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TheToxinsThatAffectedYourGreatGrandparentsCouldBeInYourGenes|Innovation|Smithsonian

Smithsonian.com
TheToxinsThatAffectedYourGreatGrandparents
CouldBeInYourGenes
BiologistMichaelSkinnerhasenragedthechemicalcommunityand
shockedhispeerswithhisbreakthroughresearch

(BrianSmale)
ByJeneenInterlandi
SmithsonianMagazine|Subscribe
December2013
MichaelSkinnersbiggestdiscoverybegan,asoftenhappensinsciencestorieslikethisone,withabrilliantfailure.
Backin2005,whenhewasstillatraditionaldevelopmentalbiologistandtheaccoladesandattackswerestillinthe
future,adistraughtresearchfellowwenttohisofficetoapologizefortakinganexperimentonesteptoofar.Inhis
laboratoriesatWashingtonStateUniversity,sheandSkinnerhadexposedpregnantratstoanendocrinedisruptora
chemicalknowntointerferewithfetaldevelopmentinthehopeofdisturbing(andtherebygainingmoreinsight
into)theprocessbywhichanunbornfetusbecomeseithermaleorfemale.Butthechemicaltheyused,an
agriculturalfungicidecalledvinclozolin,hadnotaffectedsexualdifferentiationafterall.Thescientistsdidfindlower
spermcountsanddecreasedfertilitywhenthemaleoffspringreachedadulthood,butthatwasnosurprise.Thestudy
seemedlikeabust.
Byaccident,though,Skinnerscolleaguehadbredthegrandchildrenofthoseexposedrats,creatingafourth
generation,orthegreatgrandchildrenoftheoriginalsubjects.ItsOK,Skinnertoldher.Youmightaswell
analyzethem.Ifnothingelse,hethought,theexercisemighttakehermindoffhermistake.Soshewentaheadand
studiedtheratstestesunderamicroscope.
WhattheyfoundwouldnotonlychangethedirectionofSkinnersresearchbutalsochallengeabedrockprincipleof
modernbiology.AndSkinnerwouldbecometheforerunnerofanewwayofthinkingaboutthepossiblelongterm
healthconsequencesofexposuretoenvironmentalchemicals.

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Hisdiscoveriestouchonthebasicquestionofhowbiologicalinstructionsaretransmittedfromonegenerationtothe
next.ForhalfacenturyithasbeencommonknowledgethatthegeneticmaterialDNAcontrolsthisprocessthe
lettersintheDNAstrandspelloutmessagesthatarepassedfromparenttooffspringandsoon.Themessages
comeintheformofgenes,themolecularequivalentofsentences,buttheyarenotpermanent.Achangeinaletter,a
resultofarandommutation,forexample,canalteragenesmessage.Thealteredmessagecanthenbetransmitted
instead.
ThestrangethingaboutSkinnerslabratswasthatthreegenerationsafterthepregnantmotherswereexposedtothe
fungicide,theanimalshadabnormallylowspermcountsbutnotbecauseofachangeintheirinheritedDNA
sequence.Puzzled,Skinnerandhisteamrepeatedtheexperimentsonce,twice,15timesandfoundthesame
spermdefects.Sotheybredmorerats,andtestedmorechemicals,includingsubstancesthatleadtodiseasesinthe
prostate,kidney,ovariesandimmunesystem.Againandagain,thesediseasesalsoshowedupinthefourthand
fifthgenerationoffspringofmothersexposedtoachemical.
Inessence,Skinnerexplains,whatyourgreatgrandmotherwasexposedtocouldcausediseaseinyouandyour
grandchildren.
And,startlingly,whateverdiseasepathwayachemicalwasopeningintheratsfurcoveredbodies,itdidnotbeginor
endatamutationinthegeneticcode.Skinnerandhisteamfoundinsteadthatasthetoxinsfloodedin,theyaltered
thepatternofsimplemoleculescalledmethylgroupsthatlatchontoDNAinthefetusgermlinecells,whichwould
eventuallybecomeitseggsorsperm.Likeburrsstucktoaknitsweater,thesemethylmoleculesinterferedwiththe
functioningoftheDNAandrodeitdownthroughfuturegenerations,openingeachnewonetothesamediseases.
Theseburrs,knowntobeinvolvedindevelopment,persistedforgenerations.Thephenomenonwassounexpected
thatithasgivenrisetoanewfield,withSkinneranacknowledgedleader,namedtransgenerationalepigenetics,or
thestudyofinheritedchangesthatcantbeexplainedbytraditionalgenetics.
AstudybySkinnerandcolleaguespublishedlastyearinthejournalPLOSOnehasuppedtheanteconsiderably.The
burrswerenotjusthaphazardlyattached,Skinnerfound.Instead,theyfastenedthemselvesinparticular
arrangements.Whenhebathedtheinsidesofhispregnantratsinbugspray,jetfuelandBPA,theplasticscomponent
recentlybannedfrombabybottles,eachexposureleftadistinctpatternofmethylgroupattachmentsthatpersistedin
thegreatgrandchildrenofexposedrats.
Notonlyisyourgreatgrandmothersenvironmentaffectingyourhealth,Skinnerconcluded,butthechemicalsshe
wasexposedtomayhaveleftafingerprintthatscientistscanactuallytrace.
Thefindingspointtopotentiallynewmedicaldiagnostics.Inthefuture,youmayevengotoyourdoctorsofficeto
haveyourmethylationpatternsscreened.ExposureoflabratstothechemicalDDTcanleadtoobesityinsubsequent
generationsalinkSkinnersteamreportedinOctober.Hypothetically,adoctormightsomedaylookatyour
methylationpatternsearlyinlifetodetermineyourriskforobesitylater.Whatsmore,toxicologistsmayneedto
reconsiderhowtheystudychemicalexposures,especiallythoseoccurringduringpregnancy.Theworkraises
implicationsformonitoringtheenvironment,fordeterminingthesafetyofcertainchemicals,perhapsevenfor
establishingliabilityinlegalcasesinvolvinghealthrisksofchemicalexposure.
Thesepossibilitieshavenotbeenlostonregulators,industries,scientistsandotherswhohaveastakeinsuch
matters.Therearetwoforcesworkingagainstme,Skinnersays.Ononeside,youhavemoneyedinterests
refusingtoacceptdatathatmightforcestrongerregulationsoftheirmostprofitablechemicals.Ontheotherside,you
havegeneticdeterministsclingingtoanoldparadigm.
***
MichaelSkinnerwearsagrayStetsonwithatanstrap,andleansbackeasilyinhischairinhisofficeonthePullman
campus.Hisflyfishingrodstandsinthecorner,andacolossalnorthernpikeismountedonthewall.Anavidfly
fisherman,Skinner,age57,wasbornandraisedontheUmatillaIndianReservationineasternOregon.TheSkinners
arenotofIndiandescent,buthisparentsownedafamilyfarmthereagoodculturalexperience,hesays.His
fatherworkedininsurance,andheandhisfourbrothersgrewupjustasfivegenerationsofSkinnershadbeforethem
huntingandfishingandcowboying,learningawayoflifethatwouldsustainthemintoadulthood.
Helovedtheoutdoors,andhisfascinationwithhownatureworkedpromptedaschoolguidancecounselors
suggestionthatacareerinsciencemightbejustthething.Hewasabout12,andtruetoformhestuckwithit.Inhigh
schoolandthenatReedCollegehewrestledcompetitively,andtodayhissupportersandcriticsalikemaydetectabit
ofhisoldgrapplingselfinhowheapproachesaproblemheadon.Itprobablytaughtmehowtoconfront,rather
thanavoidchallenges,hesaysnow.Thesportalsoledhimtohisfuturewife,RobertaMcMaster,orBobbie,who
servedashishighschoolwrestlingteamsscorekeeper.Iwasfascinatedthatsomeonesoyoungknewexactlywhat
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hewantedtodowithhislife,Bobbierecalls.Heproposedmarriagebeforeheadingforcollege,andthetwohave
beentogethereversinceandhavetwogrownchildren.
HeattendedWashingtonStateUniversityforhisPhDinbiochemistry,andduringthattimeheandBobbieoftenlived
ongamethathedhunted.Itwasnotunheardoftofindafreshlykilleddeerhanginginthecarportoftheirstudent
housing.Theywereleanyears,Bobbiesays.Buttheyweregoodones.
AfterpositionsatVanderbiltandtheUniversityofCalifornia,SanFrancisco,SkinnerreturnedtoWashingtonState
University.Iwantedabigresearchcollegeinaruraltown,hesays.Hespentthenextdecadestudyinghowgenes
turnonandoffinovariesandtestes,andhowthoseorganscellsinteract.Hewasntaimingtotakeonthecentral
ideainbiologyformuchofthe20thcentury:geneticdeterminism,thebeliefthatDNAisthesoleblueprintfortraits
fromhairandeyecolortoathleticability,personalitytypeanddiseaserisk.
Insomesensethisinterpretationofgeneticdeterminismwasalwaysoversimplified.Scientistshavelongunderstood
thatenvironmentsshapeusinmysteriousways,thatnatureandnurturearenotopposingforcessomuchas
collaboratorsinthegreatartofhumanmaking.Theenvironment,forexample,canrampupandpullbackongene
activitythroughmethylgroups,aswellasahostofothermoleculesthatmodifyandmarkupapersonsfull
complementofDNA,calledthegenome.ButonlychangesintheDNAsequenceitselfwerenormallypassedto
offspring.
SocertainwaseveryoneofthisbasicprinciplethatPresidentBillClintonpraisedtheefforttocompletethefirstfull
readingofthehumangenome,sayinginJune2000thatthisachievementwouldrevolutionizethediagnosis,
preventionandtreatmentofmost,ifnotallhumandiseases.Whenstackedagainstsuchenthusiasm,Skinners
findingshavefeltlikeheresy.Andforawhile,atleast,hewascriticizedaccordingly.
***
CriticsoftheSkinnerledresearchpointedoutthatthedosesofvinclozolininhisratstudieswerewaytoohightobe
relevanttohumanexposure,andinjectingtheratsasopposedtoadministeringthetoxinsthroughtheirfood
exaggeratedtheeffects.Whathesdoingdoesnthaveanyrealobviousimplicationsfortheriskassessmentsonthe
chemical,EPAtoxicologistL.EarlGraywasquotedtellingPacificStandardmagazinebackin2009.Untilthe
resultsarereplicated,Imnotsuretheyevendemonstratebasicscienceprinciples.
Skinnerrespondstoassaultsonhisdatabysayingthatriskassessment,ofthetypethattoxicologistsdo,hasnotbeen
hisgoal.Rather,hesinterestedinuncoveringnewbiologicalmechanismsthatcontrolgrowth,developmentand
inheritance.Myapproachisbasicallytohititwithahammerandseewhatkindofresponseweget,hesays.He
remainscalm,evenwhencalledontodefendthatapproach.Conflictswithindividualssolveverylittle,hesays.
Thebestwaytohandlethesethingsistoletthesciencespeakforitself.
Thatsciencehasreceivedalotofattention(thevinclozolinstudyhasbeencitedinthescientificliteraturemorethan
800times).Recently,thejournalNatureReviewsGeneticsaskedfiveleadingresearcherstosharetheirviewsonthe
importanceofepigeneticinheritance.Amixtureofexcitementandcaution,ishowtheeditorsdescribedthe
responses,withoneresearcherarguingthatthephenomenonwasthebestcandidateforexplainingatleastsome
transgenerationaleffects,andanothernotingthatitmight,iffullydocumented,haveprofoundimplicationsforhow
weconsiderinheritance,formechanismsunderlyingdiseasesandforphenotypesthatareregulatedbygene
environmentinteractions.
ThoughmostofSkinnerscriticshavebeenreassuredbynewdatafromhislabandothers,hesayshestillfeels
embattled.Ireallytrytobeascientistfirstandforemost,hesays.Imnotatoxicologist,orevenan
environmentalist.Ididntcometothisasanadvocatefororagainstanyparticularchemicalorpolicy.Ifound
somethinginthedata,andIpursueditalongalogicalpath,thewayanybasicresearcherwould.
PAIDCONTENT

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