air pollution, epigenetics and cardiovascular health: a human intervention trial

Conditions: Heart Rate; Heart Rate Variability; Inflammation

Summary: in this study, the pills formulated are being used to try to ameliorate the effect of air pollution on epigenetic changes, specifically dna methylation, potentially linked with particulate matter air pollution inhalation and cardiovascular health effects. the way in which this is achieved is that the vitamins, which act as methyl donors, add a methyl group to the dna to reverse the loss observed on exposure to air pollution. specifically for this study, the methyl donor supplement has been made by jamieson laboratories, and consists of 50mg vitamin b6 and 1 mg vitamin b12, (both within health canada approved limits) and 2.5 mg folic acid. the non-vitamin ingredients are those commonly used in pill formation. however, the folic acid concentration is 2.5mg, which is above the 1.0mg limit set by health canada for a natural health product. this concentration, however, has been used in previous academic studies safely and effectively, and was also formulated by jamieson laboratories. (clinicaltrials.gov number, nct00106886; current controlled trials number, isrctn14017017. hope2 study).

air pollution is a pervasive environmental threat estimated to cause \~800,000 deaths every year worldwide, mostly due to cardiovascular disease. this proposal addresses a fundamental mechanistic and pharmacologic question about effects of air pollution, which can most effectively be addressed through controlled human exposure experiments: does exposure have epigenetic effects that may have downstream subclinical or clinical consequences, and can adverse effects be safely reduced pharmacologically? consistent evidence from in- vitro and human studies have shown that exposure to air particulate matter pollution (pm, i.e., fine particles) induces hypomethylation of the dna, an epigenetic process that can underlie the activation of inflammatory genes and is postulated to link inhalation of pm into the lungs with cardiovascular inflammation and adverse responses. our goal is to determine whether a pharmacological intervention with methyl-donors (i.e., folic acid, vitamins b6 \& b12, betaine, methionine, and choline) can avert this dna methylation loss and mitigate the cardiovascular effects induced by pm exposure. the investigators will use experiments of human controlled exposure to pm - which reproduce conditions of exposure similar to those found in real life in urban environments - to conduct a double-blind, placebo-controlled crossover study. the investigators will test whether pharmacological intervention with methyl-donors attenuates the effects of pm exposure on dna methylation (aim 1), mrna expression \& plasma cytokines (aim 2), and blood pressure, arterial vasoconstriction, endothelial function, and autonomic control of the heart (aim 3). the investigators' study is poised to be the first human investigation to translate a wealth of animal data showing that methyl-donors can be used to modulate epigenetic states and avert environmental effects. the investigators have a unique opportunity to achieve this goal because we have access to one of the few facilities worldwide for human controlled-exposure studies, as well as to state-of-the-art resources for epigenetics investigations. the investigators will examine dna methylation and mrna expression in t-helper cells from human individuals, a cell type with key roles in determining adverse hypertensive and endothelial responses, as shown in several animal models. the investigators will test the effects of methyl-donors on a battery of cardiovascular endpoints that are highly sensitive to pm exposure. the investigators will explore the use of advanced statistical methods for mediation analyses to understand the relationships among pm, dna methylation, rna expression, plasma cytokines, and cardiovascular endpoints. the study will be conducted by an investigative team that has conducted seminal work in all of the research areas on which this proposal is built upon, including environmental epigenetics, cardiovascular effects of pm, and human controlled exposure studies.

Eligibility criteria:
inclusion criteria: * healthy volunteer * age 18-60 years old * non-smoker * must be able to fast 8 hours prior to exposure visits and for a further 4 hours during the exposure exclusion criteria: * subjects must not be regularly taking multivitamins, vitamins c \& e, folate, medications, fish oil or aspirin, oral or inhaled steroids, for 4 weeks before and during the trial. * lipid abnormalities * asthma or respiratory disease * hypertension (bp\> 140/90) or taking any blood pressure drug * known cardiac disease * abnormal homocysteine or glucose levels

Keywords: air pollution particulate matter 2.5 (pm2.5) methyl donor dna methylation mrna epigenetics controlled human exposures cardiovascular responses