Person:

Peng, Cheng

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.

Background: Among nondiabetic individuals, higher fasting blood glucose (FBG) independently predicts diabetes risk, cardiovascular disease, and dementia. Ambient PM2.5 (particulate matter with aerodynamic diameter ≤ 2.5 μm) is an emerging determinant of glucose dysregulation. PM2.5 effects and mechanisms are understudied among nondiabetic individuals. Objectives: Our goals were to investigate whether PM2.5 is associated with an increase in FBG and to explore potential mediating roles of epigenetic gene regulation. Methods: In 551 nondiabetic participants in the Normative Aging Study, we measured FBG, and DNA methylation of four inflammatory genes (IFN-γ, IL-6, ICAM-1, and TLR-2), up to four times between 2000 and 2011 (median = 2). We estimated short- and medium-term (1-, 7-, and 28-day preceding each clinical visit) ambient PM2.5 at each participant’s address using a validated hybrid land-use regression satellite-based model. We fitted covariate-adjusted regression models accounting for repeated measures. Results: Mean FBG was 99.8 mg/dL (SD = 10.7), 18% of the participants had impaired fasting glucose (IFG; i.e., 100–125 mg/dL FBG) at first visit. Interquartile increases in 1-, 7-, and 28-day PM2.5 were associated with 0.57 mg/dL (95% CI: 0.02, 1.11, p = 0.04), 1.02 mg/dL (95% CI: 0.41, 1.63, p = 0.001), and 0.89 mg/dL (95% CI: 0.32, 1.47, p = 0.003) higher FBG, respectively. The same PM2.5 metrics were associated with 13% (95% CI: –3%, 33%, p = 0.12), 27% (95% CI: 6%, 52%, p = 0.01) and 32% (95% CI: 10%, 58%, p = 0.003) higher odds of IFG, respectively. PM2.5 was negatively correlated with ICAM-1 methylation (p = 0.01), but not with other genes. Mediation analysis estimated that ICAM-1 methylation mediated 9% of the association of 28-day PM2.5 with FBG. Conclusions: Among nondiabetics, short- and medium-term PM2.5 were associated with higher FBG. Mediation analysis indicated that part of this association was mediated by ICAM-1 promoter methylation. Citation: Peng C, Bind MA, Colicino E, Kloog I, Byun HM, Cantone L, Trevisi L, Zhong J, Brennan K, Dereix AE, Vokonas PS, Coull BA, Schwartz JD, Baccarelli AA. 2016. Particulate air pollution and fasting blood glucose in nondiabetic individuals: associations and epigenetic mediation in the Normative Aging Study, 2000–2011. Environ Health Perspect 124:1715–1721; http://dx.doi.org/10.1289/EHP183

Background: IgE-mediated sensitization may be epigenetically programmed in utero, but early childhood environment may further alter complex traits and disease phenotypes through epigenetic plasticity. However, the epigenomic footprint underpinning IgE-mediated type-I hypersensitivity has not been well-understood, especially under a longitudinal early-childhood life-course framework. Methods: We used epigenome-wide DNA methylation (IlluminaHumanMethylation450 BeadChip) in cord blood and mid-childhood peripheral blood to investigate pre- and post-natal methylation marks associated with mid-childhood (age 6.7–10.2) total serum IgE levels in 217 mother-child pairs in Project Viva—a prospective longitudinal pre-birth cohort in eastern Massachusetts, USA. We identified methylation sites associated with IgE using covariate-adjusted robust linear regressions. Results: Nineteen methylation marks in cord blood were associated with IgE in mid-childhood (FDR < 0.05) in genes implicated in cell signaling, growth, and development. Among these, two methylation sites (C7orf50, ZAR1) remained robust after the adjustment for the change in DNA methylation from birth to mid-childhood (FDR < 0.05). An analysis of the change in methylation between cord blood and mid-childhood DNA (Δ-DNAm) identified 395 methylation marks in 272 genes associated with mid-childhood IgE (FDR < 0.05), with multiple sites located within ACOT7 (4 sites), EPX (5 sites), EVL (3 sites), KSR1 (4 sites), ZFPM1 (3 sites), and ZNF862 (3 sites). Several of these methylation loci were previously associated with asthma (ADAM19, EPX, IL4, IL5RA, and PRG2). Conclusion: This study identified fetally programmed and mid-childhood methylation signals associated with mid-childhood IgE. Epigenetic priming during fetal development and early childhood likely plays an important role in IgE-mediated type-I hypersensitivity. Electronic supplementary material The online version of this article (10.1186/s13148-018-0488-x) contains supplementary material, which is available to authorized users.