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    Fetal Origin Gruppuso-041112

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    Hervi Laksari
    1) The document reviews how the field has transitioned from thinking about "fetal exposures" to harmful substances to the concept of "fetal origins" of adult diseases. 2) Key examples that helped establish this concept include Barker's findings linking low birth weight to increased risk of heart disease and diabetes later in life, and studies of the Dutch Hunger Winter showing health effects in offspring from restricted food intake during pregnancy. 3) The fetal origins hypothesis suggests that environmental factors in utero like nutrition, stress, and toxic exposures can influence lifelong health by altering fetal development and programming through epigenetic changes.

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    Fetal Origin Gruppuso-041112

    Uploaded by

    Hervi Laksari
    44 views29 pages
    1) The document reviews how the field has transitioned from thinking about "fetal exposures" to harmful substances to the concept of "fetal origins" of adult diseases. 2) Key examples that helped establish this concept include Barker's findings linking low birth weight to increased risk of heart disease and diabetes later in life, and studies of the Dutch Hunger Winter showing health effects in offspring from restricted food intake during pregnancy. 3) The fetal origins hypothesis suggests that environmental factors in utero like nutrition, stress, and toxic exposures can influence lifelong health by altering fetal development and programming through epigenetic changes.

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    1) The document reviews how the field has transitioned from thinking about "fetal exposures" to harmful substances to the concept of "fetal origins" of adult diseases. 2) Key examples that helped establish this concept include Barker's findings linking low birth weight to increased risk of heart disease and diabetes later in life, and studies of the Dutch Hunger Winter showing health effects in offspring from restricted food intake during pregnancy. 3) The fetal origins hypothesis suggests that environmental factors in utero like nutrition, stress, and toxic exposures can influence lifelong health by altering fetal development and programming through epigenetic changes.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    44 views29 pages

    Fetal Origin Gruppuso-041112

    Uploaded by

    Hervi Laksari
    1) The document reviews how the field has transitioned from thinking about "fetal exposures" to harmful substances to the concept of "fetal origins" of adult diseases. 2) Key examples that helped establish this concept include Barker's findings linking low birth weight to increased risk of heart disease and diabetes later in life, and studies of the Dutch Hunger Winter showing health effects in offspring from restricted food intake during pregnancy. 3) The fetal origins hypothesis suggests that environmental factors in utero like nutrition, stress, and toxic exposures can influence lifelong health by altering fetal development and programming through epigenetic changes.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    of 29

    FetalOriginsofAdultDisease

    ThePublicHealthandScientificCommunities
    Evolution

    PhilipA.Gruppuso,MD
    ProfessorofPediatrics
    ProfessorofMol/CellBiol&Biochem(Research)
    Disclosures:None

    Thanksto:
    AlishaLakhani,MPH,AlpertMedicalSchoolClassof2014
    AnnieMurphyPaul,authorofOrigins
    NIH/NIEHSandEPA.
    Objectives:
    Reviewthehistoricalcontextforthetransitionfromfetal
    exposurestofetalorigins
    Discusstheepidemiologicevidenceandbasicscience(fetal
    programmingandepigenetics)relatingtofetalorigins
    Appreciatethechallengesinincorporatinginformationon
    fetaloriginsintoclinicalcare

    CONCEPTandhistoryof EXAMPLESofFetal SIGNIFICANCEtopublic


    FetalExposuresversus Origins;relevantbasic health,personalhealth,
    Origins science andpatientmanagement
    FetalExposures

    TheThreeTragedies

    FetalExposures

    50yearsago,thalidomide,adrugformorningsicknessandsleeplessnessinpregnancy
    wasfoundtoberesponsiblefor10,000casesofphocomeliainEurope.

    Thalidomide

    Dr.WidukindLenzand
    lawyerKarlSchutleHillen
    droveacrosstheGerman
    countrysideinterviewing
    womenwhosechildren
    hadsimilarsymptoms.

    Chemie Gruenenthal removedthalidomidefromthemarketin1962whenmedia


    removedthalidomidefromthemarketin1962whenmedia
    coverageforcedarecall.
    coverageforcedarecall.
    FetalExposures

    In1973inSeattle,Dr.KennethJonesandDr.DavidSmithfoundseveralunrelated
    childrenwithasimilarcondition:shortstature,flattenedfaces,absentphiltrum,joint
    andcardiacanomalies.

    FetalAlcoholSyndrome

    Commonfactor
    Common factor heavyalcoholconsumptionduringpregnancy
    heavyalcoholconsumptionduringpregnancy
    FetalExposures

    EmergenceofFetalAlcoholSpectrumDisorder
    1953,ClinicalObstetrics:alcoholisnotinjuriousand
    neednotbeeliminated.
    June1973,Lancet JonesandSmithdescribeFetal
    AlcoholSyndrome
    1989:AccordingtotheSurgeonGeneral,women
    shouldnotdrinkalcoholicbeveragesduringpregnancy
    becauseoftheriskof birthdefects.
    1996:InstituteofMedicineprovidesadiagnostic
    frameworkforFetalAlcoholSpectrumDisorder
    ACOG,2009:IFYOU'REPREGNANT,THINK!DON'T
    DRINK!

    CDC(Current):Alcoholuseduringpregnancycancausebirthdefectsand
    CDC(Current):Alcoholuseduringpregnancycancausebirthdefectsand
    developmental
    developmentaldisabilities.Womenwhoarepregnantormightgetpregnantshould
    disabilities.Womenwhoarepregnantormightgetpregnantshould
    abstain
    abstainfromusingalcohol.
    fromusingalcohol.
    FetalExposures

    Whatdopatientssee?

    Allpublichealthofficialsinthe Ifyoudodecidetodrinkalcohol
    UnitedStatesrecommendthat whileyouarepregnant,it'sbest
    pregnantwomenplayitsafeby tosticktolightdrinking.That's
    steeringclearofalcoholentirely.So nomorethanoneortwo unitsof
    doexpertsatthe AmericanCollege alcohol,nomorethanonceor
    ofObstetriciansand twiceaweek. Heavyorbinge
    Gynecologists andtheAmerican drinkingisdangerousforyour
    AcademyofPediatrics. baby.Heavydrinkingissixor
    moreunitsofalcoholaday.

    Criticalissues:Definingexposurelevelandidentifyingthresholdsforpathogenicity
    Criticalissues:Definingexposurelevelandidentifyingthresholdsforpathogenicity
    FetalExposures

    DES TheBridgefromFetal

    ExposurestoFetalOrigins

    Dr.HowardUlfedlerdiagnosedtwoclear
    celladenocarcinoma(CCA)casesin
    teenagegirlswhosemothershadtaken
    DESwhilepregnant.
    CCA,normallydiagnosedpost
    menopause,occurredatamedianageof
    19inwomenexposedtoDESinutero.
    Riskwas40Xthatinthegeneral
    population.

    AfterUlfedlers
    After Ulfedlers 1971
    1971NEJMarticle,theFDAissuedawarningthatDESshouldnotbe
    NEJMarticle,theFDAissuedawarningthatDESshouldnotbe

    used
    usedbypregnantwomen.
    bypregnantwomen.

    FetalExposures

    DiethylstilbestrolEffects
    Syntheticnonsteroidalestrogen

    Actsasanendocrinedisruptor

    Secondgenerationdaughters:Clear
    celladenocarcinomaofthevagina,
    and...
    Uterotubalanomalies
    Resultinghighrateofmiscarriage
    Secondgenerationsons
    Epididymalcysts,microphallus
    Cryptorchidism,testicularhypoplasia

    Recentdata:Hooveretal.,NEJMOct2011
    Recentdata:Hooveretal.,NEJMOct2011
    AdverseHealthOutcomesin

    4,653WomenExposedtoDESInUtero

    Infertility

    Spontaneous Abortion

    Preterm Delivery

    Ectopic Pregnancy

    Breast Cancer
    0 2 4 6 8 10 12
    Hazard Ratio
    FetalOrigins

    Paradigmshift Inutero exposurescanmanifestthemselvesaslateasadultlife.

    FetalOriginsofAdultDisease
    Linkbetweenhealth,behavioral,and

    emotionalcharacteristics,inchildhood

    andadulthood,andtheinutero

    environment

    FetalOriginscoinedin1989by

    clinicalepidemiologistandphysician,

    DavidBarker

    Emergenceoftheconcept:threewellestablishedexamplesoffetalorigins.
    Emergenceoftheconcept:threewellestablishedexamplesoffetalorigins.
    FetalOrigins

    TheBarkerHypothesis

    Ethel Margaret Burnside,

    Nurse Midwife

    Barker DJ. BMJ, 2003.

    FetalOrigins

    Oddsratiosforimpaired
    glucosetoleranceortype
    Burnsides Data
    2diabetesaccordingto
    +
    birthweightamong370
    Atlas of Mortality from menaged64yearsborn
    Selected Diseases in England inHertfordshire
    and Wales, 19681978

    Hales et al. Br Med Bull 2001


    FetalOrigins

    Autumn1944 WesternHollandwasblockadedbytheNazis,whoturnedawayall
    shipments.ThisledtoafoodshortageduringoneofEuropescoldestwinters.

    TheDutchHungerWinter
    TheDutchsurvivedon<500caloriesper
    day(ofprewarconsumption)
    Foodrestrictionduringpregnancyhad
    dramaticconsequencesfortheoffspring
    Higherratesofobesity,diabetes,heart
    disease,higherbloodpressure,
    hypercholesterolemia,andglucose
    intolerance

    StudiesbyTessaRoseboom
    StudiesbyTessaRoseboom andcolleaguesestablishedmanyoftheserelationships
    andcolleaguesestablishedmanyoftheserelationships

    during
    duringthe1990swhenthechildrenoftheHungerWinterwereintheir50s.
    the1990swhenthechildrenoftheHungerWinterwereintheir50s.

    FetalOrigins

    June5th to10th ,1967:WarbetweentheIsraelisandtheneighboringstatesofEgypt,


    Jordan,andSyria atimeofhighstressforcivilians

    StressandDevelopment
    Healthrecordsof~89000peopleborn
    inJerusalembetween1964and1976
    Offspringofwomenintheir2nd month
    inJune1967weresignificantlymore
    likelytodevelopschizophreniaasyoung
    adults.Relativeriskwas
    4.3infemales
    1.2inmales

    Hypothesis???
    Hypothesis???

    ClinicalImplications

    SignificanceofFetalOrigins
    ResearchtothePatient
    Effectonlifestylerecommendationsfor:

    Alcoholconsumption
    Weightgain
    Stressavoidance
    Dietcomposition
    Exercise

    Thisresearchhasalreadyinfluencedhowphysicianscounselpatients.
    Thisresearchhasalreadyinfluencedhowphysicianscounselpatients.
    ClinicalImplications

    SignificanceofFetalOriginsResearchtothe
    Patient:ChangingRecommendations

    Circa1970 Current
    AlcoholConsumption FewLimitations CompleteAbstinence
    WeightGain EattoAppetite LimitWeightGain
    StressAvoidance Not(Barely?)Discussed Misinformation?
    DietComposition SomeRecommendations NationalEatingDisorder
    Exercise LifeStyleActivity Perplexing

    NetEffect:MATERNALTREPIDATION
    Net Effect:MATERNALTREPIDATION
    TheDevelopmentalOriginsofHealth

    andDisease(DOHaD)

    ScienceofDOHaD Epigenetics

    Epigenetics
    Definition:Thestudyofheritablechangesingene

    expressionandfunctionthroughmechanismsother

    thanthoseinvolvingchangesintheDNAsequence

    Involvesmechanismsthatactivateorinactivategenes:

    Alteredhistoneacetylationandmethylation
    AlteredDNAmethylation
    Criticaltodifferentiationofcellularfunctionina

    developingorganism

    AnimportantcontributortoDOHaD
    Whatisthescopeofof therelationship
    betweenDOHaD andepigenetics?
    Maternalpsychologicalstressandriskforpsychiatricdisease
    intheoffspring
    Excessmaternalweightgainandriskofobesity,metabolic

    disease,andtype2diabetesintheoffspring

    Maternaldietcompositionandtheoffspringsriskforcancer

    Environmentalexposures(bisphenolA,phthalates,arsenic,

    airpollution...)ANDEVERYTHING
    CEHProject

    BrownUniversitysChildrens

    EnvironmentalHealthProject

    Focus:Understandingtheeffectsof
    environmentalfactorsonthehumanfetus
    requiresthestudyofhumanfetaltissues.
    Primarygoaloftheproject Establishanexperimental
    paradigmtostudytheeffectofexposuresonhumanfetal
    tissues.
    Longtermgoal Usethismodelsystemtostudymechanisms
    relatingtofetalorigins
    CEHProject

    BrownUniversitysChildrens

    EnvironmentalHealthProject

    FundedbyNIH(NIEHS)andEPA
    PI Dr.KimBoekelheide,MD,PhD
    ResearchProjects
    Project1:HumanAdiposeTissueandtheMetabolicSyndrome
    Project2:HumanFetalTestisandEndocrineDisruption
    Project3:HumanFetalLung,ArsenicExposure,andTissueRemodeling
    Cores
    AdministrativeCore(LindaCovington)

    TissueProcurementCore(MaureenPhippsandStefanKostadinov)

    XenotransplantCore(SusanHall)

    CommunityOutreachandTranslationCore(Prof.PhilBrown)

    CEHProject

    ProofofPrinciple TestisXenograft
    Hegeretal.:22weekgestationhumanfetaltestis,2daysafter
    transplantationintoanimmunodeficientrat.
    CEHProject

    RenalSubcapsularLungXenograft

    MoniquedePaepeandcolleagues
    CEHProject

    HumanAdiposeTissueXenografts

    8 days 14 days 35 days

    14 days 35 days

    CEHProject

    TissueProcurementCore
    Toconsentornottoconsent

    Impactonprogressofthe
    project
    Impactoftheresultsonthe
    participants
    CEHProject

    CommunityOutreachand
    TranslationCore
    Disseminationofinformation
    Assessingtheimpactoffetalorigins
    research
    Whatisthestartingpoint? Knowledgebaseand
    attitudesamongcaregiversandpatients
    Howdoesknowledgeaffectthebehaviorofthese
    groups?
    Howshouldnewknowledgebeused?
    ThankYou

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