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

/ 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. Project Number: 1K99ES037025-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Jie Chen | Institution: HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH, BOSTON, MA | Award Amount: $121,473 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZES1 MGE-K (K)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11228617