Using the blood exposome to discover causes of chronic diseases
Stephen M. Rappaport, M.D.
Wednesday, June 10, 2015
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Chapters
Introduction
Genes or environment?
Global cancer mortality
Global heart-disease mortality
Assessing genetic factors in epidemiology
Genetic ‘dark matter’
Assessing exposures in epidemiology
Half of all deaths can be attributed to known exposures
Finding unknown causes of chronic diseases
Editorial
Scientific citations to ‘exposome’ (Google Scholar)
Capturing all exposures
A glimpse of the blood exposome
Chemical space of the blood exposome
More than 30,000 small-molecules features detected in 0.1 ml of serum
Foods are chemicals that are metabolized by human and microbial enzymes to produce more chemicals
Exposome-wide association studies (EWAS)
Untargeted EWAS
Untargeted EWAS of cardiovascular disease
Follow-up studies
Some context
Reactive electrophiles: an overlooked class of small molecules
Adducts as biomarkers of exposure to reactive electrophiles
Targeted protein adducts
Reactive electrophiles from benzene metabolism
Measurement of cysteinyl adducts of BO and 1,4-BQ
Benzene-related adducts in Chinese workers
BO and 1,4-BQ adducts of HSA in Chinese workers (n = 439)
So - we can measure targeted adducts for electrophiles of interest, such as reactive benzene metabolites. But what about unknown electrophiles?
By measuring all adducts at a given locus we perform ‘adductomics’
Cys34 adductomics via LC-HRMS
Analysis pipeline for adductomics
Pilot test with plasma from 18 volunteers
Cys34 Adductomics for EWAS
BMJ Research
Xuanwei adductomics (Pilot study)
Differences in adduct levels
Cys34 disulfide of glutathione is significantly lower in all solid-fuel users
Differences in adduct levels
Six adducts give best model of personal BaP
Nine adducts give best model of person PM2.5
Cys34 adducts in archived neonatal dried blood spots (ANBS) as biomarkers of fetal exposure
Work of Katie Hall and Hasmik Grigoryan
Prominent adducts detected in 50 control ANBS
Work of Lauren Petrick and Will Edmands
Detecting small molecules in ANBS
Metabolomics with dried blood spots
Discriminating blood & filter features
Small molecules in ANBS
Chemical space (ESI (-) mode)
Two exposome agendas
Future of the exposome and disease etiology
Best wishes from Berkeley
Workshop: Measuring the exposome: Strategies and preliminary results
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