Air Pollution, Epigenetics and Cardiovascular Health: A Human Intervention Trial
Condition: Heart Rate; Heart Rate Variability; Inflammation
MeSH terms: Inflammation
Study type: Interventional
Phase: Phase 1

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).
    

Detailed description: 
      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.
    

Intervention name(s): methyl donor; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The design will include a 2 week placebo run-in followed by a baseline blank study (2-hrs exposure to medical air) to provide benchmarks for all assessed variables. Participants will then receive a 4-week placebo treatment before the first PM2.5 exposure study. A 4-week methyl-donor treatment (Dose: 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 once a day) will precede the 2nd PM2.5 exposure.; Placebo
Other intervention name(s): Vitamin B6; Vitamin B12; Folic Acid; Placebo
Intervention MeSH terms: Vitamins; Folic Acid; Vitamin B 12; Vitamin B 6; Vitamin B Complex
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Other
Keywords: air pollution; particulate matter 2.5 (PM2.5); methyl donor; DNA methylation; mRNA; epigenetics; controlled human exposures; cardiovascular responses