Environmental Risk Factors and Parkinson's Disease

NeurobiologyofDisease10,119–127(2002)doi:10.1006/nbdi.2002.0507

EnvironmentalRiskFactorsandParkinson’sDisease:SelectiveDegenerationofNigralDopaminergicNeuronsCausedbytheHerbicideParaquat

AlisonL.McCormack,*MonaThiruchelvam,

AmyB.Manning-Bog,*ChristineThiffault,*J.WilliamLangston,*DeborahA.Cory-Slechta, andDonatoA.DiMonte*,1

*TheParkinson’sInstitute,Sunnyvale,California94089;and DepartmentofEnvironmentalMedicine,UniversityofRochester,Rochester,NewYork14642

ReceivedDecember21,2001;revisedMarch22,2002;acceptedforpublicationApril12,2002

Environmentaltoxicantsand,inparticular,pesticideshavebeenimplicatedasriskfactorsinParkin-son’sdisease(PD).Thepurposeofthisstudywastodetermineifselectivenigrostriataldegenerationcouldbereproducedbysystemicexposureofmicetothewidelyusedherbicideparaquat.Repeatedintraperitonealparaquatinjectionskilleddopaminergicneuronsinthesubstantianigra(SN)parscompacta,asassessedbystereologicalcountingoftyrosinehydroxylase(TH)-immunoreactiveandNissl-stainedneurons.Thiscelllosswasdose-andage-dependent.Severallinesofevidenceindi-catedselectivevulnerabilityofdopaminergicneuronstoparaquat.ThenumberofGABAergiccellswasnotdecreasedintheSNparsreticulata,andcountingofNissl-stainedneuronsinthehippocam-pusdidnotrevealanychangeinparaquat-treatedmice.Degeneratingcellbodieswereobservedbysilverstaining,butonlyintheSNparscompacta,andglialresponsewaspresentintheventralmesencephalonbutnotinthefrontalcortexandcerebellum.Nosigni cantdepletionofstriataldopaminefollowedparaquatadministration.Ontheotherhand,enhanceddopaminesynthesiswassuggestedbyanincreaseinTHactivity.These ndingsunequivocallyshowthatselectivedopami-nergicdegeneration,oneofthepathologicalhallmarksofPD,isalsoacharacteristicofparaquatneurotoxicity.Theapparentdiscrepancybetweenpathological(i.e.,neurodegeneration)andneuro-chemical(i.e.,lackofsigni cantdopamineloss)effectsrepresentsanotherimportantfeatureofthisparaquatmodelandisprobablyare ectionofcompensatorymechanismsbywhichneuronsthatsurvivedamagearecapableofrestoringneurotransmittertissuelevels.©2002ElsevierScience(USA)

KeyWords:dopamine;pesticide;substantianigra;striatum;GABA;stereology;hippocampus;mice;neurotoxicity.

INTRODUCTION

Thepossibilitythatparaquat(1,1 -dimethyl-4,4 -bi-pyridinium)maydamagethenigrostriataldopami-nergicsystemandthereforecontributetotheneuro-pathologyofParkinson’sdisease(PD)was rstpro-posedinthemid1980sfollowingtheobservationthat

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itschemicalstructurecloselyresemblesthatofMPP (1-methyl-4-phenylpyridiniumion)(Fig.1).BecauseMPP isthetoxicmetabolitethatmediatestheeffectsoftheparkinsonism-inducingagentMPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine),thischemicalsimilaritypointedtoparaquatasapotentialenviron-mentaltoxicantinvolvedinPD(SnyderandD’Amato,1985).Sincethen,epidemiologicalevidencehascontinuedtostimulateinterestintherelationshipbetweenparaquat,nigrostriataldegenerationandpar-kinsonism.Anumberofcase-controlstudieshave

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