiwan[80]andSwitzerland[78],ortoheavyvehiculartrafficinTaiwan[81]andBeijing[79].
ThelackofsignificantfindingsofoxidativestressinAllenetal.
[83]mighthavetodowithshorterexposuretimes,withdifferencesinmakeupofpollution,withdifferencesinlevelsofactivity,i.
e.
,workerspresumablyweremorephysicallyactiveduringexposurethanpassivelyexposedsubjectsinAllenetal.
,assuggestedbytheauthors,ortootherasyetunknownreasons.
Jacobsetal.
[84]choseauniquemethodofassessingpollutionexposure,i.
e.
,bymeasuringtheareaoccupiedbycarboninrespiratorytractmacrophages,in79Belgiannon-smokingadultdiabetics.
Theauthorsalsoexamineddistancebetweensubjectresidenceandmajorroadsbygeocoding.
ThebiomarkermeasuredwasoxidizedLDLinplasma,ariskfactorforatherosclerosis.
TheyfoundthatbothincreasedcarbonloadinganddecreaseddistancefrommajorroadsweresignificantlyassociatedwithhigherlevelsofoxidizedLDL.
Similarly,usingananimalmodel,namelyatheroscleroticapolipoproteinEknockoutmice,Table2Associationbetween24-hourambientmonitorandpersonalECconcentrationswithdifferenthrvmeasures(fromSuhandZanobetti[72])HRVmeasureAmbient(Centralmonitor)PersonalmonitorChange(%)95%confidenceintervalChange(%)95%confidenceintervalSDNN-1.
0-3.
7to1.
7-4.
66-7.
99to-1.
22RMSSD-3.
6-9.
5to2.
8-10.
97-18.
00to-3.
34PNN50-0.
34-10.
55to11.
04-15.
16-26.
33to-2.
29HF-2.
36-11.
67to7.
92-13.
41-23.
95to-1.
41LF/HFratio2.
60-1.
89to7.
296.
220.
15to12.
64Resultsinboldfaceindicatestatisticalsignificanceatthe95%confidencelevel.
GrahameandSchlesingerParticleandFibreToxicology2012,9:21Page11of19http://www.
particleandfibretoxicology.
com/content/9/1/21Lundetal.
[93]foundthatacuteexposuretoamixtureofgasolineanddieselengineemissionsresultedinincreasedvascularandplasmamarkersofoxidativestressandtheexpressionofproatherogenicfactors.
Kipenetal.
[85]exposedhealthyyoungsubjectsinNewJerseyeithertodieselexhaustortoalaboratory-generatedPM2.
5secondaryorganiccarbonatmosphere(~190μg/m3each),withfilteredaircontrolforeachex-posure.
Eachpollutantatmospherecausedanincreaseinwhitebloodcellproteasomeactivity,andthedieselex-haustcausedanincreaseinredbloodcellproteasomeactivityaswell,whichtheauthorssuggestedtoindicateoxidativestress.
TheDelfinoetal.
studies[74,75]inLosAngelesdidnotfindoxidativestressassociatedwithsec-ondaryorganiccarbon,butthelaboratory-generatedSOAatmosphereofKipenetal.
didresultinsuchanas-sociation.
TheSOAgeneratedinthelaboratoryusedvegetativeorganicgases,whiletheambientSOAinLosAngelespresumablyismostlyfromvehicular-derivedor-ganicgases.
Whetherdifferencesinchemicalcompos-itionduetothedifferencesinsourceordifferencesinmethodsofassessmentofoxidativestress,orwhetherthehigherconcentrationsinthelaboratorySOAcom-paredtoambientlevelscanexplainthedisparatefind-ingsbetweentheKipenetal.
andDelfinoetal.
studies,isnotclear.
Whileallofthestudiesnotedabovedirectlyexaminedmarkersofoxidativestress,theresults,however,cannotbeneatlysummarizedforseveralreasons:Severalstudies,inparticularthoseinvolvingurbanemissions,didnotmeasurePM2.
5species,andonlyafewmeasuredPM2.
5metals,whichhaveahighpotentialforinducingoxidativestress[3].
Studiesweredoneinseveralcountries,withvaryinglevelsandlikelycompositionofurbanairpollutants.
Althoughmostofthestudiesusedurinary8-OHdGasabiomarkerofoxidativestress,somestudiesusedothermarkers,anditisn'tclearaprioriwhetheroxidativestressimpactsofPMontelomereerosionareequivalentforvariousmarkers.
Giventheselimitations,weofferthefollowingassess-mentofthesestudies:InstudiesperformedintheU.
S.
,primaryvehicularemissions,suchasEC/BCandprimaryOC,wereassociatedwithincreasesinbiomarkersofoxidativestress,butsecondaryorganiccarbon,presumablymostlyofvehicularorigin,wasnot.
InstudiesperformedinEuropeandAsia,oxidativestressmeasureswereassociatedwithgreaterexposuretoambientemissionsfromroadsorattolls(vs.
officeworkercontrols);forthosedrivinginurbanvs.
suburban/ruralareasorlivingclosertoroads;forthosewithhigherlevelsofcarboninairwaymacrophages;orforthosewithgreaterexposuretoemissionsfoundinworklocationsinvolvingdieselsorbuses.
Whileexposuretothesedifferentatmospheresdominatedbyvehicularemissionsclearlyresultedinoxidativestress,littleinformationwasgenerallyprovidedastowhichspecificcomponentsofsuchatmospheresmayhavebeeninvolved.
OnlyonestudyexaminedspecificPM2.
5species,findingassociationswithOCandCu,butnotEC,Fe,orMninbusmaintenanceworkers.
ExposurestoatmospheresparticularlyhighinPM2.
5metals(boilermakers)ortoambientlevelsofspecificmetalssuchasVwereassociatedwithoxidativestress.
However,onlythreestudiesexaminedmetals,andassociationswerenotalwayswiththesamemetals.
Overall,thestudiesreviewedinthissectionsuggestthatexposuretospecificPMsources,namelyvehicular,areassociatedwithoxidativestress,butbecausefewofthestudiesincludedspecificPMspecies,itisn'tpossibleasyettodeterminewhichspeciesweremostlikelyre-sponsiblefortheoxidativestress.
Studiesinthenextsection,usingadifferentproxyforoxidativestress,namelychangeinheartratevariability(HRV),maypro-videmoredetailsonthepotentialforseveralPMspeciestobesoassociated.
StudiesprovidingmeasuresofHRVHeartratevariabilityisareflectionoftheautonomicner-voussystemcontrolofcardiacfunction.
AlteredHRVhasbeennotedinpatientswithhypertensionandheartfail-ure,andhasbeenlinkedtoincreasedCVDmortality[92].
Cascio[94]notedthatincreasedcardiac-relateddeathsanddecreasedautonomiccontrolofcardiacfunctioncanbemodulated,atleastinpart,byoxidativestress.
Further-more,anapparentlycausalrelationshipbetweenoxidativestressandchangesinvariousmeasuresofHRVhasbeenfoundwithexposuretopollutantsinanumberofstudies,asdiscussedbelow.
Schwartzetal.
[95]foundsignificantdecreasesintheHFcomponentofHRVinpeoplehavingadeletionfortheproteinGSTM1,partofthecellulardefenseagainstoxidativestress,afterexposuretoPM.
Forthosethatdidnothavethedeletion,however,therewerenochangesintheHFcomponent.
Useofstatinsprotectedthosewiththisgeneticdeficiencyagainstoxidativestressassociatedwithexposuretoairpollution.
Chahineetal.
[96]alsofoundthatonlythosepeoplelackinggenesprotectiveagainstoxidativestress,includingadifferentgeneticvari-antthanexaminedbySchwartzetal.
[95],experiencedGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page12of19http://www.
particleandfibretoxicology.
com/content/9/1/21reductionsintwomeasuresofHRVafterPMexposurecomparedtonormalcontrols.
Theyconcludedthatoxida-tivestresswasanimportantpathwayfortheeffectsofparticlesonautonomicnervousfunction.
Thisissup-portedbyananimalstudy[97],inwhichasignificantin-creaseintheSDNNcomponentofHRV,whichreflectsbeat-to-beatintervals,andasignificantdecreaseintheratioofhighfrequency(HF)tolowfrequency(LF)com-ponents30minutesafterexposuretourbanairparticlesbyinstillationwasassociatedwithincreasedoxidativestressinheartsofrats;however,SDNNremainedatnor-mallevelswhenincreasedoxidativestresswaspreventedbyadministrationofanti-oxidantspriortoexposure(LF/HFwasnotanalyzedinthisregard).
Finally,Probst-Henschetal.
[98]foundthatindividualsdeficientin"oxidant-scavenging"glutathioneS-transferase(GST)geneshadsignificantHRValterations,comparedtothosenotsodeficient.
Takentogether,thesestudiesindicatethatchanges(mainlyreductions)inHRVafterexposuretopollutantscanreflectinducedoxidativestress.
Brooketal.
[2]notedthat".
.
.
pathwaysthatreducedendogenousoxida-tivestresshaveaprotectiveeffectthatmitigatesreduc-tionsinHRVduetoambientPMexposure.
"Overall,thesestudiessuggestthatassociationsbetweenoxidativestressandchangesinmeasuresofHRVarecausative,andthatsuchHRVchangescanbeconsideredtobemarkersofoxidativestressinducedbypollutantexpos-ure,inthissenseparalleltoincreasesin8-OHdGfoundinstudiesdiscussedinprevioussections.
ThissectionreviewsstudiesofHRVchangesinpeopleforwhomex-posuretopollutants,suchasBC,wasreasonablywellcharacterized,forinstance,withuseofpersonalmoni-tors,withambientmonitorswhichtraveledwithsub-jects,withmonitorsincloseproximitytoaroadtowhichnearbysubjectresidenceswerealsoincloseprox-imity,orbyuseofwindback-trajectoryanalysis.
SuhandZanobetti[72]usedbothpersonalmonitorsandacentralpollutionmonitortoassessexposuretoBC,sulfate,andPM2.
5intheAtlantaarea.
Theauthorsfoundnosignificantassociationswithfivedifferentmea-suresofHRVwhencentralmonitorreadingswereused.
However,riskestimateswere3to45timeshigher,andBCwassignificantlyassociatedwithchangesinallfivemeasuresofHRV(Table2),whenpersonalmonitorswereused.
Thus,forapollutantsuchasBC,havinglargespatialvariabilityacrossametropolitanarea,useofcen-tralmonitorreadingsfailedtoaccuratelycharacterizedifferencesinexposuretoBCandunderstatedtheextentandsignificanceofHRVchangesand,thus,ofrelatedoxidativestress,relativetomoreaccurateexposureesti-matesforBC.
NoHRVassociationswerenotedforei-thersulfate(onlypersonalmonitordataavailable)ortotalPM2.
5.
Adaretal.
[86]usedamobilemonitorwhichfollowedelderlynon-smokingretireesduringtheiractivities.
BothBCandPM2.
5concentrationsweresharplyhigherwhensubjectswereonbusesthanatothertimes.
HRVchanges(5minand24hmeans)wereessentiallymonotonicwithchangesinBCandPM2.
5concentrations,andweresig-nificantinthegreatmajorityofcasesforbothpollutants.
Schwartzetal.
[87]examinedfourdifferentmeasuresofHRVfor1and24hperiods.
Subjectslivedinapart-mentsadjacenttoamajorBostonroadway;themonitorwasalsoincloseproximitytotheroadway.
BCwascon-sistentlyassociatedwithchangesinallfourHRVmea-suresevaluated,whilePM2.
5wasonlyoccasionallyassociated.
Theauthorsthenusedanalgorithmtore-moveBCfromPM2.
5eachhour,andtermedtheremain-der"secondaryPM,"whichcontainedregionalsulfateandSOCbutnotBC.
TheyfoundnoassociationswithHRVchangesandsecondaryPM.
Furthermore,SDNNdeclinedmonotonicallywithincreasingPM2.
5fromthelowestPM2.
5leveltoabout18μg/m3.
Attheserelativelylowlevels,theinvestigatorsnotedthatPM2.
5andBCwerehighlycorrelated.
However,fromabout20μg/m3tothehighestPM2.
5levels(about50μg/m3),therela-tionshipbetweenSDNNandPM2.
5wasflat,i.
e.
,therewerenochangesintheSDNNmeasureofHRV.
AtthesehigherPM2.
5concentrations,PM2.
5wasnolongerwellcorrelatedwithBC.
Ebeltetal.
[88]examinedHRVchangesin16non-smokingpatientswithCOPDinVancouver,Canada.
BothambientandpersonalmonitoringwereusedtoobtainmeasuresofPM2.
5;personalmonitoringofsulfatewasalsoperformed.
Non-sulfatePM2.
5wasdeterminedbyvariousalgorithmswhicheffectivelysubtractedpersonalsulfateexposurefromPM2.
5measures.
OfthedifferentmeasuresofPM2.
5,onlynon-sulfateurbanPM2.
5wasassociatedwithchangesinHRV(SDNN,R-MSSD).
TheseresultsaretheobverseofthoseofSchwartzetal.
[87],inthatEbeltetal.
subtractedsulfurtodetermineurbannon-sulfate,whichwouldincludeBC.
However,inbothstudies,ambientPMreflectingBCorurbanair,butnotsulfateorregionalair,wasassociatedwithalteredHRV.
Creasonetal.
[89]examinedtherelationshipbetweentheHFandLFmeasuresofHRVwithPM2.
5concentra-tionsover24consecutivedaysin56elderly,non-smokingmen.
Sulfatewasmeasured,andreportedtoaverage14%ofPM2.
5concentrations,butwasnotreportedseparatelyfromPM2.
5.
Theauthorsfounda"U"shapedrelationshipbetweenchangesinHRVmeasuresandPM2.
5;HRVchangesweremostpronouncednearthemidpointofPM2.
5concentrations,andHRVwasmostnormalatthelowestandhighestPM2.
5concentra-tions.
Whenatwodayairmass,containingthehighestand3rdhighestPM2.
5concentrationswasremovedfromtheanalysis,fortheremaining22daysamonotonicGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page13of19http://www.
particleandfibretoxicology.
com/content/9/1/21reductioninHFwasobservedwithincreasingPM2.
5,similartothereductioninSDNNobservedwithincreas-ingBCbybothAdaretal.
[86]andSchwartzetal.
[87].
Theauthorsusedback-trajectoryanalysistoshowthatthetwodayairmass,havingPM2.
5concentrationsofap-proximately53and37μg/m3,camefromruralPennsyl-vania,whereasontheother22days,theauthorssuggestedthaturbanorindustrialPM2.
5sourceswerepresent.
ThelackofassociationwithPM2.
5ondaysdominatedbyruralairmassesparallelsthefindingsofSchwartzetal.
[87]thatPM2.
5insecondaryairmasseswasnotassociatedwithchangesinHRV,eventhoughPM2.
5levelswerehighestonsuchdays.
Parketal.
[90]studied497subjectsusingbacktrajec-toryanalysistocreatesixdifferentsourcedirectionstoassessexposure.
Ofprimaryinterestarethefourdirec-tionswhichhadverysimilarBC,PM2.
5,andsulfatecon-centrations(e.
g.
,PM2.
5between14.
1and15.
1μg/m3;BCbetween0.
99and1.
1μg/m3;andsulfatebetween3.
8and4.
2μg/m3),substantiallyhigherthantheremainingtwodirections(NandNW).
Thesefourdirectionswere:SW(airmasspassedoverPhiladelphiaandNewYorkbeforefollowingtheI-95corridortowardBoston).
S(airmassoriginatedintheCarolinasandenteredMassachusettsfromtheoceantotheS).
W(airmasspassedovernorthernOhioandmiddleNewYorkstate,mostlynorthofPennsylvania).
Local(slowmovingairmasses,relativelystagnantoverBoston).
Ondayswhenairmasseswerelessurban(SandW),therewerenoHRVchangesassociatedwithanyemis-sions.
WhenairmassesarrivedinBostonfromtheSW,BCwassignificantlyassociatedwithchangesinthreeoffourHRVmeasures;nootherPM2.
5specieswereasso-ciatedwithsuchchanges.
Whentheairwasslowermov-ingandmorelocal,PM2.
5,sulfate,andBCwereallassociatedwithHRVchanges,althoughBCwasasso-ciatedmoreconsistently.
Fortwootherwindtrajectories(NandNW),levelsofallpollutantswerelowrelativetotheotherfourdirec-tions.
AnassociationwithPM2.
5wasobservedfortheNwindtrajectory,andoneforsulfatewasseenfortheNWwindtrajectory.
Theauthorssuggestedthattheeffectap-parentlyseenforsulfateinthiscase,despitelowsulfatelevels,mayactuallybeduetothepresenceoftransitionmetals.
Lippmannetal.
[99]foundsignificantreductionsinHRVinmiceexposedtoambientairinupstateNewYorkonlywhenthewindtrajectorywasfromtheNW,passingoveraSudbury,Ontarionickelsmelter.
TwostudiesthatdidnotmonitorPM2.
5speciesareincludedinthissectionbecausetheydemonstratethatHRVchangescanbeabolishedusingafacemaskthatfil-teredouturbanparticles,suggestingthatthecauseofHRVreductionsmaybetraffic-relatedPMasopposedtoassociatedgaseousvehicularemissions.
Langrishetal.
[91]recruited15young,non-smokersinBeijingforacross-overstudy.
Subjectswalkedapredeterminedcourseonseparateoccasions,eitherwithorwithoutafacemask.
PersonalPM2.
5monitorswereused.
Asignificantde-creasein24-hSDNNwasobservedwhensubjectsdidnotusefacemasks,suggestingproductionofoxidativestress.
SignificantreductionsinLFwerealsoobserved,butinter-pretationofthiseffectwasn'tstraightforward,sinceLFreflectstoneofthesympatheticnervoussystemanditmighthavebeenaffectedtosomeextentbysimplywear-ingamask.
BeijingPM2.
5levelswhenfacemaskswereusedwere140μg/m3vs.
86μg/m3whenmaskswerenotused.
Inanotherstudy,Langrishetal.
[92]madesimilarfindings,usingsubjectswithcoronaryarterydisease(averageage62).
Inaddition,theyalsostudiedotherCVDendpoints,suchasST-segmentdepressionandarterialbloodpressure,andfoundthatuseofthefacemaskreducedboth.
Usingelectronparamagneticresonance,theauthorsalsoestablishedthatambientPMinBeijinghasveryhighoxidativestresspotential.
Theresultsofthestudiesreviewedinthissectionmaybesummarizedasfollows:Whentherewerereasonablyaccuratesubjectexposuremeasures,BCwasconsistentlysignificantlyassociatedwithalterationsinvariousmeasuresofHRV.
Amongthesestudies,thoseabletodistinguishBCfromsecondaryairmasseswithoutBC,ruralairmassesfromthosewithindustrialorurbanpollution,urbanPMwithoutsulfatevs.
thosecontainingsulfate,orpersonallymonitoredBCfrompersonallymonitoredsulfate,HRVmeasureswereinfluencedbyBCorurbanorindustrialair,butnotsulfate,regionalairmassescontaininglowlevelsofBC,orruralairmasses,eventhoughhighintotalPM2.
5.
Inthesestudies,PM2.
5wasconsistentlyassociatedwithHRVchangeswhenitwashighlycorrelatedwithBC,butlesssootherwise.
AlthoughmetalswerenotmonitoredinanyoftheHRVstudies,thesulfatefindinginParketal.
[90]fortheairmasswithlowPMandlowsulfatewhichpassedneartheSudburynickelsmelterissuggestiveoftheNiassociationfoundbyLippmannetal.
[99],i.
e.
,HRVwasalteredinamousemodelonlywhenthewindtrajectorywassuchthattheairmasspassednearthenickelsmelter.
ThosepollutantsthatwereassociatedwithalterationinHRVwerealsoassociatedwithproductionofoxidativestresswhich,asnoted,canmediateHRVchanges.
GrahameandSchlesingerParticleandFibreToxicology2012,9:21Page14of19http://www.
particleandfibretoxicology.
com/content/9/1/21ConclusionsThedevelopmentofCVDisduetobothgeneticanden-vironmentalfactors.
However,atanindividuallevel,bothsusceptibilitytoandthechronologicalageatonsetofCVDvariesbetweensubjectswhomayhavesimilarclassicalriskfactors.
Aportionofthisinterindividualdifferencelikelyreflectsdifferencesinbiologicalaging.
Furthermore,thereisevidencethatoxidativestressmaybeapathogeneticmechanism/riskfactorthatunderliesbothsuchagingandthedevelopmentofCVD,sinceoxi-dativestresshasbeenshowntoberelatedtotheiniti-ationandprogressionofCVD.
Shortenedtelomerelengthisamarkerofbiologicalageandakeyprocessrelatedtodevelopmentofage-relatedpathology.
Telomereshorteningitselfappearstobeacauseofincreasedratesofmorbidityandmortality,bothdirectlyastissuefunctionnormallygraduallydeclines,andindirectlyasaccumulationofsenescentcellsacceleratedevelopmentofpathologies.
Studiesdiscussedinthispaperhaveshownthatoxida-tivestressacceleratestelomereerosion,andthatstrategiestoreduceoxidativestresscanhelpmaintaintelomerelength.
Furthermore,biologicalagingappearstoberelatedtothecumulativeburdenofoxidativestress.
Telo-mericlengthseemstoberelatedtothedevelopmentofCVDincertainpopulationgroups,oxidativestressappearstobeaconsistentriskfactorfordevelopmentofCVD,andmeantelomerelengthcanactnotonlyasamarkerofthisprocess,butacause.
Vehicularemissionsinvarioussettingshavebeenasso-ciatedwithdevelopmentofoxidativestress.
BaseduponasmallnumberofinvestigationsexaminingmetalsinPM2.
5,suchspeciesasNi,V,Cu,Zn,Mn,andCrhaveallbeenlinkedtosomemeasureofoxidativestress.
StudiesreviewedhereinalsofoundthatBCandprimaryorganiccarbonisstrongly,andconsistently,associatedwithvari-ousmeasuresofoxidativestresswhentherewasaccur-atesubjectexposure.
Secondaryairmasses,ruralairmassesorsulfatewhenexaminedinHRVstudieswithaccurateexposureassessmentwerenotassociatedwithoxidativestressinthesestudies.
Sincecertaincomponentsofairpollutionorspecifictypesofpollutionhavebeenfoundtoresultinoxidativestress,itisconceivablethatthismechanismunderliesanarrayofdiseasesassociatedwithincreasingage,inpar-ticularCVD,theleadingcauseofdeathintheU.
S.
Inthisreview,wehaveproposedthatoxidativestresscausedbyexposuretocertainairpollutantsmayberesponsibleforincreasedmortalityandmorbidityandforacceleratingahostofCVDstatesorriskfactors,bymeansofaccelerat-ingtheerosionoftelomerelength.
Ifthishypothesisistrue,thenitispossiblethatairpollutantswhichcauseoxidativestressmightberesponsibleforthemajorityofairpollution-relatedCVDmortalityandmorbidity.
Insum,thereissubstantialevidencetobelievethatve-hicularemissions,andspecificcomponentsofsuchemissions,shortenlivesbyacceleratingtheerosionoftelomeresviaoxidativestress,thusadvancingvariouscardiovasculardiseases.
Thismayconstituteageneral-izedpathwaybywhichoxidativestressmayinducemuchofthemorbidity/mortalityduetovehicularemissions,ashypothesizedbytheHealthEffectsInstitute[4],althoughanyroleofoxidativestressintelomereerosionwasnotmentionedinthatReport.
Thisproposedpathwaymayalsoexplainthefindingthatreductionofaunitofambi-entBCwasfoundtoextendlife4to9timesmorethanreducingacomparableamountoftotalPM2.
5[100].
MoreanalysisisneededtounderstandtheextenttowhichotherPM2.
5speciesmaybeinvolved,andalsotounderstandwhichmeasuresofoxidativestresscanmostreliablypredictacceleratedtelomereerosion.
UncertaintiesandresearchrecommendationsThereareanumberofquestionsanduncertaintiesthatremaintobeaddressedinrelationtothehypothesispro-posedinthispaper.
–Variousbiomarkersareoftenusedtoreflectenvironmentalpollutantexposuresand/orasasurrogatemeasureofadiseaseprocess[101,102].
Inordertobeusefulinthisregard,themarkermusthavesomepredictivevalidity,butthisisoftennotthecaseinthatwhilesomemarkersmaybegenerallyindicativeofoxidativestress,theymayhavelittlerelationshiptodiseaseprocessesoroutcomes[101,103].
Partoftheproblemmayliewithartifactsproducedduringthesamplecollectiontosampleanalysisprogression,orduetointeractionwithfactorsnotbeingassessed[101].
Furthermore,itisnotalwaysclearwhetherspecificmarkersarereflectiveofacuteorchronicexposuretoanoxidativestressor.
Inaddition,abiomarkermeasuredinonecellortissuemaynotreflectlevelsandactivityinothercellsortissuesand,thus,maynotbeanappropriatesurrogate;therefore,thesemarkerscannotbeusedinterchangeably.
[104].
Whileoxidationproductsofnucleicacids,lipidsandproteinsmaybefoundinvarioustissues,ourunderstandingoftherelationshipbetweentitersinvarioustissuesanddiseaseprocessesisoftenunclear[105].
Thus,withregardtotheroleofoxidativestressinacceleratingtherateoftelomereshortening,weneedtounderstandifdifferentmarkersfordetectingoxidativestressareessentiallyequivalentinindicatingtheextentofsuchshorteningandunderwhatexposureconditionstheymayormaynotbesoreflective.
Inotherwords,weneedabetterunderstandingofwhichmeasuresofGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page15of19http://www.
particleandfibretoxicology.
com/content/9/1/21oxidativestressareunambiguouslyassociatedwithacceleratedtelomereerosion.
–Itisinterestingtonotethatcigarettesmoke,aknownetiologicalfactorforCVD,hasbeenshowntocorrelatewithacceleratedshorteningoftelomeresinsomestudiesbutnotinothers[106].
Ithasbeensuggestedthatsincethecorrelationbetweentelomerelengthandsmokingappearstobesmall,itisdetectableonlywithlargesamplesizesandmanystudiesmayhavebeentoosmalltodetectanysuchassociation[102,106].
Furthermore,theliteraturethatrelatescigarettesmokingtobiomarkersofoxidativestressalsoprovidesconflictingresults,andthismayalsobeduetosmallorselectedsamplesorutilizationofambiguousmarkers[104,107].
Itisconceivablethatsomeinconsistencywithmarkersofoxidativestress,telomerelengthandexposuretoairpollutants,asnotedherein,maybeduetothesefactorsaswell.
–ThereneedstobeafullerunderstandingofwhichPM2.
5speciescauseoxidativestress.
ItiscrucialtohavemorehumanpanelstudieswithaccurateexposureandwhichincludemetalsamongthePM2.
5speciesexamined.
AnotherwaytotestwhichPM2.
5speciesmaycauseadverseeffectsistoperformmorecrossoverstudieswithfacemasksindifferentsettings,soastoruleoutcertainPMcomponentsofsuchairmassesascausesofoxidativestress.
Thiswillhelpinsettingregulatorypolicytoprotectpublichealthifonlyparticles,andnotassociatedgases,continuetobecausallyrelatedtooxidativestress.
–Itwouldbeusefultoundertakefurtherstudiestoconfirm(orotherwise)thatsecondaryairmasseswithlittlevehicularorindustrialemissionsdonotcauseoxidativestress.
Onewaytodosuchtestswouldbetoexaminepeopleinareasdominatedbyruralairmassesenrichedwithsecondaryorganiccarbonandsulfate,butfarfromdieselsources,roadwaysandindustry.
TestsforcirculatingandurinarybiomarkersandHRVchangescouldbeconductedinconcertwithmonitoringthatwouldincludemetalspecies,someofwhichcanapparentlycauseadversehealtheffectshundredsofmilesfromtheirsourceevenwhenpresentintraceamounts.
–TheexposureissuesnotedabovewouldapplyevenmoretostudiesinAsiaandEurope,wherecloseproximitytotrafficortooperatingdieselsawayfromtraffic(e.
g.
,inrepairshopsorinspectionstations)wasthemetricforexposure,withpollutantssuchasBCoftennotmonitored.
Innear-roadenvironments,itwillbeimportanttoseeifcomponentsofroaddust,oftenmarkedbySi,mightalsocauseoxidativestress.
Perhapsathreewaytestcouldbeused:(A)aroadwithalmostnodiesels,inadryareawhereroaddustwouldaccumulate;(B)aroadwithalmostnodiesels,inawetterareahavinglittleroaddustaccumulation,sothatparticleswouldmostlybefromvehicularemissionsbutlessfromroaddust;and(C)aroadwithmanydiesels.
Effectswithandwithoutfacemaskscouldbecompared,atvaryingdistancesfromeachroad,incombinationwithpersonalpollutionmonitors.
Itispossiblethatfacemasksmightnotpreventoxidativestressineverycase,anditispossiblethatoxidativestressmaynotbepresentineverycase,whichwouldagainbeusefulknowledgeforprotectingpublichealth.
–Inspiteofresultsfromanimalandinvitrostudies,theineffectivenessofadministeredantioxidantsinreducingCVDmorbidityormortalityinsomehumanclinicalandinterventiontrialshasledtoaquestioningoftheimportanceofoxidativestressindiseasepathogenesis[108,109].
Forexample,acomprehensivestudyfoundthatstandardover-the-counterantioxidantsappearnottohave"expected"beneficialeffectsonreducingCVDmortalityandmorbidity[110].
TheAntioxidantSupplementationinAtherosclerosisPrevention[111],astudyinwhich520menandwomenwererandomizedtoreceiveeitherVit.
E,slowreleaseVit.
C,oracombinationofthetwo,foundthatmen,butnotwomen,benefittedfromthecombinationtherapyintermsoftheextentofprogressionofcarotidintimamediathickness.
Otheranti-oxidants,suchasNAC(N-acetyl-cysteine),mightbemorehelpfulthanstandardvitamins,butseemtohavereceivedlessstudy.
NACactsasanantioxidantbyreplenishinglevelsofglutathione(GSH),acrucialanti-oxidantproducedbythebody,andhasalongerbiologicalhalf-timeinthebodythando"over-the-counter"anti-oxidantssuchasvitaminC.
AnotherstudyfoundthatoxidativestressinducedbypollutioninnursinghomeresidentsinMexicoCitywassignificantlyreducedbydietarysupplementationofomega-3fattyacids[112].
Thus,itmaybethatthemixedresultsinreducingCVDwithantioxidantsmaybeduepartlytothetypesofanti-oxidantscustomarilyused,and/orinparttothelackofspecificandsensistivebiomarkersbywhichtoassessoxidativestressphenotypesthatunderlyCVD[108].
Ifthehypothesisthatairpollutantsshortentelomeresviaoxidativestressissubstantiated,thendiscoveringhowtoreduceoxidativestressviainexpensiveinterventionsbecomesahighpriority.
CompetinginterestsTGandRBSdeclarenocompetinginterests.
Authors'contributionBothauthorscontributedthroughoutthereportintermsofwritingandediting.
TGlargelycontributeddiscussionsofoxidativestresseffectsofairpollution,RBlargelycontributeddiscussionsofeffectsofoxidativestressonGrahameandSchlesingerParticleandFibreToxicology2012,9:21Page16of19http://www.
particleandfibretoxicology.
com/content/9/1/21telomerelengthandrelationshipofCVDtotelomerelengthandoxidativestress.
Allauthorsreadandapprovedthefinalmanuscript.
DisclaimerThisarticleisdedicatedtothememoryofRichardWolf.
TheopinionsexpressedhereinarethoseoftheauthorsanddonotnecessarilyreflecttheopinionorpolicyoftheUnitedStatesDepartmentofEnergy.
Authordetails1UnitedStatesDepartmentofEnergy,1000IndependenceAvenue,SWWashington,DC20585,USA.
2DepartmentofBiologyandHealthSciences,DysonCollegeofArtsandSciencesPaceUniversity,OnePacePlaza,NewYork,NY,USA.
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