Epigenetic and Mitochondrial Biomarkers Linking Air Pollution and Temperature on Human Health: The Normative Aging Study

Fine particulate matter (particulate matter with aerodynamic diameter ≤2.5 micron or PM2.5) exposure, as well as changes in ambient meteorological conditions are associated with adverse health consequences. However, the underlying mechanisms have not been clearly delineated. Systemic inflammation and oxidative stress are two of the primary pathways proposed to account for the association of PM2.5 / air temperature with health related outcomes. In this dissertation work, we proposed to use two types of novel molecular biomarkers: (1) nuclear DNA (nDNA) methylation, and (2) mitochondrial DNA (mtDNA) integrity to assess inflammatory and oxidative stress pathways linking environmental insults and health. Specifically, in Chapter I, we evaluated the mediating role of promoter region DNA methylation of inflammatory biomarkers (IFN-γ, IL-6, ICAM-1, and TLR-2) linking PM2.5 exposure and abnormal glucose metabolism in The Normative Aging Study. Our study showed that PM2.5 concentrations are associated with higher fasting blood glucose (FBG) level, and this association was in part mediated through ICAM-1 gene methylation, particularly at the longer (28-day) moving average investigated. Our study demonstrates a novel approach of mediation analysis in epigenetic studies and highlights a mediating role of ICAM-1 gene methylation in air-pollution associated abnormal glucose metabolism. In Chapter II, we assessed the relative effects of PM2.5 mass and PM2.5 components on a novel oxidative stress-related marker—blood mtDNA abundance in The Normative Aging Study. Our study showed that long-term exposure to PM2.5 mass and specific PM2.5 components is associated with decreased mtDNA abundance. Our findings from multi-pollutant modeling suggest that nitrate (NO3-) was associated with higher mitochondrial oxidative stress independent of PM2.5 mass concentration, and mass alone may not fully capture the oxidation potency of PM2.5. In Chapter III, we explored short-term changes in daily mean and daily standard deviation (SD) (variability) of ambient air temperature with blood mtDNA lesions in The Normative Aging Study. We observed short-term increases in mean air temperature were associated with higher mtDNA lesions in elderly adults, supporting the hypothesis that changes meteorological conditions may induce pathophysiological responses among susceptible populations