Understanding the effects of air pollution on neurogenesis and gliogenesis in the growing and adult brain
Enrica Boda
1,2, Antonello E Rigamonti
3and Valentina Bollati
3Exposuretoairpollution—andparticularlytoparticulate matter(PM)–isstronglyassociatedwithhigherriskof neurodevelopmentaldisorders,poormentalhealthand cognitivedefects.Inanimalmodels,disruptionofCNS developmentanddisturbancesofadultneurogenesis contributetoPMneurotoxicity.Recentstudiesshowthat gestationalPMexposurenotonlyaffectsembryonic neurodevelopment,butalsodisturbspostnatalbraingrowth andmaturation,byinterferingwithneurogenic/gliogenic events,myelinationandsynaptogenesis.Similarly,adult neurogenesisisaffectedatmanylevels,fromneuralstemcell amplificationuptothematurationandintegrationofnovel neuronsintheadultbrainparenchyma.Theunderlying mechanismsarestillbyandlargeunknown.Beyondmicroglia activationandneuroinflammation,recentstudiesproposea rolefornovelepigeneticmechanisms,includingDNA methylationandextracellularvesicles-associatedmicroRNAs.
Addresses
1DepartmentofNeuroscienceRitaLevi-Montalcini,UniversityofTurin, Italy
2NeuroscienceInstituteCavalieriOttolenghi(NICO),UniversityofTurin, RegioneGonzole,10–10043Orbassano,Turin,Italy
3DepartmentofClinicalSciencesandCommunityHealth,Universityof Milan,Milan,Italy
Correspondingauthor:Boda,Enrica([email protected])
CurrentOpinioninPharmacology2020,50:xx–yy
ThisreviewcomesfromathemedissueonNeurosciences:
neurogenesis
EditedbyAnnalisaBuffoandStefaniaCeruti
https://doi.org/10.1016/j.coph.2019.12.003 1471-4892/ã2019ElsevierLtd.Allrightsreserved.
Exposuretoair pollutionisincreasinglyacknowledgedas oneofthemaincontributorstotheglobaldiseaseburden[1].
Ithasbeenestimatedthatin201691%oftheworldpopula- tionwaslivinginplaceswheretheWHOairqualityguide- lineslevelswerenotmet(https://www.who.int/news-room/
fact-sheets/detail/ambient-(outdoor)-air-quality-and- health).Amongthekeyairpollutantsthatposehealthrisks, particulatematter(PM)isoneofthemostwidespread.PMis
aheterogeneousmixture of smallsolidor liquidparticles releasedintotheatmosphereduringcombustionprocesses oremittedbyindustrialactivitiesandnaturalsources.PM generally comprises water soluble and insoluble compo- nents,includinginorganiccompounds,polycyclicaromatic hydrocarbons,heavymetalsandothertoxicsubstances,and microbialcomponents,suchasbacteriaandtheirproductsof degradation(e.g.lipopolysaccharide)andviruses[2].PMis definedaccordingtoitsaerodynamicdiameter,withcoarse PMsmallerthan10mm(PM10)andfineandultrafinePM smaller than 2.5 (PM2.5) or0.1 (PM0.1) mm,respectively.
Thankstotheirsmallsize,wheninhaled,PMparticleshave the capability to percolate through the respiratory tract.
WhilePM10istrappedintheupperairways,PM2.5reaches thelungsanddepositsinthealveolararea.Ultrafineparticles couldevenpenetrateintothebloodcirculationandover- cometheblood-brain-barrier(BBB)[3,4],orpassthrough thenasalmucosaanddirectlyenterthebrain[5,6].Ofnote, inhalednanoparticleshave been showntocrosstheplacental barrierandtodepositinthefetaltissuesinanimalmodels [7], suggesting apossiblemother-to-fetus transfer ofair- borneultrafinePM.
Chronic exposureto air pollution hasbeen consistently associated with risk of cardiovascular and respiratory diseases, and different types of cancer [1]. Increasing evidence also indicatesthat thecentral nervous system (CNS)isatargetforairpollution.Inuteroandearlychild exposuretohighlevelsofairpollution,andinparticularto PM,isassociatedwithhigherriskofneurodevelopmental disorders, long-lasting behavioral alterations and cogni- tive defects[8,9]. Moreover, during adulthood, chronic PM exposure has been associated with poor mental health,increasedriskofonsetandworseningofdepres- sion[9],whilebothshortandlongtermexposurehasbeen associatedwithcognitive/memorydeterioration[10,11].
Moststudiesinanimalmodelsthataimedatestablishing a causative link between air pollution and anatomical/
functionalCNSalterations,andatunveilingtheunderly- ing mechanisms, are focused on the effects of PM. In rodents, PM exposure results in neurodevelopmental, cognitiveandbehavioralalterationsreminiscentofthose observedinhumans,whoseextentanddurationdepend onPMsize,dosesandtimingofexposure[12–15,16,17].
Mechanistically,disruptionofCNSdevelopmentandof adultneurogenesiswasfoundtocontributetoPMdetri- mental effects, suggesting the occurrence of similar events inhumans(Figure1).
Inthisreview,wesummarizerecentadvancementstoward theunderstanding of the cellular andmolecular mecha- nisms mediating PM effects on thedevelopmental and adultneurogenesisandgliogenesis,discusslimitationsof theavailablestudiesandhighlightpersistingopenissues.
InuteroandneonatalexposuretoPMinduces neurodevelopmentalalterations inanimal models
Inmice,chronicprenatalexposuretohighlevelsoffineand ultrafinePMwasreportedlyassociatedwithreducedbrain weightandventriculomegalyatbirthandduringthefirst postnatalperiod[13,18].Thisistheoutcomeofthedisrup- tionof specific anddiverse neurodevelopmentalevents.
Exposure to diesel exhaust particles (DEP) in mouse pregnantdamsthroughoutgestationresulted,intheoff- spring, in increased cortical (i.e. prefrontal cortex) and hippocampal(i.e.dentategyrus,DG)volumesatembry- onicday(E)18,whichswitchedtodecreasedcorticalvol- umeandnormalizedhippocampalsizeinpostnatalday(P) 30 males (but not in females), compared to untreated animals[19].Similarly,maternal inhalation ofcarbonblack nanoparticles(producedbytheincompletecombustionof petroleumproducts)resultedinaninitialincreaseofpar- valbumin-positive(+)neuronsintheuppermostlayersof themotorcortex,followedbyalargereductionatlatertime points [20]. These results suggest that gestational PM
exposuremaydifferentiallyaffectdistinctphasesofbrain development and cause an initial tissue overgrowth — possiblyduetoneuralstemcell(NSC)/progenitoroverex- pansion—followedbypostnatalregressiveevents.Thus, theeffectsonCNSdevelopmentofinuteroPMexposure canbepersistentandextendbeyondtheembryonicperiod.
Inlinewiththisinterpretation,tworecentstudies[12,21]
haveshownthatchronicprenatalexposuretohighdosages of PM2.5 resulted in increased neuronal and astrocyte apoptosis in thecortex and distincthippocampal subre- gions, including the DG, of the offspring at P14-P30.
Postnatalhippocampalneurogenesisandastrogliogenesis appearedalsodramaticallyreduced,duetothesuppression ofNSCproliferationinthesubgranularzone(SGZ).Simi- larly,parenchymalastro-and oligodendro-gliaamplifica- tion was affected, as indirectly assessed by the large decreaseoftheproliferationmarkerPCNAinthecortex ofP1-P30offspring[21].Inagreementwiththisfinding, gestationalchronic exposureto fineand ultrafineparti- cles has been associated with precocious myelination andprematureoligodendroglia proliferation/differentia- tion switch in the corpus callosum of the adolescent offspring[13,22].Dendritic complexity[15] and num- ber of asymmetric excitatory synapses impinging on hippocampal neurons were also significantly reduced in adolescent (P14) mice prenatally exposed to PM2.5.Theremainingsynapses showed altered— and
Figure1
Effects in young adults
Newborn neurons:
proliferation -proliferation
-proliferation CC -volume
-PV+ neurons
OPC expansion
OPC maturation &
myelination apoptosis
of neurons and astrocytes
apoptosis of neurons and astrocytes
-dentritic
complexity Unaltered
astrogliogenesis -survival
-acquisition of mature markers
-dendritic complexity BBB
breakdown
EV-associated miRNAs Microglia
& astrocyte reactivity
DNA methylation
NSCs/intermediate progenitors:
In-utero PM exposure Adult PM exposure
CORTEX DG/SGZ
Current Opinion in Pharmacology
PM-inducedalterationsdetectedintheadultmousebrainfollowingin-uterooradultexposure.
Orangeboxes(above)includetheproposedunderlyingmechanisms.BBB,blood-brainbarrier;CC,corpuscallosum;DG/SGZ,hippocampal dentategyrus/subgranularzone;EV,extracellularvesicles;NSCs,neuralstemcells;OPC,oligodendrocyteprecursorcell;PM,particulatematter;
PV,parvalbumin.
possibly compensatory —features, includingincreased number ofpresynapticvesicles,thickenedpostsynaptic density anddecreased synapticspace [12].
Thus, gestationalPM exposure notonly affectsembry- onicneurodevelopment,butalsodisturbspostnatalbrain growth and maturation,by interfering with neurogenic/
gliogenicevents,myelinationandsynaptogenesis. Preg- nancy appears to beaparticularlyvulnerable time win- dow, since neonatal exposure had milder effects, and mostly affected myelination [23,24] and expression of synaptic proteins[14].
PM exposuredisturbs adultneurogenesis in animal models
In the adult mouse brain, generation of new neurons continuesinthesubventricularzone(SVZ)ofthelateral ventriclesandintheSGZofthehippocampus[25].Adult neurogenesisintheSVZcannotbedetectedinhumans, whereascontroversialevidencehasbeenprovidedabout thegeneration of newneuronsin theadult humanhip- pocampus [26,27,28].Thus,whileadulthippocam- palneurogenesisisimplicatedincognitiveprocessesand moodregulationinrodents[29],whetherthisoccursalso in adult humansis highly debated. Nevertheless,adult neurogenesisinrodentsrecapitulatesmanyaspectsofthe developmental neurogenic/gliogenic events. Therefore, the study of the mechanisms mediating PM-induced perturbations of the adult neurogenic niches is still of interest,asitcanunveilcriticaltoxicityprocessesoperat- ingin bothdevelopingand matureCNS.
Inarecentstudy,acuteexposuretofineDEPcausedan impairment of adult neurogenesis in mice. This effect was gender-specific, with males showing fewer newly- generatedneuronsinSGZ,SVZandolfactorybulb(OB), compared to control animals, and females displaying fewernew neuronsonly intheOB[30].Reduced neu- rogenesiswasaconsequenceofdecreasedproliferationof NSCs/progenitors,reducedsurvivalofimmatureneurons, and alteredspecification/differentiationof newbornele- ments(i.e.reduced fractionofnewborncells expressing the mature neuronalmarker NeuN 3 weeks after their generation [30]). Moreover, life-long exposure to con- centratedwater-solublesubfractionofPM0.2dramatically reducedthenumberofSGZnewbornneurons-butnot of newborn astrocytes- in adult male rats, which also showed contextual memory defects and depressive behaviors [16].Thus,PMappearstonegativelymodu- late the neurogenic events atmany levels, from NSCs division up tothe maturation and integration ofnovel neuronsintheadultbrainparenchyma.Inlinewiththis view,chronicinhalationofammoniumsulfate,themajor inorganic component in PM2.5 (as resulting from the reaction of ammonia, mostly originating from animal farming and synthetic fertilizers, with sulfur dioxide emitted bytheburningoffossilfuels[31]),diminished
thedendriticcomplexityofimmatureneuronsintheDG of aged rats [32]. However, in this latter study, no alteration of SGZ/SVZ NSC/progenitor proliferation and of the specification of their derivatives could be detected, highlighting a specific neurotoxicity of the distinct componentsofPM.
Proposed mechanismsunderlyingthe effects ofPM onneurogenesisand gliogenesis Inrodents,neuroinflammationaccompaniedbymicroglia andastrocyteactivationwerecardinaleffectsofPMexpo- sure,wheneveritoccurs[12–15,16,19,20,23,24,30].Phar- macologicaltreatmentsaimedatblockingmicrogliapolari- zation — such as the peroxisome proliferator-activated receptor g (PPARg) agonist pioglitazone — protected against PM-induced suppression of SGZ proliferation andrescued thenumberofnewbornneurons,indicating amajorroleofmicrogliareactivityinthenegativemodula- tionofadult hippocampalneurogenesis[30].Neverthe- less,mechanistically,whichactivatedmicrogliaphenotype (i.e.proregenerativeM2versusneurotoxicM1versus‘dark microglia’[33])isfavoredupon/afterPMexposureandhow microgliaactivationinhibitstheneurogeniceventsremain obscure.Beyondthereleaseofhighlevelsofpro-inflam- matorycytokinesorreactiveoxygenspeciesthatcaninhibit NSC/progenitor proliferation and alter the specification andsurvivaloftheirderivatives[34],aninterestinghypoth- esisisthatPM-inducedmicrogliaactivationcouldresultin increased phagoptosis(i.e. the engulfment of immature viableneurons[35]).Inlinewiththishypothesis,Bolton andcolleagues[19]reportedincreasedmicroglia-neuron physicalinteractionsinthecortexoftheoffspringofPM- exposeddams.
Notably, upon prenatal and neonatal PM exposure, microglia activation and astrogliosis occurred predomi- nantlyinmales[19,23,24,36].Consistently,neuroinflam- mation was more pronounced in malesthan in females uponexposuretoDEPduringadulthood[37],inlinewith a more marked reduction of adult neurogenesis [30].
This suggeststhatsex-dependentfactors, includingthe hormonal background, may influence the individual’s vulnerabilitytoPMeffects.Interestingly,microgliaacti- vation and neuroinflammation extended well beyond PM-exposure, when it occurredin utero, in line with a primingaction ofairpollution.
Moreover,whatisthetriggerformicrogliaandastrocyte activation remains elusive. Fine and ultrafine particles couldentertheCNSanddirectlystimulateglialreactiv- ity.Giventherelativelysmallextensionoftheolfactory mucosa,itislikelythatinhumans—atdifferencewith rodents—themainentrancerouteforPMistheblood.In line with this view, astroglia reactivity was observed predominantly aroundbloodvessels [38].Nevertheless, glial cells and NSCs/progenitors may be reached by a plethora of other factors— and evencells — from the
periphery,thankstothedisruptionofBBBintegrityand increased leakage induced by PM exposure [13,16].
Amongtheseelements,pulmonarycell-derivedextracel- lular vesicles (EVs) may represent important lung-to- brain mediators of PM effects [39,40]. EVs are lipid bilayer-delimited particles, actively released from cells in responseto stress. After internalizationwithintarget cells,EVsdelivertheircontent,includingproteins,lipids andmiRNAs,andprofoundlyinfluencetherecipientcell molecular state and function [41]. Interestingly, recent studies[39,40]showedthat,inhumans,themiRNAcargo of plasma EVs released following PM exposure has a signaturerelevantforthemodulationofglialcellreactiv- ity (e.g. miR-9, involved in microglia activation and neuroinflammation [42]) and NSC/progenitor functions (e.g.miR-128,miR-302,let-7andmiR-9,regulatingneu- ralprecursorproliferationandneurogenesis[43];miR-21, miR-9,miR-200,miR-17,miR-7,miR-302c,limitingoli- godendroglia differentiation or enriched in immature oligodendrocyteprecursors[44]).Finally,anovelepige- neticmechanismpossiblymediatingPMeffectsondevel- opmentalandadultneurogenesismaybetheregulationof DNAmethylationinNSCsandtheirderivativesthathas been showntoberesponsive to extrinsicsignals and to influencemultipleaspectsofneurogenesisfromstemcell maintenanceuptosynaptogenesis[45].Thishypothesis is corroborated by the observation of increased DNA methyltransferase DNMT1 in the brains of male mice perinatally exposed to DEP [46]. Notably, in human placenta,PMexposurewasassociatedwithalteredmeth- ylation level of DNA repair and clock genes [47,48], which are also essential for adult and developmental neurogenesis[49–51].
Concludingremarksand open issues
Convincingevidence,obtainedinanimalmodels,shows thatCNS developmentandadult neurogenesisarepro- foundlyimpactedbyPMexposurethroughoutlife,with significantbehavioralandcognitivealterations.Thisfield ofresearchisstillinitsinfancyandstrenuouseffortsare stillneededto clarifytheprecisemechanismsbywhich PMaffectsneurodevelopmentaleventsandadultneuro- genesis,andthemolecularsubstratesofgenderandtime window-specificdifferencesinPM sensitivity.Available mechanisticstudieshavefrequentlyexploitedheteroge- neousPM dosages,composition,administrationmodali- ties and timing. This scenario has so far impeded a complete understanding of the processes subserving PM effects. Nevertheless, research on the effects of PM on other systems has greatly advanced in the last years and identified interesting candidate mechanisms thatcouldbealso atthebasisofPM neurotoxicity.
Authors’contribution
EnricaBoda:Conceptualization;Investigation;Visualiza- tion; Writing — original draft; Writing — review &
editing.
Antonello E. Rigamonti: Conceptualization; Investiga- tion;Visualization; Writing —originaldraft;Writing — review&editing.
ValentinaBollati:Conceptualization;Investigation;Visu- alization;Writing—originaldraft;Writing—review &
editing.
Conflictofintereststatement
Theauthorsdeclarenoconflictofinterest.Thefunding sponsorshadnoroleintheinterpretationofdataorinthe writingofthemanuscript.
Acknowledgements
Weapologizetocolleagueswhoseworkwecouldnotincludeduetospace limitations.WethankDr.SaraBonzanoforprecioushelpinfiguregraphics.
OurworkissupportedbytheIndividualfundingforbasicresearch(Ffabr) grantedbytheItalianAgencyfortheEvaluationofUniversityand Research,andlocalfundsbyUniversityofTurintoEB.Thisstudywasalso supportedbyMinisterodell’Istruzione,dell’Universita` edellaRicerca—
MIURproject‘DipartimentidiEccellenza2018–2022’toDept.of Neuroscience‘RitaLeviMontalcini’,UniversityofTurin.
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