ExposuretoToxicChemicalsinYourEverydayEnvironment

CharlesIde,Ph.D.Director,EnvironmentalIns=tute

WesternMichiganUniversity

ModernLife:HumanMadeChemicalsintheEnvironment

•  Pes=cidesandfer=lizersusedinagriculture•  Industrialchemicals

•  Dailyusechemicals(home,work)

•  GlobaltransportduetotheweatherpaMerns(majorcontamina=oninthearc=c)

•  Humanmadechemicalsareeverywhereonearth

FavoriteIdeFrogStudies

•  RelatedtotheEnvironment–  Theherbicide,atrazine,altersmetabolicgeneexpressionthatburnsuptadpolefatandmuscle,decreasinggrowthandincreasingmortalitybymetamorphosis

–  PCBs,industrialcontaminantsfoundinGreatLakeswatersheds(e.g.,KalamazooRiver)andworldwide,altersdevelopmentaltadpolegeneexpressionincludingthatofendocrinegenesneededforon‐=memetamorphosis

– Methylmercury,acontaminantfromcoalfiredpowerplants,reducescytokineproteinexpressionduringdevelopmentofthetadpolenervoussystemresul=nginabnormalmotorbehavior

AtrazineEffectsonGrowth,Metabolism,Func=onalGeneExpression,andMitochondrialDisposi=onin

Frogs

•  AtrazineEffectsondevelopingfrogsincludesdrama=cchangesinmetabolicgeneexpression(Dr.AnnaLangerveld;Ph.D.toRonCeles=ne).

•  Fatmetabolismisaltered,leavingproteinmetabolismtotakeuptheslack;mitochondriathatproducethecell’senergyaredegenera=ng(ReneeZaya,Ph.D.candidate).

AtrazineAltersFatDeposi=oninDevelopingFrogs

•  Fatbodiesareusedbyfrogsa[ermetamorphosisforreproduc=on

•  Atrazinedrama=callyreducesfatbodysize

Control(0ppb)femalestage62tadpolefatbody.Bar=1mm

Exposed(400ppb)femalestage62tadpolefatbody.Bar=1mm

NormalMaleandFemaleGonadsinXenopusFrogs(fromHayesetal)

AtrazineInducedHermaphrodi?cGonadinaXenopusFrog(fromHayesetal)

Parkinson'sDisease

•  Currentlyscien=stshaveliMleunderstandingofwhatcausesParkinson's,wherea=nygroupofdopamine‐producingneuronsdeepwithinanareaofthebrainknownasthesubstan=anigradie.

•  ThiscelldeathleadstoashortageoftheneurotransmiMerdopamineandtothetremors,rigidity,andslowmovementthatmarkthediseaseasitprogressesslowlyoveraperiodofyearsordecades.

•  Parkinson'saffectsabout1millionpeopleinNorthAmerica.

α-synucleinAggregatesAreAssociatedwithParkinsonism

•  A.Normalsec=onfrompostmortemhumanbrain(ponto‐cerebellartractinpons)showinglightbackgroundICCstainingforα-synuclein.

•  B.α-synucleinaggregatesasglialcytoplasmicinclusionsappearinasimilarsectionfromanMSApatientwithParkinsonism.

Pes=cidesandimpairmentofmitochondrialfunc=oninrela=onwithParkinsoniansyndrome.

GomezC,BandezMJ,NavarroA.(FrontBiosci.2007Jan1;12:1079‐93.)

•  TheParkinsoniansyndromeinducedbypes=cidesisassociatedwiththeimpairmentofmitochondrialfunc=on.

•  Toxicantsthatinhibitselec=velyNADH‐dehydrogenaseac=vity,asrotenoneorpyridaben,alsoshowaselec=veinhibi=onofO2uptakeinratbrain.

•  Paraquatproducedanon‐selec=veinhibi=onaffec=ngalltherespiratorychaincomplexes.

GeneExpressionDeficitsinBrainTissuesfromPa=entswithParkinsonismResembleThosefrom

Pes=cideExposedAnimals

Nongene?ccausesofParkinson'sdisease.

ChadeAR,KastenM,TannerCM.JNeuralTransmSuppl.2006;(70):147‐51.Review.

•  Studyofthenongene=ccausesofParkinson'sdisease(PD)wasencouragedbydiscoveryofaclusterofparkinsonismproducedbyneurotoxicpyridine1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine(MPTP)inthe1980s.

•  Pes=cideexposurehasbeenassociatedwithincreasedriskinmanystudies.

•  Otherproposedrisksincluderuralresidenceandcertainoccupa=ons.•  CigareMesmoking,useofcoffee/caffeine,andnon‐steroidalan=‐

inflammatorydrugs(NSAIDs)allappeartolowerriskofPD.•  Dietarylipidandmilkconsump=on,highcaloricintake,andheadtrauma

mayincreaserisk.•  ThecauseofPDislikelymul=factorial.Underlyinggene=csuscep=bility

andcombina=onsofriskandprotec=vefactorslikelyallcontribute.Thecombinedresearcheffortbyepidemiologists,gene=cists,andbasicscien=stswillbeneededtoclarifythecause(s)ofPD.

BigPicture

•  Aging–causedbyinefficientmitochondrialelectrontransport;freeOxygenradicalsdamageDNA,proteins,etc.

•  Proteasomestopsremovingworn‐out,misshapenproteins,whichleadstomorecellularinefficiency,andul=matelycelldeath

•  Pes=cidescausebraincellstoageprematurelybydisrup=ngelectrontransportandproteasomalfunc=on

•  Thus,environmentallyinducedneurologicaldiseaseshouldincreaseasmorepes=cidesareplacedintheenvironment

•  MoreParkinsonismcasesoccuringeographicareaswherepes=cidesareheavilyused(e.g.,theMidwest)

IndustrialContaminants

•  Polychlorinatedbiphenyls•  Mercury

209DifferentCongenersofPCBs

•  Co‐planar– Mosttoxic

–  Needtobeinco‐planarorflatposi=ontobindtoreceptors

•  Nonco‐planar–  Responsiblefordisrup=ngcalciumhomeostasis,neurologicalandneuromuscularfunc=on

KalamazooRiverWatershed–PartoftheLakeMichiganBasin

FavoriteIdeLabFrogStudies

– PCBs,industrialcontaminantsfoundinGreatLakeswatersheds(e.g.,KalamazooRiver)andworldwide,altersdevelopmentaltadpolegeneexpressionincludingthatofendocrinegenesneededforon‐=memetamorphosis

MorphologyandBehavioralEffectsAssociatedwithExposuretoAroclor1254

•  Decreased/aberrantescapeswimmingbehavior

•  Paralysis•  Parkinson’s‐like,

uncontrolledtwitching•  Shorter,crinkledtails

Aroclor1254AltersMelanocyteStructure

•  Changeinmelanocyteshape

•  PCBexposureblocksmelanocytearboriza=oninresponsetolight

•  UVlightfromthesuncannowmutatebraincellDNA

Stage46Xenopustadpole

%Survival/D

MSO

%Gen

eexpression

/Con

trol

%Gen

eexpression

/Con

trol

%Survival/D

MSO

GeneExpressionin18DayOldTadpoles:

BioindicatorsofExposure

•  ExposuretolowlevelsofAroclor1254(5and50ppb)increasedgeneexpression

–  NGF–  ß‐ac=n

–  CPP32ß–  ICE–  POMC

–  p53

%Gen

eexpression

/Con

trol

%Survival/D

MSO

DecreasesinGeneExpressionArePredic=veBioindicators

•  Decreasedgeneexpressionathighdoses(700ppb)correlatedwithdecreasedsurvivalandtheonsetofadversehealtheffects–  NGF–  ß‐ac=n

•  Decreasesingeneexpressionoccurredintadpolesexposedto300ppbandgreater

%Gen

eexpression

/Con

trol

%Survival/D

MSO

PCBsAlterHearingDevelopmentinFrogs(andHumans)

•  Katbamna,B.,A.JelasoLangerveld,andC.F.Ide(2006)Aroclor1254impairsthehearingabilityofXenopuslaevis.JournalofCompara=vePhysiologyA:Sensory,Neural,andBehavioralPhysiology192(No.9):971‐983.

Ea=ngFish

Introduc=on•  ContaminantsaMachtosediment,which

iseatenbyzooplanktonthenbioaccumulated,thenbiomagnifiedfromsmallertolargerfish

•  Concentra=onofchemicalscanbemillionsof=meshigherintoppredatorsthaninwater

•  Maytakeyearsofea=ngcontaminatedfishtocauseadversehealtheffects

•  Fishcontainingharmfulchemicalsmaynotlook,smellortastebad

FetalExposuretoPCBs

•  Fetusismoresensi=ve–  Crossestheplacenta–  Accumulatesinbreastmilk

–  Somestudiesshow•  Lowerbirthweight•  Smallerhead

•  Prematurebirth

•  LowerIQ

“EffectsofPCBexposureonNeuropsychologicalFunc=oninChildren”

•  PCBadverselyeffectsneurodevelopment– Taiwan– Michigan– NewYork– TheNetherlands– Germany– TheFaroeIslands

Mercury

•  205,583lakeacres(allinlandlakes)inMichigan,478rivermilesunderfishconsump=onadvisory

•  Mercurycan’tberemovedfromfishbecauseitiscontainedinmeat,notfat

•  Nomorethanamealaweekofcontaminatedfish

•  Fishlowinmercuryincludeshrimp,cannedlighttuna,salmonPollockandcauish.Fastfoodandfishs=cksareusuallylowaswell

EvenMoreImmediateToxicants

•  EthylAlcohol(wine,beer,gin,vodka,scotch,etc.)

•  ChemicalsinCosme=cs(acetone,isopropylalcohol,hydroquinone,botox)

FetalAlcoholSyndrome:TadpoleModel

•  Ethanoldisruptsconnexin43expressingcellsintherhombomeresofXenopuslaevis(Bhar=Katbamna,TracyBarsheff,CharlesF.Ide)

ChemicalsintheHomeandWorkplace:Acetone

•  Solventusedinnailpolishremover,paintremover,glue,cleaners,tobaccosmoke

•  Sub‐chronicexposure(inhala=on10%ofyour=me)causescentralnervoussystemdepression,irrita=onofeyes,nose,throat;neurobehavioralchanges

ChemicalsintheHomeandWorkplace:IsopropylAlcohol

•  Becomesacetoneinyourbody•  Inhala=oncausesirrita=onofeyes,nose,andthroat,centralnervoussystemdepression

•  Skinexposurecauseseczema,sensi=vity,andforhighexposures(spongebathtolowerfever),respiratorydistress,stupor,andcomainchildren

•  Releasedfromcosme=cs,liniments,skinlo=ons,permanentwavelo=ons,pharmaceu=cals,hairtonics,skinastringents,mouthwashes,perfumes,oils

ChemicalsintheHomeandWorkplace:Hydroquinone

•  Usedinphotographicdevelopment,skinlighteners,hairdyes,othercosme=cs,cigareMesmoke

•  Skinapplica=oncanproduceochronosis(adversepigmenta=on,calcifica=onandcar=lageinflamma=on);also,irrita=on,staining,andallergiccontactderma==s

•  Airborneexposurewithothertoxicantscanproducecornealulcers,opacity,lossofvisionseveralyearsa[erexposure

•  Highlytoxictoorganismsintheenvironment

ChemicalsintheHomeandWorkplace:Botox

•  ToxinproducedbyClostridiumbotulinumbacteria(mosttoxicsubstanceknowntohumans;foundinimproperlypreservedfood)

•  Blocksneuromusculartransmission(causesparalysis);injectedtotemporarilyremovefrownlinesandbrowfurrows

•  Adverseeventsfromcosme=cuseincludesheadaches,focalfacialparalysis,muscleweakness,dysphagia,flu‐likesyndromes,andallergicreac=ons

•  Incosme=cuse,clientssome=mescomplainofinappropriatefacialexpressionsuchasdroopingeyelid,unevensmile,lossofabilitytoclosetheeyeforupto6weeks.

ConclusionI

•  Ourmodernlifestyleischallengingourgenes,cells,and=ssuestodealwithavarietystressors,someofwhichwehavenothadtosolveduringourlongevolu=on

•  Peopleareexposeddailytomoreandmorechemicalsthatarenowthebasisofourindustrialandagriculturalproduc=vity,and,insomecases,ourpersonalgrooming

•  Intheshortterm,thesechemicalexposurescanbeirrita=ngandcauseminorhealthproblems;inothercases,chronicexposurecanproducecancer,neurologicaldisease,andimmunesystemdysfunc=on

ConclusionII

•  Humangenomeanalysisisrevealingmoreeverydayabouthowgoodandbadhealtharecausedbyourhiddengene=csrespondingtoenvironmental(chemical)exposures

•  Mostofusdonotknowourspecificgene=cs,whatwearesuscep=bleto,andwhatwecansolve/resist

•  Soavoidthechemicals!Becareful!