Table Of ContentSonia Dagnino · Anthony Macherone
Editors
Unraveling
the
Exposome
A Practical View
Unraveling the Exposome
(cid:129)
Sonia Dagnino Anthony Macherone
Editors
Unraveling the Exposome
A Practical View
Editors
SoniaDagnino AnthonyMacherone
DepartmentofEpidemiology TheJohnsHopkinsSchoolofMedicine
andBiostatistics,MRC-PHECentre AgilentTechnologies
forEnvironmentandHealth,School Baltimore,Maryland,USA
ofPublicHealth
ImperialCollegeLondon
London,UK
ISBN978-3-319-89320-4 ISBN978-3-319-89321-1 (eBook)
https://doi.org/10.1007/978-3-319-89321-1
LibraryofCongressControlNumber:2018952071
©SpringerInternationalPublishingAG,partofSpringerNature2019
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe
materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,
broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation
storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology
nowknownorhereafterdeveloped.
Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication
doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant
protectivelawsandregulationsandthereforefreeforgeneraluse.
The publisher, the authors and the editors are safe to assume that the advice and information in this
bookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor
theeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinorforany
errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional
claimsinpublishedmapsandinstitutionalaffiliations.
ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG.
Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland
Foreword
With the completion of the human genome project in 2003, it was anticipated that
new genomic methods would find causes as well as treatments for the chronic
diseases that account for most human mortality (Guttmacher and Collins 2003).
Certainly, new omic technologies fostered genome-wide association studies
(GWAS) that can glean causal factors from essentially all genetic loci. But results
from roughly 2000 GWAS have found only modest effects of common genetic
variants (Welter et al. 2014). Indeed, GWAS findings are consistent with heritable
cancerrisksfromentiregenotypesthataretypicallyabouteightpercentinfamilies
and twins (Hemminki and Czene 2002; Rappaport 2016). Thus, it is reasonable to
inferthatexposuresandgene–exposureinteractionsarethemajor causesofcancer
andotherchronicdiseases.Butincontrasttohigh-techGWAS,searchesforcausal
exposureshavebeenlimitedtoonlyafewhundredchemicalsormixturesandhave
relieduponlow-techmethods,primarilyquestionnaires.
This contrast of technologies used to characterize genetic and “environmental”
factorsledChristopherWildtopromotean“exposome”—representingallexposures
experiencedduringlife—asacomplementtoGWASinetiologicalinvestigationsof
cancer (Wild 2005). In this context, Wild considered “environmental exposures”
with the implication that the exposome was comprised of substances derived from
external sources, such as pollutants, food contaminants, and lifestyle factors. Wild
alsorecognizedthat,whereas thegenomeisessentiallystatic, theexposomevaries
throughoutlifeand,therefore,presentschallengesforepidemiologicstudies.Yet,he
was optimistic that nascent omic technologies (in 2005), i.e., transcriptomics, pro-
teomics, and metabolomics, could someday identify “signatures or fingerprints” of
causalexposures(Wild2005).
I was intrigued with Wild’s speculations and, with colleague Martyn Smith,
functionalized the exposome as the totality of chemicals that can be measured in
blood (Rappaport and Smith 2010). In doing so, we expanded Wild’s view of
exposure to include all chemicals that reach the “internal chemical environment,”
regardless of their origins from external or internal sources. This extended the
exposome umbrella to cover endogenous molecules like hormones as well as
v
vi Foreword
substances generated by human and microbial metabolism, lipid peroxidation,
inflammation,etc.
A compilation of about 1600 circulating molecules and metals, derived from
studies of normal humans, led to further insights into the nature of the “blood
exposome” (Rappaport et al. 2014). On the one hand, this dataset revealed that
chemicals derived from foods, drugs, and endogenous sources covered the same
dynamic range of blood concentrations (pM–mM), while those from pollution
sources were present at 1000-fold lower levels (fM–μM). But on the other hand,
chemical-similaritymaps,representingthechemicalspaceandchronicdiseasespace
of these circulating chemicals, were surprisingly similar. This indicates that all
sources of exposure (foods, drugs, pollution, and endogenous processes) generate
chemicalsthatcontributetochronicdiseases,andthusareworthyofinvestigation.
The vast chemical space and dynamic range of the blood exposome emphasize
the importance of untargeted methods for discovering causes of disease. In fact,
state-of-the-artliquidchromatography–massspectrometrycannowdetectthousands
of small molecules and proteins in a few microliters of archived blood from
prospectivecohorts.Likewise,preprocessingmethodsformetabolomicsandprote-
omics are rapidly evolving to filter and normalize untargeted proteomics and
metabolomics data that are appropriate for statistical analyses. Thus we can now
conductexposome-wideassociationstudies(EWAS)ascomplements toGWASin
epidemiologicstudies(Rappaport2012)andtherebyidentifycausal“signaturesand
fingerprints”ofexposurethatfueledWild’sspeculationin2005.
Although the exposome paradigm was originally proposed and developed for
etiologicresearch,ithasgrowntoencompassotheravenuesofinquiry.Thatis,our
conceptualization of “exposure” has evolved from single substances, derived pri-
marilyfromairandwaterpollutionandthediet,tothemyriadchemicalsemanating
fromarraysofexternalandinternalsources(RappaportandSmith2010;Wild2012).
Thishasled,inturn,totherealizationthattheexposomeisperhapsthebiggestofthe
big data entities, whose characterization will require advanced computation, bioin-
formatics,andstatistics.Andfinally,ascombinedGWAS/EWASleadtodiscoveries
ofcausalexposuresandgene–exposureinteractions,publichealthprofessionalswill
beabletodevelopinterventionsforreducingdiseaserisks.
Inthisbook,UnravellingtheExposome:APracticalView,theeditors Anthony
MacheroneandSoniaDagninohaveassembledadiverseteamofauthorswhodelve
into the many channels of research and practice emerging from the exposome
paradigm.Byblendingthemultidisciplinaryendeavorsofepidemiologists,exposure
scientists,toxicologists,statisticians,physicians,chemists,andomicsscientists,this
bookoffersanessentialoverviewof“exposomics”forhealthprofessionals.
EnvironmentalHealth StephenM.Rappaport
UniversityofCalifornia
Berkeley,CA,USA
Foreword vii
References
GuttmacherAE,CollinsFS(2003)Welcometothegenomicera.NEnglJMed349
(10):996–998
HemminkiK,CzeneK(2002)Attributablerisksoffamilialcancerfromthefamily-
cancerdatabase.CancerEpidemiolBiomarkPrev11(12):1638–1644
Rappaport SM (2012) Biomarkers intersect with the exposome. Biomarkers 17
(6):483–489
RappaportSM(2016)Geneticfactorsarenotthemajorcausesofchronicdiseases.
PLoSOne11(4):e0154387
Rappaport SM, Smith MT (2010) Epidemiology. Environment and disease risks.
Science330(6003):460–461
Rappaport SM, Barupal DK, Wishart D, Vineis P, Scalbert A (2014) The blood
exposomeanditsroleindiscoveringcausesofdisease.EnvironHealthPerspect
122(8):769–774
WelterD,MacArthurJ,MoralesJ,BurdettT,HallP,JunkinsH,KlemmA,FlicekP,
Manolio T, Hindorff L, Parkinson H (2014) The NHGRI GWAS catalog, a
curated resource of SNP-trait associations. Nucleic Acids Res 42(Database
issue):D1001–D1006
WildCP(2005)Complementingthegenomewithan“exposome”:theoutstanding
challenge of environmental exposure measurement in molecular epidemiology.
CancerEpidemiolBiomarkPrev14(8):1847–1850
WildCP(2012)Theexposome:fromconcepttoutility.IntJEpidemiol41(1):24–32
Preface
In2013,IwasaskedtowriteachapterforImmaFerrerandE.MichaelThurmanin
the next volume of Comprehensive Analytical Chemistry, Vol. 61 (Elsevier B.V.
Amsterdam: The Netherlands. ISBN: 978-0-444-62623-3), entitled The Future of
GC/Q-TOFinEnvironmentalAnalysis.Lackingpossessionofacrystalball,Ibegan
to research exactly what I could espouse about the future of time-of-flight mass
spectrometryintheenvironmentalsciences.Indoingso,IcameacrossatopicIhad
heard of only once before from Frank David of the Research Institute of Chroma-
tography in Belgium—Exposomics. Through the efforts of writing the chapter, it
became very clear that the concept of the exposome filled an immense gap for the
understandingofhownongeneticchemicalexposuresfrombothwithinandoutside
ofthebodycontributedtotheonsetandprogressionofchronicdisease.
Several years later, I presented “Exploring the exposome: a critical quantity for
determining the causes of chronic human disease” as the Plenary Speaker at a
meetingoftheLondonBiologicalMassSpectrometryDiscussionGroupatUniver-
sity College, London. While there, I ran into Sonia Dagnino whom I had met
previously when she was a post-doctoral fellow in Shane Snyder’s lab at the
University of Arizona. Sonia spoke to me about an opportunity to edit a book for
Springerabouttheexposomeandweagreedtopartnerasco-editorsontheproject—
thusthejourneybegan.
Through both Sonia’s and my exposome networks, we secured contributions
from the top experts in the field of exposomics. We thank the authors for their
contributions,andtrulybelievethisvolumewillbeaprincipalreferenceforthefield
ofexposomics.
Baltimore,MD,USA AnthonyMacherone
ix
Contents
PartI TheUtilityoftheExposomeParadigm
1 UsingExposomicstoAssessCumulativeRisksfromMultiple
EnvironmentalStressors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
MartynT.Smith,ClionaM.McHale,andRosemariedelaRosa
2 ThePublicHealthExposome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
PaulD.Juarez
3 TheU.S.MilitaryandtheExposome. . . . . . . . . . . . . . . . . . . . . . . . 63
ChristopherBradburneandJohnA.Lewis
4 FramingFetalandEarlyLifeExposomeWithinEpidemiology. . . . 87
JessicaE.LaineandOliverRobinson
PartII MeasuringtheInternalExposome
5 EpigeneticsandtheExposome. . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
MichellePlusquin,NellyD.Saenen,andTimS.Nawrot
6 Metabonomics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
TobyAthersuch
7 TranscriptomicsWithintheExposomeParadigm. . . . . . . . . . . . . . 183
D.A.Sarigiannis
PartIII MeasuringSourcesofExposure
8 TheFoodExposome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
AugustinScalbert,IngeHuybrechts,andMarcJ.Gunter
xi
xii Contents
9 TheDustExposome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
I.R.Schultz,S.Cade,andL.J.Kuo
10 FromtheOutsideIn:IntegratingExternalExposures
intotheExposomeConcept. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
YuxiaCuiandDavidBalshaw
PartIV DataAnalysisfortheExposome
11 StatisticalModelstoExploretheExposome:FromOMICs
Profilingto‘Mechanome’Characterization. . . . . . . . . . . . . . . . . . . 279
MarcChadeau-HyamandRoelVermeulen
12 Exposome-WideAssociationStudies:AData-Driven
ApproachforSearchingforExposuresAssociated
withPhenotype. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
ChiragJ.Patel
PartV ExposomeCharacterizationAroundtheGlobe
13 HERCULES:AnAcademicCentertoSupport
ExposomeResearch.. . . .. . . .. . . .. . . .. . . .. . .. . . .. . . .. . . .. 339
MeganM.NiedzwieckiandGaryW.Miller
14 EXPOsOMICs:Meet-in-the-MiddleandNetworkPerturbation. . . 349
ChristianaA.Demetriou,DavideDegliEsposti,KristiPullen
Fedinick,andPaoloVineis
15 BuildinganEarlyLifeExposomebyIntegratingMultiple
BirthCohorts:HELIX. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
MartineVrijheidandLeaMaitre
16 TheHEALSProject. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
D.A.Sarigiannis
PartVI Conclusion
17 UnravellingtheExposome:ConclusionsandThoughts
fortheFuture. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
SoniaDagnino
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
