Genomic DNA methylation, cardiovascular disease, and short-term exposure to traffic air pollution

Background: Short-term exposure to particulate air pollution has been associated with increased hospitalization and death, particularly from cardiovascular disease (CVD). CVD-related processes, such as oxidative stress, atherosclerosis and aging, are associated with lower genomic DNA methylation content in blood DNA. Whether DNA methylation is modified by air particle exposure, and whether such alterations are associated with cardiovascular disease is undetermined. Objectives: In a cohort of elderly men in the Boston area, we sought to determine whether: i) recent exposure to black carbon (BC), a marker of traffic particles, was associated with decreased genomic DNA methylation content estimated in LINE-1 and Alu repetitive elements; ii) decreased genomic DNA methylation was associated with cardiovascular factors, including arterial blood pressure, serum levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), diagnosis of Coronary Heart Disease (CHD) and stroke, and statin use. Methods: We conducted a repeated measure investigation of DNA methylation in 718 subjects from the Normative Aging Study. Each subject was examined 1-3 times, for a total of 1,097 visits. Ambient BC hourly concentrations were measured at a monitoring site located approximately 1 km from the site of the examination. Repetitive element DNA methylation was measured on bisulfite-treated blood DNA using high-precision quantitative PCR-Pyrosequencing analysis. We used linear mixed regression models to obtain standardized regression coefficients (beta) expressing the fraction of a standard deviation change in LINE-1 or Alu methylation, after adjusting for multiple clinical and environmental covariates. Results: LINE-1 methylation decreased in association with higher BC ambient level. The association was significant when the average of the last four hours or of the day before the exam were considered, with stronger effects when BC average levels were measured over longer time windows (2-7 days) [e.g., beta = -0.11; 95%CI -0.18, -0.04; P = 0.002 for the 7-day moving average of BC levels]. Alu methylation showed no significant association with BC levels. Lower LINE-1 methylation was associated with higher systolic (beta = -0.06; 95%CI -0.12, -0.00, P = 0.04), diastolic (beta = -0.08; 95%CI -0.14, -0.01, P = 0.03), and mean (beta = -0.08; 95%CI -0.14, -0.01, P = 0.02) arterial blood pressure. LINE-1 methylation was also inversely associated with serum VCAM (beta = -0.07; 95%CI -0.14, -0.01, P = 0.03), but not with serum ICAM (beta = -0.00; 95%CI -0.09, 0.08, P = 0.96). Lower LINE-1 methylation was found in subjects with CHD (beta = -0.29; 95%CI -0.44, -0.14, P < 0.001), and stroke (-0.31; 95%CI -0.57, -0.05, P = 0.02). Current use of statins, a class of medications that have been shown to have antioxidant effects and abrogate cardiac effects of air particles, was associated with increased LINE-1 methylation (beta = 0.18; 95%CI 0.04, 0.32, P = 0.01). Alu methylation showed no association with arterial blood pressure, serum VCAM and ICAM, CHD, stroke, and statin use. Conclusions: Genomic blood DNA methylation estimated in LINE-1 repetitive elements, is reduced after short-term exposure to traffic particles. Such changes may reproduce epigenetic processes related to cardiovascular disease and may represent a mechanism by which particulate air pollution affects human health.