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Epigenetic Effect Modifications With Ozone Exposure on Healthy Volunteers

2015-06-12 02:38:22 | BioPortfolio

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.

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.

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Conditions

Exposure to Environmental Pollution, Non-occupational

Intervention

Clean air, Ozone

Location

EPA Human Studies Facility
Chapel Hill
North Carolina
United States
27514

Status

Recruiting

Source

Environmental Protection Agency (EPA)

Results (where available)

View Results

Links

Published on BioPortfolio: 2015-06-12T02:38:22-0400

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