Investigating the Molecular Signatures and Pathways Indicative of Air Pollution Toxicity in Lung Carcinogenesis Using Single- and Multi-omics Analyses Restricted; Files Only

Abstract

The overarching goal of this dissertation was to elucidate the biological connections linking air pollution exposures to lung carcinogenesis by applying mixture analysis, high-dimensional mediation analysis, and novel multi-omics integration analysis, with the aim of identifying a highly correlated network of multi-omics signatures and pathways.

 

Aim 1: The effects of air pollution exposure on circulating proteins remain underexplored, and prior studies have rarely considered pollutant mixtures. In 208 participants from the Cancer Prevention Study (CPS)-II Nutrition Cohort, we evaluated six ambient air pollutants individually and in mixtures, identifying numerous proteins linked to immune response, inflammation, cell signaling, and cell growth, with some associations differing by current and former smokers. The consistency across single-pollutant and mixture models, alongside evidence that single-pollutant models may underestimate effects, underscores the importance of investigating air pollution mixtures.

 

Aim 2: The biological mechanisms linking air pollution to lung carcinogenesis remain poorly understood. Using pre-diagnosis plasma protein profiles from 95 matched case-control pairs from the CPS-II Nutrition Cohort, we applied two complementary methods, HIMA and Meet-in-the-Middle approaches, to compressively identify key mediating proteins and pathways. We found proteins and pathways related to inflammatory and cytokine/chemokine signaling, immune modulation, and altered cell activities may play significant roles in air pollution-associated lung cancer.

 

Aim 3: To advance understanding of air pollution-associated lung cancer, we analyzed pre-diagnosis plasma protein and metabolite profiles from 106 cases and 13 controls in the CPS-II Nutrition Cohort using a posterior multi-omics integration approach. We identified three components, comprising multiple proteins and metabolites with moderate to strong intercorrelations, that were associated with air pollution and could distinguish lung cancer cases from controls in a certain degree. These molecules and their enriched pathways converged in inflammatory signaling, cell survival, immune responses, and metabolic regulation, offering novel insights and reinforcing findings from single-omics analyses.

 

Conclusion: This dissertation identified novel and highly correlated multi-omics signatures and pathways indicative of the role of air pollution exposures in elevating lung cancer risk, which expanded our knowledge of the molecular mechanisms of air pollution-associated lung cancer.

Table of Contents

Distribution Agreement           1

Abstract             4

Acknowledgments     6

Table of Tables               1

Table of Figures             2

Introduction   4

Data source    8

Aim 1   10

Abstract             12

Methods            15

Results                21

Discussion       25

Tables 33

Figures                 40

Supplementary Information 44

References      69

Aim 2   75

Abstract             77

Introduction   79

Methods            81

Results                85

Discussion       88

Conclusion      94

Tables 95

Figures                 98

Supplementary Information 105

References      114

Aim 3   117

Abstract             119

Introduction   121

Methods            123

Results                127

Discussion       129

Conclusion      132

Tables 133

Figures                 135

Supplementary Information 139

References      144

Summary of results and future directions  146

Summary of results   147

Aim 1   147

Aim 2   148

Aim 3   149

Future directions         150

References      152

About this Dissertation

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School	Laney Graduate School
Department	Environmental Health
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Public Health Environmental Health
Keyword	air pollution lung cancer metabolomics mechanisms multi-omics proteomics mixture mediation
Committee Chair / Thesis Advisor	Liang, Donghai, Emory University
Committee Members	Marsit, Carmen J. , Emory University Kesarwala, Aparna H. , Emory University Sarnat, Jeremy A. , Emory University Everson, Todd M. , Emory University Wang, Ying , American Cancer Society

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