Review Article Neurotoxicants Are in the Air: Convergence

Review ArticleNeurotoxicants Are in the Air Convergence of Human Animaland In Vitro Studies on the Effects of Air Pollution on the Brain

Lucio G Costa12 Toby B Cole13 Jacki Coburn1 Yu-Chi Chang1

Khoi Dao1 and Pamela Roque1

1 Department of Environmental and Occupational Health Sciences University of Washington 4225 Roosevelt Suite No 100Seattle WA 98105 USA

2Department of Neuroscience University of Parma Via Volturno 39 43100 Parma Italy3 Center on Human Development and Disability University of Washington Seattle WA 98195 USA

Correspondence should be addressed to Lucio G Costa lgcostauwashingtonedu

Received 6 November 2013 Revised 23 December 2013 Accepted 24 December 2013 Published 12 January 2014

Academic Editor Ambuja Bale

Copyright copy 2014 Lucio G Costa et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

In addition to increasedmorbidity andmortality caused by respiratory and cardiovascular diseases air pollutionmay also negativelyaffect the brain and contribute to central nervous system diseases Air pollution is a mixture comprised of several componentsof which ultrafine particulate matter (UFPM lt100 nm) is of much concern as these particles can enter the circulation anddistribute to most organs including the brain A major constituent of ambient UFPM is represented by traffic-related air pollutionmostly ascribed to diesel exhaust (DE) Human epidemiological studies and controlled animal studies have shown that exposureto air pollution may lead to neurotoxicity In addition to a variety of behavioral abnormalities two prominent effects causedby air pollution are oxidative stress and neuroinflammation which are seen in both humans and animals and are confirmedby in vitro studies Among factors which can affect neurotoxic outcomes age is considered the most relevant Human andanimal studies suggest that air pollution (and DE) may cause developmental neurotoxicity and may contribute to the etiologyof neurodevelopmental disorders including autistic spectrum disorders In addition air pollution exposure has been associatedwith increased expression of markers of neurodegenerative disease pathologies

1 Introduction

Air pollution is a mixture comprised of several componentsincluding ambient particulate matter (PM) gases organiccompounds and metals The association between air pol-lution and morbidity and mortality caused by respiratoryand cardiovascular diseases is well established [1ndash3] Amongair pollution components PM is believed to be the mostwidespread threat and has been heavily implicated in disease[2 4 5] PM is broadly characterized by aerodynamic diame-ter (eg PM

10and PM

25 equivalent to lt10 120583m and 25 120583m

in diameter respectively [2]) Ultrafine particulate matter(UFPM lt100 nm) is of much concern as these particlescan more easily enter the circulation and distribute tovarious organs including the brain [6 7] Of most relevanceis also the fact that UFPM can gain access to the braindirectly through the nasal olfactory mucosa reaching first

the olfactory bulb [7ndash11] In vitro studies have shown thatPM is cytotoxic and that toxicity is size-dependent with thesmaller UFPM being better able to enter the cells and exerttoxic effects [12ndash15]

The populations of many countries (eg China IndiaMiddle East and Central America) are commonly exposedfor extended periods to relatively high levels (gt100 120583gm3)of PM [2] and such concentrations can be easily reachednear trafficked roads and significantly exceeded in certainoccupational settings [16] Oxidative stress and inflammationare the two cardinal processes by which air pollution isbelieved to exert its peripheral toxicity [2 17 18] PMhas beenshown to affect lung cardiovascular and nervous systemfunctions by mechanisms that involve oxidative stress [1920] and oxidative damage has been shown to be a primarymechanism of PM toxicity [4 19 21] For example alter-ations in expression of some oxidative stress-related genes

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 736385 8 pageshttpdxdoiorg1011552014736385

2 BioMed Research International

and other markers of oxidative stress have been shown inrodents following DE exposures [20 22ndash25]The same seemsto be true with regard to the nervous system as markers ofoxidative stress and neuroinflammation are increased as aresult of exposure to air pollution [7 26]

Traffic-related air pollution is a major contributor toglobal air pollution and diesel exhaust (DE) is its mostimportant component [27] DE contains more than 40 toxicair pollutants and is a major constituent of ambient PMparticularly of UFPM and DE exposure is often utilized asa measure of traffic-related air pollution

This commentary is intended to briefly summarize themain findings to date on the effects of air pollution (andmore specifically of traffic-related air pollution) on the centralnervous system by analyzing and comparing findings fromhuman epidemiological studies controlled animal studiesand in vitro experiments Particular attention is devoted toage as a potential susceptibility factor as air pollution mayplay an etiological role in neurodevelopmental and neurode-generative disordersThere appears to be a significant conver-gence of findings between humans and animals pointing tosimilar alterations in the central nervous system (CNS) andto common mechanisms involving increased oxidative stressand neuroinflammation Limited in vitro studies supportthese in vivo findings and should be expanded to betterdefine underlying mechanisms A number of additionalissues that warrant further investigations (eg role of gendergenetic susceptibility) are also discussed

2 Neurotoxic Effects of Air Pollutionin Humans

In recent years evidence has been slowly accumulatingsuggesting that air pollution may negatively affect the CNSand contribute to CNS diseases [7 26 28ndash30] Human epi-demiological studies have shown that elevated air pollutionis associated with decreased cognitive function in childrenadults and the elderly [29 31ndash37] Olfactory dysfunctionauditory deficits depressive symptoms and other adverseneuropsychological effects have also been reported [32 35 3839] Few studies have examined neurotoxic effects followingcontrolled exposure of humans to DE for example acuteexposure to 300 120583gm3 DE has been shown to cause airwayinflammation and to induce EEG changes [27 40]

Young as well as aging individuals appear to be par-ticularly susceptible to air pollution-induced neurotoxic-ity [31ndash34 36 37 41ndash43] In case of pre- or postnatalexposures this might cause or contribute to developmentaldisabilities and behavioral abnormalities while during agingsuch exposures may contribute to neurodegenerative dis-eases Indeed increased incidences of neurodegenerative dis-ease pathologies namely increased beta-amyloid 42 hyper-phosphorylated tau and increased alpha-synuclein havebeen found [41 43ndash45] suggesting that air pollutionmay con-tribute to the etiopathogenesis of neurodegenerative diseasesPrimary mechanisms of air pollution neurotoxicity appearto be related to oxidative stress and neuroinflammationwhich are also involved in the etiopathology of various neuro-degenerative diseases [46ndash49]

In addition to a series of animal studies (discussedbelow) human studies are also suggestive of developmentalneurotoxicity of air pollution Studies inMexicoCity revealedelevated levels of neuroinflammatory markers in the brainsof children exposed to high levels of air pollution [31 43]as well as cognitive deficits [32] In a recent comparison ofchildren (average age 12 years) exposed to either high or lowair pollution in various Mexican locations the former werefound to have higher levels of proinflammatory markers inthe cerebrospinal fluid and in serum [50]

Newman et al [51] reported hyperactivity in 7-year-oldchildren associated with early life exposure to traffic relatedair pollution Two studies by Volk et al [52 53] found thatresidential proximity to freeways and gestational and early lifeexposure to traffic-related air pollution were associated withautism (OR = 186 95 CI 104ndash345) This was confirmedby another recent study in which perinatal DE exposurewas significantly associated with autism spectrum disorders(ASD) particularly in boys [54] The latter findings areparticularly of interest as there is increasing evidence indi-cating that children with ASD have higher levels of oxidativestress [55ndash57] as well as increased neuroinflammation andsystemic inflammation [58ndash60] As noted earlier these arethe typical effects found in individuals exposed to severe airpollution The etiology of ASD is unknown though ASDhave a hereditary component [61 62] A number of candidatesusceptibility genes for ASD have been identified but nosingle anomaly appears to predominate though the total frac-tion of ASD attributable to genetic inheritance may be about30ndash40 [62] Thus environmental factors are increasinglysuspected as playing a pivotal role in the etiology of ASDmost likely when affecting susceptible individuals [62ndash64]Using mouse models of ASD to study the neurotoxicologyof gene-environment interactions may be a promising novelavenue to investigate a potential role of air pollution in theetiology of ASD [65]

In summary the available evidence in humans albeitlimited is highly suggestive that exposure to high levelsof air pollution can negatively affect the CNS and perhapscontribute to neurodevelopmental andor neurodegenera-tive diseases Furthermore as indicated markers of oxida-tive stress neuroinflammation and neurodegeneration areincreased in postmortem human brain samples and in otheraccessible tissues similarly to what is observed in animals

3 Neurotoxic Effects of Air Pollution inAnimals and In Vitro Studies

Animal observations and controlled studies confirm andexpand the observations in humans and limited in vitroevidence is suggestive of potential mechanisms For examplein a postmortem study in Mexico City similar neuropatho-logical lesions in the prefrontal cortex were observed in bothchildren and dogs [31] Dogs exposed to Mexico City airpollution presented evidence of chronic inflammation neu-rodegeneration and DNA damage in various brain regions[28 66] In mice exposed to concentrated PM neuroinflam-mation was seen in the brain as evidenced by increasedlevels of various cytokines and of NF-120581B [67] The latter

BioMed Research International 3

result was also found in ApoEminusminus mice exposed to UFPMtogether with increases inmitogen-activated kinase pathwaysand of GFAP (glial fibrillary acidic protein) [68] Furtherstudies in ApoEminusminus mice which are known to be more proneto oxidative damage have shown that subchronic exposureto concentrated ambient particles causes degeneration ofdopaminergic neurons in the substantia nigra as a result ofoxidative stress [69] Increases in proinflammatory cytokines(eg IL-1120573 IL-6) have been found in the brains of miceexposed to traffic in a highway tunnel [70]

Several animal studies have involved controlled expo-sures to DE Exposure of adult mice to DE has been reportedto alter locomotor activity spatial learning and memory andnovel object recognition ability [71ndash73] Nasal instillation ofnanoparticle-rich DE alters emotional behavior and learningcapability in rats [74] Biochemical and molecular studieshave evidenced that some prominent effects of DE exposureon the CNS are oxidative stress and neuroinflammation[14 19 75] Prolonged exposure of rats to DE was foundto increase several proinflammatory cytokines in differentregions of the brain including the striatum [76] A short-term exposure of rats to high levels of DE found similarinduction of proinflammatory cytokines and other enzymesin brain regions and in lung [23] Neuroinflammation mayresult from systemic inflammation which may affect the CNSthrough circulating cytokines or by direct entry of UFPMinto the brain and activation of microglia [26] Markers ofneuroinflammation have been found to be increased uponlong-term air pollution exposure in young adults at autopsy[43] and in rodents following DE exposure [16 45 76]

An in vitro study showed that DE particles can activatemicroglia and microglia-derived oxidant species caused thedemise of dopaminergic neurons [12]Thus in vitro evidencesupports the in vivo findings of a role of microglia activationoxidative stress and neuroinflammation in DE neurotoxicityDE particles have also been shown to cause oxidative stressand to increase inflammatory cytokines in brain capillariesin vitro suggesting that DE particle may directly affectthe blood-brain barrier [22] Another recent in vitro studyin mouse hippocampal slices found that DE nanoparticlesaltered glutamatergic neurotransmission and expression ofNMDA receptors in the CA1 region [77] which might haverelevance to the behavioral impact reported above

There is also initial evidence that exposure to DE maycause developmental neurotoxicity in experimental animals[78] In utero exposure to high levels of DE (10mgm3)caused alterations in motor activity alterations in motoractivity motor coordination and impulsive behavior in malemice with concomitant alterations in dopamine and sero-tonin neurochemistry [79ndash81] In another study early post-natal exposure of mice to concentrated ambient PM has beenreported to cause subtle behavioral changes (enhanced biastowards immediate rewards) without alteration in locomotoractivity [82] while depression-like responses were foundin mice exposed prenatally to urban air nanoparticles [83]Additional studies showed that prenatal DE exposures ofmice caused altered locomotor activity and spatial learn-ing and memory changes in gene expression (including

X-chromosome inactivation factor) changes in neuronaldifferentiation neuro-inflammation and oxidative damage[71 72 80 83ndash87] Of interest is that the effects of prenatalexposure to DE on gene expression in the olfactory bulbwere nullified by rearing the mouse pups with environmentalenrichment [87] suggesting the possibility of therapeuticbehavioral interventions in heavily exposed children Pre-natal DE exposure predisposes offspring to weight gain andto insulin resistance and induces neuroinflammation [88]A recent study found that prenatal and early life exposureof mice to DE is associated with the presence of a numberof behaviors similar to those in humans with ASD Theseincluded higher levels of locomotor activity elevated levelsof self-grooming and increased rearings [89]

In summary examination of animals exposed to airpollution ambiently or in controlled experiments revealsthe same pattern of neurotoxic effects (increased markersof oxidative stress and of neuroinflammation age-relatedsusceptibility) as in humans suggesting that animal studieswould be useful predictors of human outcomes In vitrostudies albeit very limited so far should be increased asthey should allow better definition of the exact mechanism(s)underlying the observed CNS damage

4 Questions and Research Needs

Air pollution ranks among the top ten leading risk factorsfor mortality possibly responsible for over 3 million deathseach year [7]While respiratory and cardiovascularmorbidityand mortality have been long seen as a primary consequenceof high air pollution exposure evidence emerging in thepast decade suggests that the CNS may also be a signifi-cant target As discussed in this commentary and in otherrecent reviews [7 30 39] human epidemiological studiesand animal experiments are suggesting similar patterns ofCNS damage involving oxidative stress and neuroinflam-matory processes As these alterations are believed to beinvolved in the etiopathologies of neurodevelopmental andneurodegenerative diseases it becomes apparent that thecontribution of air pollution to CNS disorders may be ofgreat significance The convergence of findings in humansand animals is of much importance as it will allow rapidtesting and verification of hypotheses which can also becorroborated by in vitro approaches A number of issuesshould be considered most of which have only been partiallyaddressed

41 Mechanisms of UFPMNeurotoxicity Beyond the OlfactoryBulb It is well established that PM may enter the brainand affect the olfactory bulb and either travel to ldquomoreremoterdquo regions or allow the damage to be transmitted to suchregions [8ndash11] For example olfaction problems have beenreported in individuals exposed to heavy air pollution [38]Olfactory dysfunction is also an early important symptomof neurodegenerative diseases particularly of Parkinsonrsquosdisease [90ndash93] in which damage to the olfactory bulb actu-ally precedes neuropathology in the motor areas such assubstantia nigra and striatum [94] There is the need tobetter understand the events and mechanisms that lead to


an involvement of the distal brain regions in the neurotoxiceffects of air pollution In addition to dopaminergic areaswhich have been shown to be affected in certain studies (eg[69]) cholinergic and glutamatergic areas important forcognitive behaviors and involved in other neurodegenerativedisorders may be affected by air pollution and should befurther investigated In addition novel paradigms of neu-rotoxic damage may also be explored For example adultneurogenesis is believed to be essential for cognitive processes[95 96] and has been shown to be negatively affected byneuroinflammation [96 97] Whether air pollution has anyeffect on adult neurogenesis remains to be investigated

42 Peripheral versus Direct Central Effects While air pollu-tion components may exert their deleterious effects directlyon the CNS the possibility and the extent of a peripheralcontribution to the central effects should be further exploredHigh levels of circulating proinflammatory cytokines maynegatively affect the CNS [26 50] and the blood-brainbarrier may represent an important site for air pollutionneurotoxicity that has been little studied so far

43 The Role of Gender in Susceptibility to Air PollutionNeurotoxicity While age represents an important factor ofsusceptibility in air pollution-induced neurotoxicity twoadditional factors gender and genetic background shouldalso be considered [98 99] With regard to gender wehad recently proposed that the differential expression ofthe enzyme paraoxonase 2 (PON2) in brain between malesand females may be responsible for a number of genderdifferences in neurotoxicity [100] PON2 is a mitochondrialenzyme capable of scavenging reactive oxygen species (ROS)thereby protecting cells from oxidative stress-induced toxi-city [100 101] In all tissues brain regions CNS cell typesand in both mice and humans PON2 which has also anti-inflammatory properties is expressed at higher levels infemales [100 102] These findings prompted us to test thehypothesis thatmalemicemay bemore susceptible to air pol-lution neurotoxicity than female animals Preliminary find-ings shown in Table 1 appear to support this hypothesis asupon exposure of mice to DE a marker of lipid peroxidation(malondialdehyde) and a proinflammatory cytokine (tumornecrosis factor-alpha) were increased in the hippocampusand to a greater extent in male animals As air pollution maybe involved in the etiopathogenesis of neurodevelopmentaland neurodegenerative diseases whose incidence is usuallyhigher in males (eg [103]) gender differences in the effectsof air pollution deserve further investigations

44 Genetic Susceptibility to Air Pollution Neurotoxicity Asin several other fields gene-environment interactions shouldbe investigated as genetic polymorphisms may modulatesusceptibility to air pollution neurotoxicity Given the promi-nent role of oxidative stress genetically based differences inantioxidant enzymesmay thus predispose certain individualsto significant air pollution neurotoxicity Glutathione (GSH)is one of the most abundant cellular thiols and a majorplayer in cellular defense against ROS as it nonenzymatically

Table 1 Gender differences in the effects of diesel exhaust

FA DEMDA (nmolg)

M 47 plusmn 02 133 plusmn 03lowastlowast

F 22 plusmn 01 42 plusmn 02lowast

TNF-120572 (pgmL)M 14 plusmn 04 98 plusmn 19lowastlowast


Male and female mice were exposed for 6 h to diesel exhaust (DE 250ndash300120583gm3) or filtered air (FA) and levels of malondialdehyde (MDA) andof tumor necrosis factor-alpha (TNF-120572) were measured in the hippocampusas markers of oxidative stress (lipid peroxidation) and neuroinflammationrespectively Results indicate the mean (plusmnSE) with 119899 = 3 DE versus FAlowast119875 lt 005 lowastlowast119875 lt 001 M versus F

119875 lt 005 (two-way ANOVAfollowed by Bonferroni test for multiple comparisons) (from [104] Costaet al unpublished results)

scavenges both singlet oxygen and hydroxyl radicals andis used by glutathione peroxidases glutathione transferasesand peroxiredoxin-6 to limit the levels of certain reactivealdehydes and peroxides within the cell When ROS pro-duction exceeds the antioxidant defense capacity of the celloxidative stress ensues leading to damage of DNA proteinsand membrane lipids The first and rate-limiting step inthe synthesis of GSH is carried out by glutamate-cysteineligase which consists of a catalytic subunit (GCLC) anda modifier or regulatory subunit (GCLM) [105] GCLCalone provides catalytic activity however in the absence ofGCLM the ability of GCLC to synthesize GSH is drasticallyreduced [106] A relatively common C588T polymorphismhas been discovered in the 51015840-flanking region of the humanGCLM gene with individuals carrying the T allele havinglower promoter activity in a luciferase reporter gene assayin response to oxidants and significantly lower plasma GSHlevels [107] Individuals with GCLM polymorphisms orwith other mutations leading to decreased GSH levels [106]would thus be expected to display an enhanced sensitivityto the adverse effects of environmental chemicals that elicitoxidative stress Gclm null mice (Gclmminusminus) have very lowGSH levels in all tissues including the brain [108] butmay upregulate alternative antioxidant pathways whileGclmheterozygous mice (Gclm+minus) have only moderate reductionsin GSH and may more closely resemble the human GCLMpolymorphism A preliminary testing of the hypothesis isshown in Table 2 Male mice exposed to diesel exhaustdisplayed the expected increase in markers of oxidative stressand neuroinflammation of interest is that the effects weremore pronounced in Gclmminusminus and in Gclm+minus mice (Table 2)These results substantiate previous findings of enhanced lunginflammation in Gclm+minus mice compared to wild-type miceupon exposure to DE [24] Given the abundance of geneticpolymorphisms of enzymes involved in oxidative stress [106109] this avenue of investigation warrants further research

5 Conclusion

While considering potential sources of compounds thatmay contribute to the etiology of neurodevelopmental and


Table 2 Genetic polymorphisms and the effects of diesel exhaust

Gclm FA DE

MDA (nmolg)++ 57 plusmn 02 212 plusmn 03lowastlowast

minusminus 52 plusmn 03 354 plusmn 03lowastlowast

+minus 97 plusmn 10 450 plusmn 07lowastlowast

IL-1120573 (pgmL)++ 127 plusmn 16 311 plusmn 61lowastlowast



Male mice were exposed for 6 h to diesel exhaust (DE 250ndash300120583gm3) orfiltered air (FA) and levels of malondialdehyde (MDA) and of interleukin1-beta (IL-1120573) were measured in the olfactory bulb as markers of oxidativestress (lipid peroxidation) and neuroinflammation respectively Results arethe mean (plusmnSE) with 119899 = 3 DE versus FA lowastlowast119875 lt 001 Gclm++ versusGclmminusminus or Gclm+minus 119875 lt 005 (two-way ANOVA followed by Bonferronitest for multiple comparisons) (Costa et al unpublished results)

neurodegenerative diseases diet has often been consideredas a primary vehicle of exposure Indeed many knownneurotoxicants and developmental neurotoxicants are foodcontaminants Yet the air we breathe seems a logical poten-tial source of chemicals which may exert neurotoxicitythough attention has been limited for several decades onlyto effects on the respiratory system and more recently onthe cardiovascular system Evidence has been accumulatingduring the past decade providing strong suggestions thatexposure to high levels of high pollution very common inmany cities all around the world is associated with damageto the CNS Human and animal studies have evidenceda series of common adverse effects of air pollution (PMin particular) with oxidative stress and neuroinflammationemerging as the hallmark effects A variety of behavioralalterations has also been reported together with changes insome neurotransmitter systems These and other aspects ofair pollution neurotoxicity need to be further investigatedParticularly troublesome is the suggestion that air pollutionmay contribute to the etiopathology of neurodevelopmentaland neurodegenerative diseases (eg autism or dementia)whose incidence is increasing in the global populationsNeedless to say that in addition to further biomedicalresearch to augment our understanding of the effects andmechanisms of air pollution on the CNS measures should betaken to curtail emissions and exposures

Conflict of Interests

The authors declare that they have no conflict of interests

Acknowledgment

Research by the authors is supported in part by Grantsfrom theNational Institute of Environmental Health Sciences(R01ES022949 and P30ES07033)

References

[1] R D Brook and S Rajagopalan ldquoAir pollution and cardiovas-cular eventsrdquoTheNew England Journal ofMedicine vol 356 no20 pp 2104ndash2105 2007

[2] R D Brook S Rajagopalan C A Pope et al ldquoParticulatematter air pollution and cardiovascular disease an update tothe scientific statement from the american heart associationrdquoCirculation vol 121 no 21 pp 2331ndash2378 2010

[3] E A Gill C L Curl S D Adar et al ldquoAir pollution and car-diovascular disease in themulti-ethnic study of atherosclerosisrdquoProgress in Cardiovascular Diseases vol 53 no 5 pp 353ndash3602011

[4] PMoslashllerN R Jacobsen J K Folkmann et al ldquoRole of oxidativedamage in toxicity of particulaterdquo Free Radical Research vol 44no 1 pp 1ndash46 2010

[5] T D Nelin A M Joseph M W Gorr and L E Wold ldquoDirectand indirect effects of particulate matter on the cardiovascularsystemrdquo Toxicology Letters vol 208 no 3 pp 293ndash299 2012

[6] G Oberdorster Z Sharp V Atudorei et al ldquoExtrapulmonarytranslocation of ultrafine carbon particles following whole-body inhalation exposure of ratsrdquo Journal of Toxicology andEnvironmental Health A vol 65 no 20 pp 1531ndash1543 2002

[7] S Genc Z Zadeoglulari S H Fuss and K Genc ldquoThe adverseeffects of air pollution on the nervous systemrdquo Journal ofToxicology vol 2012 Article ID 782462 23 pages 2012

[8] G Oberdorster andM J Utell ldquoUltrafine particles in the urbanair to the respiratory tractmdashAng beyondrdquo EnvironmentalHealth Perspectives vol 110 no 8 pp A440ndashA441 2002

[9] G Oberdorster Z Sharp V Atudorei et al ldquoTranslocation ofinhaled ultrafine particles to the brainrdquo Inhalation Toxicologyvol 16 no 6-7 pp 437ndash445 2004

[10] A Peters B Veronesi L Calderon-Garciduenas et al ldquoTranslo-cation and potential neurological effects of fine and ultrafineparticles a critical updaterdquo Particle and Fibre Toxicology vol 3article 13 2006

[11] R G Lucchini D C Dorman A Elder and B VeronesildquoNeurological impacts from inhalation of pollutants and thenose-brain connectionrdquoNeuroToxicology vol 33 no 4 pp 838ndash841 2012

[12] M L Block X Wu Z Pei et al ldquoNanometer size diesel exhaustparticles are selectively toxic to dopaminergic neurons the roleof microglia phagocytosis and NADPH oxidaserdquo The FASEBJournal vol 18 no 13 pp 1618ndash1620 2004

[13] W G Kreyling M Semmler and W Moller ldquoDosimetry andtoxicology of ultrafine particlesrdquo Journal of Aerosol Medicinevol 17 no 2 pp 140ndash152 2004

[14] T-TWin-Shwe andH Fujimaki ldquoNanoparticles andNeurotox-icityrdquo International Journal of Molecular Sciences vol 12 no 9pp 6267ndash6280 2011

[15] P Gillespie J Tajuba M Lippmann L-C Chen and BVeronesi ldquoParticulate matter neurotoxicity in culture is size-dependentrdquo NeuroToxicology vol 36 pp 112ndash117 2013

[16] S Levesque T Taetzsch M E Lull et al ldquoDiesel exhaust acti-vates and primes microglia air pollution neuroinflammationand regulation of dopaminergic neurotoxicityrdquo EnvironmentalHealth Perspectives vol 119 no 8 pp 1149ndash1155 2011

[17] M Lodovici and E Bigagli ldquoOxidative stress and air pollutionexposurerdquo Journal of Toxicology vol 2011 Article ID 487074 9pages 2011

[18] J O Anderson J G Thundiyil and A Stolbach ldquoClearing theair a review of the effects of particulate matter air pollution onhuman healthrdquo Journal of Medical Toxicology vol 8 no 2 pp166ndash175 2012

[19] S M J MohanKumar A Campbell M Block and B VeronesildquoParticulate matter oxidative stress and neurotoxicityrdquo Neuro-toxicology vol 29 no 3 pp 479ndash488 2008


[20] C S Weldy H-W Wilkerson T V Larson J A Stewartand T J Kavanagh ldquoDiesel particulate exposed macrophagesalter endothelial cell expression of eNOS iNOS MCP1 andglutathione synthesis genesrdquo Toxicology in Vitro vol 25 no 8pp 2064ndash2073 2011

[21] N Li C Sioutas A Cho et al ldquoUltrafine particulate pollutantsinduce oxidative stress and mitochondrial damagerdquo Environ-mental Health Perspectives vol 111 no 4 pp 455ndash460 2003

[22] A M S Hartz B Bauer M L Block J-S Hong and DS Miller ldquoDiesel exhaust particles induce oxidative stressproinflammatory signaling and P-glycoprotein up-regulationat the blood-brain barrierrdquo The FASEB Journal vol 22 no 8pp 2723ndash2733 2008

[23] D van Berlo C Albrecht A M Knaapen et al ldquoComparativeevaluation of the effects of short-term inhalation exposureto diesel engine exhaust on rat lung and brainrdquo Archives ofToxicology vol 84 no 7 pp 553ndash562 2010

[24] C S Weldy C C White H-W Wilkerson et al ldquoHeterozygos-ity in the glutathione synthesis gene Gclm increases sensitivityto diesel exhaust particulate induced lung inflammation inmicerdquo Inhalation Toxicology vol 23 no 12 pp 724ndash735 2011

[25] F Yin A Lawal J Ricks et al ldquoDiesel exhaust inducessystemic lipid peroxidation and development of dysfunctionalpro-oxidant and pro-inflammatory high-density lipoproteinrdquoArteriosclerosis Thrombosis and Vascular Biology vol 33 pp1153ndash1161 2013

[26] M L Block and L Calderon-Garciduenas ldquoAir pollutionmechanisms of neuroinflammation and CNS diseaserdquo Trends inNeurosciences vol 32 no 9 pp 506ndash516 2009

[27] A J Ghio C B Smith andM C Madden ldquoDiesel exhaust par-ticles and airway inflammationrdquo Current Opinion in PulmonaryMedicine vol 18 no 2 pp 144ndash150 2012

[28] L Calderon-Garciduenas B Azzarelli H Acuna et al ldquoAirpollution and brain damagerdquo Toxicologic Pathology vol 30 no3 pp 373ndash389 2002

[29] J-C Chen and J Schwartz ldquoNeurobehavioral effects of ambientair pollution on cognitive performance inUS adultsrdquoNeuroTox-icology vol 30 no 2 pp 231ndash239 2009

[30] M L Block A Elder R L Auten et al ldquoThe outdoor airpollution and brain health workshoprdquo Neurotoxicology vol 33pp 972ndash984 2012

[31] L Calderon-Garciduenas A Mora-Tiscareno E Ontiveroset al ldquoAir pollution cognitive deficits and brain abnormalitiesa pilot study with children and dogsrdquo Brain and Cognition vol68 no 2 pp 117ndash127 2008

[32] L Calderon-Garciduenas R Engle A Mora-Tiscareno et alldquoExposure to severe urban air pollution influences cognitiveoutcomes brain volume and systemic inflammation in clinicallyhealthy childrenrdquoBrain and cognition vol 77 no 3 pp 345ndash3552011

[33] U Ranft T Schikowski D Sugiri J Krutmann and UKramer ldquoLong-term exposure to traffic-related particulatemat-ter impairs cognitive function in the elderlyrdquo EnvironmentalResearch vol 109 no 8 pp 1004ndash1011 2009

[34] C Freire R Ramos R Puertas et al ldquoAssociation of traffic-related air pollution with cognitive development in childrenrdquoJournal of Epidemiology and Community Health vol 64 no 3pp 223ndash228 2010

[35] L K Fonken X Xu Z M Weil et al ldquoAir pollution impairscognition provokes depressive-like behaviors and alters hip-pocampal cytokine expression and morphologyrdquo MolecularPsychiatry vol 16 no 10 pp 987ndash995 2011

[36] M C Power M G Weisskopf S E Alexeeff B A Coull SAvron III and J Schwartz ldquoTraffic-related air pollution andcognitive function in a cohort of older menrdquo EnvironmentalHealth Perspectives vol 119 no 5 pp 682ndash687 2011

[37] J Weuve R C Puett J Schwartz J D Yanosky F Laden and FGrodstein ldquoExposure to particulate air pollution and cognitivedecline in older womenrdquo Archives of Internal Medicine vol 172no 3 pp 219ndash227 2012

[38] L Calderon-Garciduenas M Franco-Lira C Henrıquez-Roldan et al ldquoUrban air pollution influences on olfactoryfunction and pathology in exposed children and young adultsrdquoExperimental and Toxicologic Pathology vol 62 no 1 pp 91ndash102 2010

[39] M Guxens and J Sunyer ldquoA review of epidemiological studieson neuropsychological effects of air pollutionrdquo Swiss MedicalWeekly vol 141 Article ID w13322 2012

[40] B Cruts A Driessen L van Etten et al ldquoExposure to dieselexhaust induces changes in EEG in human volunteersrdquo Particleand Fibre Toxicology vol 5 article 4 2008

[41] L Calderon-Garcidueas M Kavanaugh M Block et al ldquoNeu-roinflammation hyperphosphorylated tau diffuse amyloidplaques and down-regulation of the cellular prion protein inair pollution exposed children and young adultsrdquo Journal ofAlzheimerrsquos Disease vol 28 no 1 pp 93ndash107 2012

[42] M Guxens I Aguilera F Ballester et al ldquoPrenatal exposureto residential air pollution and infant mental developmentmodulation by antioxidants and detoxification factorsrdquo Envi-ronmental Health Perspectives vol 120 no 1 pp 144ndash149 2012

[43] L Calderon-Garciduenas A C Solt C Henrıquez-Roldan etal ldquoLong-term air pollution exposure is associated with neu-roinflammation an altered innate immune response disruptionof the blood-brain barrier ultrafine particulate deposition andaccumulation of amyloid 120573-42 and 120572-synuclein in children andyoung adultsrdquo Toxicologic Pathology vol 36 no 2 pp 289ndash3102008

[44] L Calderon-GarciduenasWReed R RMaronpot et al ldquoBraininflammation and Alzheimerrsquos-like pathology in individualsexposed to severe air pollutionrdquo Toxicologic Pathology vol 32no 6 pp 650ndash658 2004

[45] S Levesque M J Surace J McDonald and M L Block ldquoAirpollution and the brain subchronic diesel exhaust exposurecauses neuroinflammation and elevates early markers of neu-rodegenerative diseaserdquo Journal of Neuroinflammation vol 8article 105 2011

[46] J L Teeling and V H Perry ldquoSystemic infection and inflam-mation in acute CNS injury and chronic neurodegenerationunderlyingmechanismsrdquoNeuroscience vol 158 no 3 pp 1062ndash1073 2009

[47] Y J Lee S B Han S Y Nam K W Oh and J T HongldquoInflammation and Alzheimerrsquos diseaserdquo Archives of PharmacalResearch vol 33 pp 1539ndash1556 2010

[48] L Qian P M Flood and J-S Hong ldquoNeuroinflammation is akey player in Parkinsonrsquos disease and a prime target for therapyrdquoJournal of Neural Transmission vol 117 no 8 pp 971ndash979 2010

[49] N Zilka Z Kazmerova S Jadhav et al ldquoWho fans the flamesof Alzheimerrsquos disease brains Misfolded tau on the crossroadof neurodegenerative and inflammatory pathwaysrdquo Journal ofNeuroinflammation vol 9 article 47 2012

[50] L Calderon-Garciduenas J V Cross M Franco-Lira et alldquoBrain immune interactions and air pollution macrophageinhibitory factor (MIF) prion cellular protein (PrP119862)


interleukin-6 (IL-6) interleukin 1 receptor antagonist (IL-1Ra)and interleukin-2 (IL-2) in cerebrospinal fluid and MIF inserum differentiate urban children exposed to severe vs lowair pollutionrdquo Frontiers in Neuroscience vol 7 article 183 2013

[51] C N Newman P Ryan G LeMasters et al ldquoTraffic related airpollution exposure in the first year of life and behavioral scoresat 7 years of agerdquo Environmental Health Perspectives vol 121 pp731ndash736 2013

[52] H E Volk I Hertz-Picciotto L Delwiche F Lurmann and RMcConnell ldquoResidential proximity to freeways and autism intheCHARGE studyrdquoEnvironmentalHealth Perspectives vol 119no 6 pp 873ndash877 2011

[53] H E Volk F Lurmann B Penfold I Hertz-Picciotto and RMcConnell ldquoTraffic-related air pollution particulate matterand autismrdquo The Journal of the American Medical Associationvol 70 pp 71ndash77 2013

[54] A L Roberts K Lyall J E Hart et al ldquoPerinatal air pollutantexposures and autism spectrum disorder in the Children ofNursesrsquo Health Study II participantsrdquo Environmental HealthPerspectives vol 121 pp 978ndash984 2013

[55] S Rose S Melnyk O Pavliv et al ldquoEvidence of oxidativedamage and inflammation associated with low glutathioneredox status in the autism brainrdquo Translational Psychiatry vol2 article e134 2012

[56] A Frustaci M Neri A Cesario et al ldquoOxidative stress-relatedbiomarkers in autism systematic review and meta-analysesrdquoFree Radical Biology and Medicine vol 52 pp 2128ndash2141 2012

[57] E Napoli SWong and C Giulivi ldquoEvidence of reactive oxygenspecies-mediated damage to mitochondrial DNA damage inchildren with typical autismrdquo Molecular Autism vol 4 article2 2013

[58] A El-Ansary and L Al-Ayadhi ldquoNeuroinflammation in autismspectrum disordersrdquo Journal of Neuroinflammation vol 9article 265 2012

[59] T C Theoharides S Asadi and A B Patel ldquoFocal braininflammation and autismrdquo Journal of Neuroinflammation vol10 article 46 2013

[60] A M Depino ldquoPeripheral and central inflammation in autismspectrum disordersrdquo Molecular and Cellular Neuroscience vol53 pp 69ndash76 2013

[61] S E Levy D SMandell and R T Schultz ldquoAutismrdquoTheLancetvol 374 no 9701 pp 1627ndash1638 2009

[62] P J Landrigan L Lambertini and L S Birnbaum ldquoA researchstrategy to discover the environmental causes of autism andneurodevelopmental disabilitiesrdquo Environmental Health Per-spectives vol 7 pp A258ndashA260 2012

[63] P J Landrigan ldquoWhat causes autism Exploring the environ-mental contributionrdquo Current Opinion in Pediatrics vol 22 no2 pp 219ndash225 2010

[64] R Deth C Muratore J Benzecry V-A Power-Charnitsky andM Waly ldquoHow environmental and genetic factors combine tocause autism a redoxmethylation hypothesisrdquo NeuroToxicol-ogy vol 29 no 1 pp 190ndash201 2008

[65] J J Schwartzer C M Koenig and R F Berman ldquoUsing mousemodels of asutism spectrum disorders to study the neurotoxi-cology of gene-environment interactionsrdquo Neurotoxicology andTeratology vol 36 pp 17ndash35 2013

[66] L Calderon-Garciduenas R R Maronpot R Torres-Jardon etal ldquoDNA damage in nasal and brain tissues of canines exposedto air pollutants is associated with evidence of chronic braininflammation and neurodegenerationrdquo Toxicologic Pathologyvol 31 no 5 pp 524ndash538 2003

[67] A Campbell M Oldham A Becaria et al ldquoParticulate matterin polluted air may increase biomarkers of inflammation inmouse brainrdquoNeuroToxicology vol 26 no 1 pp 133ndash140 2005

[68] M T Kleinman J A Araujo A Nel et al ldquoInhaled ultrafineparticulatematter affects CNS inflammatory processes andmayact via MAP kinase signaling pathwaysrdquo Toxicology Letters vol178 no 2 pp 127ndash130 2008

[69] B Veronesi O Makwana M Pooler and L C Chen ldquoEffectsof subchronic exposure to concentrated ambient particles VIIDegeneration of dopaminergic neurons in Apo Eminusminus micerdquoInhalation Toxicology vol 17 no 4-5 pp 235ndash241 2005

[70] I Bos P de Boever J Emmerechts et al ldquoChanged geneexpression in brains of mice exposed to traffic in a highwaytunnelrdquo Inhalation Toxicology vol 24 pp 676ndash686 2012

[71] K S Hougaard A T Saber K A Jensen U Vogel and HWallin ldquoDiesel exhaust particles effects on neurofunction infemale micerdquo Basic and Clinical Pharmacology and Toxicologyvol 105 no 2 pp 139ndash143 2009

[72] T-T Win-Shwe S Yamamoto Y Fujitani S Hirano andH Fujimaki ldquoSpatial learning and memory function-relatedgene expression in the hippocampus of mouse exposed tonanoparticle-rich diesel exhaustrdquo NeuroToxicology vol 29 no6 pp 940ndash947 2008

[73] T T Win-Shwe H Fujimaki Y Fujitani and S Hirano ldquoNovelobject recognition ability in female mice following exposureto nanoparticle-rich diesel exhaustrdquo Toxicology and AppliedPharmacology vol 262 pp 355ndash362 2012

[74] S Yokota H Takashima R Ohta et al ldquoNasal instillationof nanoparticle-rich diesel exhaust particles slightly affectsemotional behavior and learning capability in ratsrdquo Journal ofToxicological Sciences vol 36 no 3 pp 267ndash276 2011

[75] A D Kraft and G Jean Harry ldquoFeatures of microglia andneuroinflammation relevant to environmental exposure andneurotoxicityrdquo International Journal of Environmental Researchand Public Health vol 8 no 7 pp 2980ndash3018 2011

[76] M E Gerlofs-Nijland D van Berlo F R Cassee R P F SchinsK Wang and A Campbell ldquoEffect of prolonged exposure todiesel engine exhaust on proinflammatory markers in differentregions of the rat brainrdquo Particle and Fibre Toxicology vol 7article 12 2010

[77] D A Davis G Akopian J P Walsh C Sioutas T E Morganand C E Finch ldquoUrban air pollutants reduce synaptic functionof CA1 neurons via an NMDANO∙ pathway in vitrordquo Journalof Neurochemistry vol 88 pp 1437ndash1441 2013

[78] M Ema M Naya M Horimoto and H Kato ldquoDevelopmentaltoxicity of diesel exhaust a review of studies in experimentalanimalsrdquo Reproductive Toxicology vol 42 pp 1ndash17 2013

[79] S Yokota K Mizuo N Moriya S Oshio I Sugawara andK Takeda ldquoEffect of prenatal exposure to diesel exhaust ondopaminergic system in micerdquo Neuroscience Letters vol 449no 1 pp 38ndash41 2009

[80] S Yokota N Moriya M Iwata M Umezawa S Oshio and KTakeda ldquoExposure to diesel exhaust during fetal period affectsbehavior and neurotransmitters in male offspring micerdquo TheJournal of Toxicological Sciences vol 38 pp 13ndash23 2013

[81] T Suzuki S Oshio M Iwata et al ldquoIn utero exposure to a lowconcentration of diesel exhaust affects spontaneous locomotoractivity and monoaminergic system in male micerdquo Particle andFibre Toxicology vol 7 article 7 2010

[82] J L Allen K Conrad G Oberdoester C J Johnston BSleezer and D A Cory-Slechta ldquoDevelopmental exposure to


concentrated ambient particles and preference for immediaterewards inmicerdquoEnvironmentalHealth Perspectives vol 121 pp32ndash38 2013

[83] D A Davis M Bortolato S C Godar et al ldquoPrenatal exposureto urban air nanoparticles in mice causes altered neuronaldifferentiation and depression-like responsesrdquo PLoS ONE vol8 Article ID e6418 2013

[84] K S Hougaard K A Jensen P Nordly et al ldquoEffects of prenatalexposure to diesel exhaust particles on postnatal developmentbehavior genotoxicity and inflammation in micerdquo Particle andFibre Toxicology vol 5 article 3 2008

[85] N Tsukue M Watanabe T Kumamoto H Takano and KTakeda ldquoPerinatal exposure to diesel exhaust affects geneexpression in mouse cerebrumrdquo Archives of Toxicology vol 83no 11 pp 985ndash1000 2009

[86] T Kumamoto N Tsukue H Takano K Takeda and S OshioldquoFetal exposure to diesel exhaust affects X-chromosome inac-tivation factor expression in micerdquo The Journal of ToxicologicalSciences vol 38 pp 245ndash254 2013

[87] S Yokota H Hori M Umezawa et al ldquoGene expressionchanges in the olfactory bulb of mice induced by exposure todiesel exhaust are dependent on animal rearing environmentrdquoPLoS ONE vol 8 Article ID e70145 2013

[88] J L Bolton S H Smith N C Huff et al ldquoPrenatal air pol-lution exposure induces neuroinflammation and predisposesoffspring to weight gain in adulthood in a sex-specific mannerrdquoThe FASEB Journal vol 26 pp 4743ndash4754 2012

[89] K Thirtamara Rajamani S Doherty-Lyons C Bolden et alldquoPrenatal and early-life exposure to high level diesel exhaustparticles leads to increased locomotor activity and repetitivebehaviors in micerdquo Autism Research vol 6 pp 248ndash257 2013

[90] R I Mesholam P J Moberg R N Mahr and R L DotyldquoOlfaction in neurodegenerative disease a meta-analysis ofolfactory functioning inAhlzheimerrsquos and Parkinsonrsquos diseasesrdquoArchives of Neurology vol 55 no 1 pp 84ndash90 1998

[91] R L Doty P F Reyes and T Gregor ldquoPresence of both odoridentification and detection deficits in Alzheimerrsquos diseaserdquoBrain Research Bulletin vol 18 no 5 pp 597ndash600 1987

[92] R L Doty ldquoOlfaction in Parkinsonrsquos disease and related disor-dersrdquo Neurobiology of Disease vol 46 pp 527ndash552 2012

[93] R L Doty ldquoOlfactory dysfunction in Parkinson diseaserdquoNatureReviews Neurology vol 8 pp 329ndash339 2012

[94] H Braak E Ghebremedhin U Rub H Bratzke and K delTredici ldquoStages in the development of Parkinsonrsquos disease-related pathologyrdquo Cell and Tissue Research vol 318 no 1 pp121ndash134 2004

[95] W Deng J B Aimone and F H Gage ldquoNew neurons and newmemories how does adult hippocampal neurogenesis affectlearning and memoryrdquo Nature Reviews Neuroscience vol 11no 5 pp 339ndash350 2010

[96] G-LMing andH Song ldquoAdult neurogenesis in themammalianbrain significant answers and significant questionsrdquo Neuronvol 70 no 4 pp 687ndash702 2011

[97] C T Ekdahl J-H Claasen S Bonde Z Kokaia andO LindvallldquoInflammation is detrimental for neurogenesis in adult brainrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 23 pp 13632ndash13637 2003

[98] J E Clougherty ldquoA growing role for gender analysis in airpollution epidemiologyrdquo Environmental Health Perspectivesvol 118 no 2 pp 167ndash176 2010

[99] A Zanobetti A Baccarelli and J Schwartz ldquoGene-air pollutioninteraction and cardiovascular disease a reviewrdquo Progress inCardiovascular Diseases vol 53 no 5 pp 344ndash352 2011

[100] G Giordano L Tait C E Furlong T B Cole T J Kavanaghand L G Costa ldquoGender differences in brain susceptibility tooxidative stress aremediated by levels of paraoxonase-2 (PON2)expressionrdquo Free Radical Biology and Medicine vol 58 pp 98ndash108 2013

[101] G Giordano T B Cole C E Furlong and L G CostaldquoParaoxonase 2 (PON2) in the mouse central nervous systema neuroprotective rolerdquo Toxicology and Applied Pharmacologyvol 256 no 3 pp 369ndash378 2011

[102] L G Costa R de Laat K Dao C Pellacani T B Cole and C EFurlong ldquoParaoxonase-2 (PON2) in brain and its potential rolein neuroprotectionrdquo Neurotoxicology 2013

[103] S K van den Eeden C M Tanner A L Bernstein et alldquoIncidence of Parkinsonrsquos disease variation by age gender andraceethnicityrdquo The American Journal of Epidemiology vol 157no 11 pp 1015ndash1022 2003

[104] G Giordano A Engstrom C S Weldy T J Kavanagh F Farinand L G Costa ldquoHigher susceptibility of male mice to dieselexhaust neurotoxicityrdquo Toxicologist vol 132 no 1 p 54 2013

[105] R Dringen ldquoMetabolism and functions of glutathione in brainrdquoProgress in Neurobiology vol 62 no 6 pp 649ndash671 2000

[106] T P Dalton Y Chen S N Schneider D W Nebert and HG Shertzer ldquoGenetically altered mice to evaluate glutathionehomeostasis in health and diseaserdquo Free Radical Biology andMedicine vol 37 no 10 pp 1511ndash1526 2004

[107] S-I Nakamura K Kugiyama S Sugiyama et al ldquoPolymor-phism in the 51015840-flanking region of human glutamate-cysteineligase modifier subunit gene is associated with myocardialinfarctionrdquo Circulation vol 105 no 25 pp 2968ndash2973 2002

[108] G Giordano C C White L A McConnachie C FernandezT J Kavanagh and L G Costa ldquoNeurotoxicity of domoic acidin cerebellar granule neurons in a genetic model of glutathionedeficiencyrdquo Molecular Pharmacology vol 70 no 6 pp 2116ndash2126 2006

[109] A Crawford R G Fassett D P Geraghty et al ldquoRelation-ships between single nucleotide polymorphisms of antioxidantenzymes and diseaserdquo Gene vol 501 no 2 pp 89ndash103 2012

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


BioMed Research International


Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


Neural Plasticity


Parkinsonrsquos Disease


Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Psychiatry Journal


Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases


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Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


and other markers of oxidative stress have been shown inrodents following DE exposures [20 22ndash25]The same seemsto be true with regard to the nervous system as markers ofoxidative stress and neuroinflammation are increased as aresult of exposure to air pollution [7 26]

Traffic-related air pollution is a major contributor toglobal air pollution and diesel exhaust (DE) is its mostimportant component [27] DE contains more than 40 toxicair pollutants and is a major constituent of ambient PMparticularly of UFPM and DE exposure is often utilized asa measure of traffic-related air pollution

This commentary is intended to briefly summarize themain findings to date on the effects of air pollution (andmore specifically of traffic-related air pollution) on the centralnervous system by analyzing and comparing findings fromhuman epidemiological studies controlled animal studiesand in vitro experiments Particular attention is devoted toage as a potential susceptibility factor as air pollution mayplay an etiological role in neurodevelopmental and neurode-generative disordersThere appears to be a significant conver-gence of findings between humans and animals pointing tosimilar alterations in the central nervous system (CNS) andto common mechanisms involving increased oxidative stressand neuroinflammation Limited in vitro studies supportthese in vivo findings and should be expanded to betterdefine underlying mechanisms A number of additionalissues that warrant further investigations (eg role of gendergenetic susceptibility) are also discussed

2 Neurotoxic Effects of Air Pollutionin Humans

In recent years evidence has been slowly accumulatingsuggesting that air pollution may negatively affect the CNSand contribute to CNS diseases [7 26 28ndash30] Human epi-demiological studies have shown that elevated air pollutionis associated with decreased cognitive function in childrenadults and the elderly [29 31ndash37] Olfactory dysfunctionauditory deficits depressive symptoms and other adverseneuropsychological effects have also been reported [32 35 3839] Few studies have examined neurotoxic effects followingcontrolled exposure of humans to DE for example acuteexposure to 300 120583gm3 DE has been shown to cause airwayinflammation and to induce EEG changes [27 40]

Young as well as aging individuals appear to be par-ticularly susceptible to air pollution-induced neurotoxic-ity [31ndash34 36 37 41ndash43] In case of pre- or postnatalexposures this might cause or contribute to developmentaldisabilities and behavioral abnormalities while during agingsuch exposures may contribute to neurodegenerative dis-eases Indeed increased incidences of neurodegenerative dis-ease pathologies namely increased beta-amyloid 42 hyper-phosphorylated tau and increased alpha-synuclein havebeen found [41 43ndash45] suggesting that air pollutionmay con-tribute to the etiopathogenesis of neurodegenerative diseasesPrimary mechanisms of air pollution neurotoxicity appearto be related to oxidative stress and neuroinflammationwhich are also involved in the etiopathology of various neuro-degenerative diseases [46ndash49]

In addition to a series of animal studies (discussedbelow) human studies are also suggestive of developmentalneurotoxicity of air pollution Studies inMexicoCity revealedelevated levels of neuroinflammatory markers in the brainsof children exposed to high levels of air pollution [31 43]as well as cognitive deficits [32] In a recent comparison ofchildren (average age 12 years) exposed to either high or lowair pollution in various Mexican locations the former werefound to have higher levels of proinflammatory markers inthe cerebrospinal fluid and in serum [50]

Newman et al [51] reported hyperactivity in 7-year-oldchildren associated with early life exposure to traffic relatedair pollution Two studies by Volk et al [52 53] found thatresidential proximity to freeways and gestational and early lifeexposure to traffic-related air pollution were associated withautism (OR = 186 95 CI 104ndash345) This was confirmedby another recent study in which perinatal DE exposurewas significantly associated with autism spectrum disorders(ASD) particularly in boys [54] The latter findings areparticularly of interest as there is increasing evidence indi-cating that children with ASD have higher levels of oxidativestress [55ndash57] as well as increased neuroinflammation andsystemic inflammation [58ndash60] As noted earlier these arethe typical effects found in individuals exposed to severe airpollution The etiology of ASD is unknown though ASDhave a hereditary component [61 62] A number of candidatesusceptibility genes for ASD have been identified but nosingle anomaly appears to predominate though the total frac-tion of ASD attributable to genetic inheritance may be about30ndash40 [62] Thus environmental factors are increasinglysuspected as playing a pivotal role in the etiology of ASDmost likely when affecting susceptible individuals [62ndash64]Using mouse models of ASD to study the neurotoxicologyof gene-environment interactions may be a promising novelavenue to investigate a potential role of air pollution in theetiology of ASD [65]

In summary the available evidence in humans albeitlimited is highly suggestive that exposure to high levelsof air pollution can negatively affect the CNS and perhapscontribute to neurodevelopmental andor neurodegenera-tive diseases Furthermore as indicated markers of oxida-tive stress neuroinflammation and neurodegeneration areincreased in postmortem human brain samples and in otheraccessible tissues similarly to what is observed in animals

3 Neurotoxic Effects of Air Pollution inAnimals and In Vitro Studies

Animal observations and controlled studies confirm andexpand the observations in humans and limited in vitroevidence is suggestive of potential mechanisms For examplein a postmortem study in Mexico City similar neuropatho-logical lesions in the prefrontal cortex were observed in bothchildren and dogs [31] Dogs exposed to Mexico City airpollution presented evidence of chronic inflammation neu-rodegeneration and DNA damage in various brain regions[28 66] In mice exposed to concentrated PM neuroinflam-mation was seen in the brain as evidenced by increasedlevels of various cytokines and of NF-120581B [67] The latter

















FA DEMDA (nmolg)








5 Conclusion




Gclm FA DE











Acknowledgment


References































































































































Neural Plasticity










Psychiatry Journal









Journal of


















FA DEMDA (nmolg)








5 Conclusion




Gclm FA DE











Acknowledgment


References































































































































Neural Plasticity










Psychiatry Journal









Journal of








FA DEMDA (nmolg)








5 Conclusion




Gclm FA DE











Acknowledgment


References































































































































Neural Plasticity










Psychiatry Journal









Journal of




Gclm FA DE











Acknowledgment


References































































































































Neural Plasticity










Psychiatry Journal









Journal of













































































































Neural Plasticity










Psychiatry Journal









Journal of













































































Neural Plasticity










Psychiatry Journal









Journal of











































Neural Plasticity










Psychiatry Journal









Journal of














Neural Plasticity










Psychiatry Journal









Journal of


Documents

Review Article Neurotoxicants Are in the Air: Convergence