High-resolution Metabolomics for Profiling Environmental Exposures and Biological Response
Walker, Douglas.
2017
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Abstract: The
environment is a critical determinant of human health. Environment and gene-environment
interaction are suspected to contribute to over 85% of disease burden; however, only
limited characterization is possible with current technologies. Thus, to develop a
balanced view of human health and disease risk there is a critical need to establish
analytical methodologies that provide ... read moreenhanced population screening for identifying
exposures and biological relevance. The major objective of this dissertation was to
establish high-resolution metabolomics (HRM) as a viable platform for environmental
chemical surveillance and bioeffect monitoring in human populations. Recent advances in
high-resolution mass spectrometry, liquid chromatography and data processing algorithms
have positioned HRM as the preeminent analytical framework for precision medicine and
exposome research. Incredible potential exists for expanding HRM methodology to provide
the systematic measures required for population screening applications, yet there is a
critical need to validate that environmental exposures lead to metabolic variations
detectable in easily obtainable biological fluids. Here, the use of HRM for this purpose
was demonstrated through application of metabolome-wide association study to five
independent cohorts with well-characterized exposure measures. Metabolic variations were
then evaluated for exposure biomarkers and alterations consistent with disease-related
pathobiology. The key outcome of this work is the establishment of HRM as a central
platform linking exposures to internal dose and biological response. For each study, the
results demonstrate it is possible to detect metabolic variations due to acute or
chronic environmental exposures using HRM. These metabolic alterations, which include
biomarkers of environmental pollutants, biological response molecules and metabolic
changes consistent with disease pathobiology, are the key functional inputs required to
characterize environmental contributions to human disease. Overall, these findings
demonstrate that HRM is a sufficiently robust analytical framework for population
screening. Continued development is expected to greatly enhance measures of the
occurrence, distribution and magnitude of exposures in humans, while advancing knowledge
on mechanisms underlying environment-related
diseases.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Civil Engineering.
Advisor: Kurt Pennell.
Committee: Dean Jones, Doug Brugge, Elena Naumova, and David Gute.
Keywords: Environmental engineering, Environmental health, and Toxicology.read less - ID:
- kh04f202c
- Component ID:
- tufts:23116
- To Cite:
- TARC Citation Guide EndNote
