Environmental Mixtures, Dietary Patterns, and Risk of Type 2 Diabetes: From Prospective Associations to Metabolomic Pathways

Project Summary / Abstract
Exposure to certain environmental factors, such as air pollution and lack of greenspace, have been suggested
to contribute to risk of incident type 2 diabetes (T2D), a metabolic condition that is closely related to diet.
However, these environmental exposures are often studied in isolation, inconsistently accounting for the potential
confounding and modification effects of other exposures and diet. Furthermore, the underlying mechanism
through which exogenous exposures, including environment and diet, lead to incident T2D is unclear. High-
resolution metabolomics has emerged as a powerful tool for identifying molecular mechanisms responsive to
exogenous exposures, but its application in environmental epidemiology has resulted in inconsistent findings
due to unstandardized methods and small sample sizes. My long-term career goal is to study the health impacts
of environmental exposures by integrating omics data with traditional chronic disease epidemiology, ultimately
to inform public health policies and individual interventions aimed at mitigating adverse environmental impacts.
In Aims 1 & 2 of this proposal, I will assess the effect of exposure to chemical, physical stressors, natural and
built environment-related factors, and diet, simultaneously and sequentially, on incident T2D in three prospective
cohorts, the Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-Up Study (HPFS). These
three cohorts include ~289,000 participants who provided detailed time-varying, longitudinal information on
demographic characteristics, environmental exposures, diet, and other behavioral factors at the individual-level.
I will apply cutting-edge high-dimensional data analytic methods to disentangle the independent effects of single
exposures/sources, assess the joint effect of multiple exposures, and assess the interaction among exposures.
In Aims 3 & 4, I will characterize the metabolomic alterations responsive to the exogenous environmental and
dietary exposures and explore the pathways through which the exogenous exposures lead to incident T2D. The
metabolomics research will be performed in plasma samples collected with standardized protocols in a subgroup
of the NHS, NHSII and HPFS cohorts (n~13,669), and validated in the Canadian Longitudinal Study on Aging
(CLSA) cohort (n~10,204). I am well suited to perform this research based on 1) my past research experience in
environmental science and epidemiology, 2) the exceptional mentoring team I have assembled to ensure that
this research is of the highest quality, and 3) the unique resources of the NHS/HPFS cohorts. This study will
enable me to rigorously evaluate the impact of simultaneous exposure to various external factors including
chemical and physical stressors, natural and built environment, and diet on incident T2D, and to characterize
the underlying metabolomic changes. I will be guided by a world-class team of mentors to expand my expertise
in T2D, nutritional epidemiology, high-dimensional data analytics, and metabolomics. The proposed research
and training will enable me to establish an independent career as a leader in environmental epidemiology with
expertise in diabetes and metabolomics.

Grant Number: 1K99ES037025-01A1
NIH Institute/Center: NIH
Principal Investigator: Jie Chen