Epigenetic Effect Modifications With Ozone Exposure on Healthy Volunteers
Condition: Exposure to Environmental Pollution, Non-occupational
Study type: Interventional

Summary: 
      The purpose of this protocol is to assess whether epigenetic factors in healthy individuals
      make a person more or less responsive to lung inflammation following ozone exposures.
    

Detailed description: 
      Controlled human exposure studies to ozone have reported decreases in lung function (Devlin
      et al. 2012; Kim et al. 2011) and increased inflammation (Kim et al. 2011; Koren et al. 1991;
      Liu et al. 2009; Romieu et al. 2008). However, the range of response to ozone in healthy
      young volunteers is an order of magnitude, and if individuals are exposed to ozone some
      months later they retain their hierarchy on the response curve, suggesting that long-lived
      factors are responsible. Several studies have demonstrated that polymorphisms in oxidative
      stress genes such as GSTM1 or NQO1 may be associated with responsiveness to air pollutants
      (Bergamaschi et al. 2001; Corradi et al. 2002). However, within the past decade, many
      researchers have started exploring the epigenome as a possible link between exposures to
      environmental toxicants and disease. Epigenetics refers to non-genetic mechanisms influencing
      gene expression and phenotype (Cortessis et al. 2012). Commonly studied epigenetic changes
      include DNA methylation, histone modification, and non-coding RNA expression (i.e.
      micro-RNA). Recently, work conducted at the Harvard School of Public Health looked at DNA
      methylation as an effect modifier to air pollution-induced adverse health effects (Bind et
      al. 2012). This group, using a cohort representing previous war veterans from the VA
      Normative Aging Study, observed stronger effects in cardiovascular disease-related blood
      biomarkers with DNA methylation status, both globally and within candidate genes.
      Additionally, Salam et al. found that fractional exhaled nitric oxide, a marker of lung
      inflammation, was interrelated with short-term PM 2.5 concentration as well as NOS2
      epigenetic and genetic variations in children (2012). Thus, these studies suggest epigenetic
      changes could impact susceptibility to pollutants. Additionally, acute epigenetic changes,
      which are potential pathways of air pollution-induced health effects, have been associated
      with the inhalation of particulate matter and ambient gaseous pollutants (Baccarelli et al.
      2009; Bellavia et al. 2013; Bollati et al. 2010; De Prins et al. 2013; Madrigano et al. 2011;
      Tarantini et al. 2009). Therefore, it is possible that an individual's epigenetic profile
      could make them more or less responsive to ozone, and that ozone exposure itself could cause
      acute changes in the epigenome which could in turn affect ozone-responsiveness.

      Previous studies that have looked at epigenetic changes associated with air pollutants have
      difficultly disentangling the role of genetic and epigenetic factors. One way to do this is
      to study identical (MZ) twins. MZ twins arise when two or more daughter cells split from a
      single zygote during embryonic development, forming two individuals with identical genetic
      sequences (Fraga et al. 2005) but dissimilar epigenomes (Li et al. 2013; Szyf 2007). A number
      of diseases in which MZ twins are discordant, such as bipolar and schizophrenia disorders
      (Bonsch et al. 2012; Dempster et al. 2011), asthma (Runyon et al. 2012), autism spectrum
      disorder (Wong et al. 2013), and breast cancer (Heyn et al. 2013), implicate epigenetic
      variability as the cause. Therefore, as discordance for disease status has already been
      linked with epigenetic changes, this adds further plausibility to the notion that epigenetics
      could be responsible for the susceptibility of some subjects to ozone exposures while others
      seem non-responsive. By using MZ twins as one target population for this study, variability
      due only to epigenetics, without the influence of genetics, can be fully explored.

      For this study, the investigators will measure changes in pulmonary inflammation after a
      controlled exposure in healthy subjects and healthy twin pairs to clean air and ozone. This
      endpoint was chosen because previous work has shown that the epithelial cells lining the
      airways are the first target of ozone and respond by making pro-inflammatory cytokines such
      as IL-6 and IL-8. Epigenetic changes are dependent on tissue type, and airway epithelial
      cells can be obtained by brush biopsies during bronchoscopy and assayed for epigenetic
      changes. The investigators will determine whether differences in baseline epigenetic profiles
      between subjects are associated with responsiveness to ozone and whether ozone exposure
      itself causes acute changes in a subject's epigenome.
    

Intervention name(s): Clean air; Ozone
Intervention type(s): Other; Other
Intervention description(s): Each subject will be exposed to clean air for 2 hours. Subjects will exercise on a bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 20 L/min/m2 BSA followed by a 15 minute rest period, repeated 4 times.; Each subject will be exposed to 0.3 ppb ozone for 2 hours. Subjects will exercise on a bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 20 L/min/m2 BSA followed by a 15 minute rest period, repeated 4 times.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Controlled human exposure study; Ozone; Inflammation