Air pollution is a major public health concern, accounting for ~800,000 annual deaths. Exposure to air particulate matter (PM) has been shown to reduce lung function and increase respiratory disease rates. Inhaled PM can up-regulate systemic inflammatory responses in blood, which play important roles in PM- related lung function reduction and respiratory diseases. Blood leukocyte gene expression profiling in highly PM-exposed subjects has revealed that systemic inflammatory responses in blood are mediated by extensive gene expression shifts. This observation provides a tremendous opportunity to develop new biomarkers that are related to gene expression regulation. Histones are nuclear globular proteins that can be covalently modified by the addition of methyl, acetyl, and other chemical groups, which are inducible by certain inflammatory mediators, thus influencing chromatin structure and gene expression. Exposure to environmental pollutants has been shown to induce histone modifications in vitro. We recently observed increases in two of such modifications, i.e., H3K4 dimethylation and H3K9 acetylation, in blood leukocytes from a highly PM- exposed population. We hypothesize that ambient PM exposure may cause blood leukocyte histone modifications in response to PM-induced systemic inflammation. Such histone modifications may shift blood leukocyte gene expression toward profiles promoting further systemic inflammatory responses that, in turn, adversely affect lung function. We propose to test these hypotheses using data and biospecimens from our recently completed Beijing Truck Driver Air Pollution Study (BTDAS) in Beijing, China, one of the most polluted cities in the world. Sixty truck drivers (high exposure) and 60 indoor workers (low exposure) were recruited. We used personal air monitors and urine biomarkers to measure exposure to PM2.5, its toxic metals, and traffic exhausts on two independent work days with 1-2 week intervals. We collected after-work blood samples and lung function data, and measured inflammation markers. We propose to conduct an ancillary study to examine whether personal PM2.5 and its metal components are associated with histone modifications found to be induced by PM-contained metals in previous experimental studies;and whether PM-related histone modifications are associated with plasma inflammatory mediators) and/or lung function. We will replicate our findings from BTDAS in traffic-exposed police officers and referents in Milan, Italy, with PM2.5 levels typical of large cities in Europe/North America. Replication in a population with relatively lower exposure and different ethnicity will permit to test generalizability. The proposed study is highly time- and cost-effective and the first to examine the role of histone modifications in air pollution-related lung function reduction. Our results will offer a new researh area for future investigations on the role of histone modifications in PM-related lung function reduction. If we observed the hypothesized associations, we will seek funding to expand this line of research in large-scale studies in populations with lower exposure such as the US populations.

Public Health Relevance

Air pollution is a well known contributor to reduced lung function and respiratory diseases. This study is designed to identify novel mechanisms, i.e., histone modifications that regulate gene expression, for air pollution-related lung function reduction. Analysis of biospecimens and data from a highly air pollution- exposed population in Beijing, China, will have the potential to identify mechanisms that may not be detectable in low-exposed populations, such as US populations, and provide the groundwork to develop important novel preventive strategies to curb pollution-related respiratory diseases.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Tyson, Frederick L
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Northwestern University at Chicago
Public Health & Prev Medicine
Schools of Medicine
United States
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