Characterizing the Molecular Mechanisms Underlying the Health Effects of Fine Particulate Matters among Susceptible Populations via Multi-Omics Analysis 公开
Li, Zhenjiang (Spring 2023)
Abstract
In this dissertation, I explored and extended the existing advanced exposure assessment approach of fine particulate matter (PM2.5) and investigated the potential mediating role of metabolomic signatures, DNA methylation, and their interplay in the development of PM2.5-related adverse health outcomes. The dissertation applied an analytical framework that used high-dimensional mediation analysis to the analysis of metabolomic and epigenomic data (separately and simultaneously) in two cohorts, Emory Alzheimer’s Disease (AD) Research Center Brain Bank and the Atlanta African American Maternal-Child Cohort, to unravel the biological mechanisms underlying the associations of PM2.5 with AD-related neuropathology and preterm/early-term birth, respectively. In the brain bank cohort, we detected multiple CpG sites in prefrontal cortex tissues that mediated associations between PM2.5 exposure and AD-related neuropathology markers. Some of these CpG sites are located in genes related to neuroinflammation and neuroinflammation-mediated necroptosis in brain tissues, implicating neuroinflammation a potential underlying mechanism of PM2.5 neurotoxicity. In the prospective birth sample of African American pregnant people, metabolomic signatures detected in early-pregnancy serum samples were found to mediate the adverse effects of long- and short-term exposure to PM2.5 on the risk of preterm birth and early-term birth (ETB). Specifically, biological pathways involved in folate metabolism and glycine and serine metabolism were found to have an important role in the biological mechanism underlying PM2.5 toxicity on early birth. In addition, I employed multi-omics integration techniques and identified latent factors, derived from metabolomic and epigenomic data, that statistically mediated the association between PM2.5 exposure and the risk of ETB, which provide important information about the interplay between metabolic features and DNA methylation that appears to play a critical role in PM2.5 toxicity. The findings of the dissertation indicate that the use of omics techniques is valuable for capturing a holistic picture of the biological changes in human body responding to the PM2.5 exposure and unravelling their role in disease development. With a focus on the vulnerable populations, the older adults and pregnant women, the current project shed light on the molecular mechanisms of the pathogenesis of ETB and AD, which is key to risk assessment and intervention development among these populations.
Table of Contents
Table of Contents
Chapter 1. 1
Introduction. 1
Dissertation Aims 5
Chapter 2 Application of a fusion approach to obtain spatially resolved (200m) ambient fine particulate matter in Metropolitan Atlanta. 7
Introduction. 7
Methods. 8
Results. 11
Discussion. 12
Conclusions. 15
Tables and figures 16
Appendix for Chapter 2. 20
Chapter 3 Differential DNA Methylation in the Brain as Potential Mediator of the Association between Traffic-related PM2.5 and Neuropathology Markers of Alzheimer’s Disease. 22
Background. 22
Methods. 24
Results. 30
Discussion. 32
Conclusions. 37
Tables and figures 38
Appendix for Chapter 3. 45
Chapter 4 Metabolic Signatures as Potential Mediators in the Relationship between Ambient fine particulate matter and Pre- and Early-term Births in the Atlanta African American Maternal-Child Cohort 55
Introduction. 55
Methods. 56
Results. 57
Discussion. 65
Conclusions. 70
Tables and figures 71
Appendix for Chapter 4. 78
Chapter 5 Integration of Metabolome and Genome-wide DNA Methylation in Unravelling the Biological Mechanisms Underlying the Relationship between Ambient PM2.5 and Early-term Birth. 87
Introduction. 87
Methods. 90
Results. 96
Discussion. 99
Conclusions. 103
Chapter 6 Implications and Future Direction. 112
References 120
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