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

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