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!