A new paradigm in environmental health sciences: Using the exposome to determine the cause of chronic human disease

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1 A new paradigm in environmental health sciences: Using the exposome to determine the cause of chronic human disease Anthony Macherone, Ph.D. Sr. Applications Chemist, Agilent Technologies, Inc. Visiting Scientist, Johns Hopkins School of Medicine

2 Outline This presentation will: Define the exposome Define analytical strategies to measure the exposome Illustrate successful proof of concept

3 DEFINING THE EXPOSOME

4 Some Background Two thirds of all people die of chronic diseases Cardiovascular (29%), cancer (15%), respiratory (7%) These diseases are caused by the genome G, the exposome E, or some combination of G x E Disease risks attributed to G are modest (10% to 15%) suggesting that 85% to 90% of risks result from E (and G x E) - 50% of these have yet to be identified GWAS explains so little - Missing heritability or genetic dark matter Lanzano, et al The Lancet Hindorff LA, et al Accessed Sep. 10, Lichtenstein P, et al N Engl J Med. Manolio TA, et al Nature.

5 The Challenge. To understand how exposures influence disease manifestation and progression But In contrast to GWAS, elaborating the E matrix still relies on de facto questionnaires, geographic information and limited targeted measurements

6 The answer. Wild (2005) espoused the exposome: The sum of life-course environmental exposures (including lifestyle factors), from the prenatal period onwards Rappaport and Smith (2010) expanded the definition of the exposome to include endogenous chemicals a quantity of critical interest to understand the causes of most chronic disease (Rappaport, 2011) Wild, CP Cancer Epidemiol Biomarkers Prev. Rappaport, SM & Smith, MT Science. Rappaport, SM JESEE.

7 The Exposome: Is the counterpart to the human genome Considers the internal chemical environment arising from the totality of exposures Is a global approach to systems biology Expands beyond the G-centric hierarchy that culminates in the endogenous metabolome Nicholson, JK, et al Nature.

8 Exposure contribution to chronic disease Rappaport and Macherone, Agilent Technologies.

9 Exposure bioaccumulation is consistent with disease incidence Barnett et al., Lancet 2012

10 ANALYTICAL STRATEGIES

11 Typically targeted Analysis Requires tremendous effort Misses endogenous exposures Rappaport, SM J Expos Sci Env Epidemiol.

12 More efficient global (discovery) methods All exposures represented in a single sample Reactive electrophiles Oxidative stress Metals, etc. Rappaport, SM J Expos Sci Env Epidemiol.

13 Two-step strategy Step 1 Data-driven EWAS Identify biomarkers Step 2 Knowledge-driven investigations Elucidate: Exposure-response relationships (biochemical epidemiology) Sources of exposure and human kinetics (exposure biology) Mechanisms of action (systems biology) Reduced exposures Early diagnosis of diseases Improved public health Personalized medical interventions Rappaport, SM & Macherone, A Agilent Technologies.

14 PROOF OF CONCEPT

15 Cumulative percent Rappaport, S.M., et al Environ Health Perspect Perfluorononanoic acid Benzene Hexachlorocyclohexane Trichloromethane PCB 170 OCDD BDE 100 Cotinine Aflatoxin B1 Digoxin Arsenic DDE Simvastatin Lead Acetaldehyde 1,000-fold Genistein b-carotene Venlafaxine Testosterone Solanidine Cortisol Ethanol Aspirin Malondialdehyde Sulforaphane Folic acid, Vitamin D3 Caffeine Cholesterol Trimethylamine-N-oxide Homocysteine g-tocopherol Normal blood concentrations (1,561 chemicals) Drugs Foods Pollutants Endogenous Estradiol 0 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 Blood concentration (mm)

# entities detected (Log 10 ) ICP-MS Based on: David S. Wishart, Exploring the Human Metabolome by Nuclear Magnetic Resonance Spectroscopyand Mass Spectrometry.In Lutz, J. Sweedler, R.

16 # entities detected (Log 10 ) ICP-MS Based on: David S. Wishart, Exploring the Human Metabolome by Nuclear Magnetic Resonance Spectroscopyand Mass Spectrometry.In Lutz, J. Sweedler, R. Wevers, editors: Methodologies for Metabolomics: Experimental Strategies and Techniques, New York, NY, 2013, pp Reprinted with permission in: Anthony Macherone, The Future of GC/Q-TOF in Environmental Analysis. In Imma Ferrer and E. Michael Thurman, editors: Comprehensive Analytical Chemistry, Vol. 61, Amsterdam: The Netherlands, 2013, pp

17 Anal. Chem. 2013, 85,

Untargeted EWAS of cardiovascular disease 150 Subjects in 2 C/C studies Discovery LC/MS (2,000 features): 18 unknown chemicals were associated with CVD.

18 Untargeted EWAS of cardiovascular disease 150 Subjects in 2 C/C studies Discovery LC/MS (2,000 features): 18 unknown chemicals were associated with CVD. Of these, 3 were highly correlated, suggesting a common pathway. TMAO Choline Betaine Studies in mice showed mammalian and microbiota metabolism needed for TMAO Wang et al Nature. SM Rappaport 18

19 Follow-up studies PC Challenge (eggs) shows influence of human microbiota on metabolism Carnitine challenge (steak) shows the same effect but only in omnivores, not in vegans Tang et al NEJM. Koeth et al Nature Medicine. SM Rappaport 19

20 SUMMARY

21 Putting it all together To discover unknown exposures that cause disease: 1. Data-driven EWAS 2. Knowledge-driven studies Requires exposure scientists, industrial hygienists, food scientists and analytical chemists who measure chemicals in air, water and food Identifying causal exposures will require: Measurements of chemicals both inside and outside the body

22 Collaborative efforts Leveraging expertise

23 MORE INFORMATION

24 Articles May 1, 2013 (Vol. 33, No. 9) Exposing the Exposome The Future of GC/Q-TOF in Environmental Analysis Anthony Macherone. In: Imma Ferrer and E. Michael Thurman, editors: Comprehensive Analytical Chemistry, Vol. 61, Amsterdam: The Netherlands, 2013, pp

26 Workshops ASMS workshop Using mass spectrometry to characterize the exposome and its impact on human health. June 18 5:45 7:00 PM Elevated exposome to interest group with the society The Hamner Institute RTP September 30, 2014 Martyn Smith, David Balshaw and more SETAC - Vancouver, BC November 9-13, 2014 The exposome: a new paradigm for environmental health and exposure sciences to identify the causes of chronic human disease Shane Snyder, Shoji Nakayama, Marc Strynar and more

27 Thank you Transformative research happens once in a generation Exposomic research will find disease causes and should dominate the next generation. Stephen Morris Rappaport "The difficulty lies, not in the new ideas, but in escaping from the old ones." John Maynard Keynes

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