What Is the Exposome?

S.M. Rappaport University of California,

Berkeley

What is the exposome?

S. M. Rappaport

About 2/3 of people die of chronic diseases …

Worldwide deaths , 2010 (50M) (Data from Lozano et al., Lancet,

2012) Cardiovascular

44%

Cancer22%

Respiratory 11%

Digestive8.2%

Neurological6.0%

Urogenital, blood &

endocrine4.0%

Diabetes3.6%

Other1.8%

mostly from heart disease and cancer

Chronic diseases63%

Infectious, maternal and childhood diseases

24%

Injuries, etc.12%

Genes or environment? The population attributable fraction (PAF) represents the proportion of disease cases that would be prevented if the causal factor were eliminated.

3 SM Rappaport

E-risks of cancer

5

SM Rappaport Data from Ezzati et al., “Comparative Quantification of Mortality and Burden of Disease Attributable to Selected Risk Factors,” Global Burden of Disease and Risk Factors, Chapter 4, WHO, 2006.

Finding unknown causes of cancer • Elaborating genetic factors employs high-tech

omics (GWAS and genome sequencing)o But has explained relatively little cancer risk

• Elaborating exposures relies on low-techquestionnaires, etc.o But has explained more than a third of cancer risk

• To find unknown causes of cancer, we mustlevel the playing field

6 SM Rappaport

7 SM Rappaport

0

200

400

600

800

1000

1200

1400

1600

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Num

ber o

f cita

tions

Year

Scientific citations to ‘exposome’ (Google Scholar)

8 SM Rappaport

Wild CEBP Commentary

2nd NAS workshop

Rappaport & Smith Science Perspective

Exposomics & HELIX (EU Programs)

HERCULES (NIEHS Center)

1st NAS workshop

CHEAR (NIEHS RFA)

Phenome Center (ICL)

G Rc Pc Disease

traits

E Mc

Secondary traits Rr Pr

Mr

Disease pathways

G = genome E = exposome R = transcriptome P = proteome M = metabolome (all small molecules and metals) S. Rappaport, Biomarkers, 2012, 17(6), 48: 3-9

Causal pathway (c) Reactive pathway (r)

G Rc Pc Disease

traits

E Mc

Secondary traits Rr Pr

Mr

Chemical communication

Receptors Enzymes DNA

RNA Transcription factors

Hormones Neurotransmitters

Lipids

Signaling molecules and metabolites

Cytokines

G Rc Pc Disease

traits Secondary

traits Rr Pr

Mr

Chemical communication

E Pollutants

Drugs Food nutrients

& toxins

Antigens Foreign DNA and RNA

Microbial metabolites

Mc

G Rc Pc Disease

traits Rr Pr Secondary

traits

E

Mr

Mc

Epigenetic modifications Post-translational modifications Genetic modifications (mutations)

Altering communication

S. Rappaport, Biomarkers, 2012, 17(6), 48: 3-9

Capturing all exposures

13 SM Rappaport

S.M. Rappaport and M.T. Smith, Science, 2010: 330:460-461

EXPOSURES ARE CHEMICALS … and the blood exposome includes all chemicals in the body .

The microbiota: Comprise 90% of the cells and 95% of protein-coding genes in the human body

0

10

20

30

40

50

60

70

80

90

100

1.E-07 1.E-06 1.E-05 1.E-04 1.E-03 1.E-02 1.E-01 1.E+00 1.E+01 1.E+02 1.E+03 1.E+04 1.E+05

Cum

ulat

ive

perc

ent

Blood concentration (µM)

DrugsFoodsPollutantsEndogenous

Venlafaxine

Aspirin

Simvastatin

Digoxin

Estradiol

Testosterone

Cortisol

Homocysteine

Cholesterol

Malondialdehyde Benzene

Lead

DDE Arsenic

PCB 170

Perfluorononanoic acid

Hexachlorocyclohexane

BDE 100

Cotinine

OCDD

Trichloromethane

Acetaldehyde

Folic acid, Vitamin D3

Sulforaphane

Trimethylamine-N-oxide

γ-Tocopherol

Ethanol

Solanidine

β-Carotene

Caffeine

Aflatoxin B1

Genistein

Rappaport et al., Environ Health Perspect, 2014

Normal blood concentrations

(1,561 chemicals)

1,000-fold

A glimpse of the blood exposome

SM Rappaport 15

Chemical space of the blood exposome All chemicals n = 1,561 (weighted by blood conc.)

Extraordinary diversity (>100 chemical classes from many sources)

Rappaport et al. Environ Health Perspect, 2014

Aliphaticamino acids

Flavonoids Fatty acids

Steroids

Sugars

PCBs

Dioxins

Chemicals with disease-risk citations n = 336 (weighted by # citations)

Epidemiologists look for chemicals that cause diseases, regardless of their sources (endogenous, food, pollution, drugs).

Small circulating molecules (‘metabolome’) provide one important avenue for characterizing biologically relevant exposures

Exposome-wide association studies (EWAS)

By applying EWAS with biospecimens from healthy and diseased subjects, we can discover useful biomarkers 16

SM Rappaport

http://www.flickr.com/photos/paulieparker/246707763/

Then we can target these biomarkers in large populations

S. Rappaport, Biomarkers, 2012, 17(6), 48: 3-9

Reactive biomarkers obscure causal pathways (reverse causality). Validation of exposure biomarkers requires biospecimens obtained prior to disease (prospective cohorts).

Biospecimens for EWAS? Reactive biomarkers

(disease) Causal biomarkers

(exposure)

G Rc Pc Disease

traits Rr Pr

E

Mr

Mc

Blood exposome

Pollutant biomarkers

Endogenous biomarkers

Biomarkers of disease

Drug biomarkers

Food biomarkers

Biomarkers of exposure

SM Rappaport

Untargeted EWAS

Based on: S. Rappaport, Biomarkers, 2012, 17(6), 48: 3-9

Causal biomarkers

Reactive biomarkers

Future of the exposome and disease etiology

• Transformative research happens once in a generation • Between 1988 and 2010 genomic research dominated

investigations of disease etiology despite disappointing results

• Exposomic research via EWAS will find causes of disease and could dominate the next generation of etiologic research o This will require integrated omics technologies - that measure

chemicals comprehensively and efficiently in appropriate biospecimens - combined with advanced bioinformatics,

o and government-academia-industry partnerships

19 SM Rappaport

Best wishes from Berkeley

Support from NIEHS through grants U54ES016115 and P42ES04705, IARC (senior visiting scientist award), the EU Exposomics project and Agilent Technologies (instrument loan)

Thanks to : Paulo Vineis (ICL) Dinesh Barupal (IARC) Augustin Scalbert (IARC) David Wishart (U. Calgary) Anthony Macherone (Agilent)

Martyn Smith Hasmik Grigoryan Will Edmands Kelsi Perttula Katie Hall Samantha Lu Lauren Petrick Yukiko Yano