Colorectal cancer (CRC), a multifactorial disease, is the second leading cause of cancer deaths in the US. Preventive approaches aimed at specific, known pathways of CRC causation, such as oxidative stress, might be effective in reducing CRC morbidity and mortality. Although oxidative stress is implicated in colorectal carcinogenesis, human studies that evaluated associations of individual pro- and antioxidants with CRC have been inconclusive. The goals for this dissertation were to develop, compare and evaluate comprehensive "oxidative balance scores (OBS)", comprised of individual dietary, and environmental exposures that are known to affect physiologic oxidative processes, and to investigate the association of oxidative balance with risk of colorectal neoplasms and biomarkers of oxidative stress.
Four OBS were created to reflect combined summary measures of dietary and non-dietary anti- and pro-oxidant exposures. A higher score represents a predominance of anti- over pro-oxidant exposures. In a pooled analysis of three colonoscopy-based case-control studies, a substantial, statistically significant lower risk of incident, sporadic colorectal adenomas was found with higher levels of OBS. The results also suggested a dose dependent decrease in F2-isoprostanes, a sensitive and specific marker of oxidative stress in vivo, with increasing levels of OBS, providing support for OBS as a valid measure of oxidative balance. In a large prospective cohort study, higher OBS were associated with lower risk of CRC. In a biomarker-based pooled analysis of two case-control studies of incident, sporadic colorectal adenomas, results suggested that lipid peroxidation, as indicated by circulating F2-isoprostanes, may be 1) positively associated with risk for incident, sporadic colorectal adenoma in women, but not men, and 2) inversely associated with antioxidant micronutrient exposures, with some differences according to sex.
In conclusion, I introduced three novel methods for constructing OBS in this dissertation. Results of this dissertation support the use of pathway exposure scores to measure complex multicomponent exposures, provide evidence to suggest that oxidative balance is strongly associated with colorectal adenoma and cancer incidence, and support further investigations of oxidative balance with other chronic diseases. My dissertation also provides a framework for the development of oxidative balance-based interventions to reduce colorectal cancer risk.
Table of Contents
TABLE OF CONTENTS ILLUSTRATIONS LIST OF TABLES CHAPTER 1. BACKGROUND 1 Background 1 Epidemiology of Colorectal Cancer 1 Risk Factors for Colorectal Cancer 5 Colorectal carcinogenesis 10 Oxidative Stress, Oxidative Balance and Colorectal Carcinogenesis 15 Environmental Components of Oxidative Balance 19 Oxidative Balance Score (OBS) 27 Biomarkers of oxidative stress 28 Objectives 30 Specific Aims 30 CHAPTER 2. USING PATHWAY-SPECIFIC COMPREHENSIVE EXPOSURE SCORES IN EPIDEMIOLOGY: APPLICATION TO OXIDATIVE BALANCE IN A POOLED CASE-CONTROL STUDY OF INCIDENT, SPORADIC COLORECTAL ADENOMAS 31 Abstract 32 Introduction 33 Materials and Methods 34 Results 41 Discussion 43 Tables and Figures 48 CHAPTER 3. OXIDATIVE BALANCE SCORES AND RISK OF INCIDENT COLORECTAL CANCER IN A U.S. PROSPECTIVE COHORT STUDY 60 Abstract 61 Introduction 62 Materials and Methods 63 Results 70 Discussion 72 Tables and Figures 76 CHAPTER 4. ASSOCIATIONS OF PLASMA F2-ISOPROSTANES WITH ANTIOXIDANT MICRONUTRIENT LEVELS IN A CASE-CONTROL STUDY OF INCIDENT, SPORADIC COLORECTAL POLYPS 87 Abstract 88 Introduction 89 Materials and Methods 90 Results 95 Discussion 98 Tables and Figures 103 CONCLUSIONS AND PUBLIC HEALTH IMPLICATIONS 111 FUTURE DIRECTIONS 115 REFERENCES 118
About this Dissertation
|Committee Chair / Thesis Advisor|
|Oxidative Balance and Colorectal Neoplasms ()||2018-08-28||