Project at a Glance

Title: Peripheral blood gene expression in subjects with coronary artery disease and exposure to particulate air pollutant components and size fractions

Principal Investigator / Author(s): Delfino, Ralph

Contractor: UC Irvine

Contract Number: 09-341

Research Program Area: Health & Exposure

Topic Areas: Health Effects of Air Pollution


Background: Cardiovascular disease outcomes have been associated with exposure to ambient particulate matter (PM) air pollution in many epidemiological studies. Experimental studies have revealed potential mechanisms behind the epidemiological results and many of these studies have revealed changes in the expression of important genes in key biological pathways with exposure to air pollution from fossil fuel combustion. Few epidemiological studies have examined this. We hypothesized that blood cell gene expression levels along biological pathways relevant to cardiovascular outcomes would be associated with traffic-related air pollutant exposures in elderly subjects with coronary artery disease.

Methods: Available data were collected in a cohort panel study funded by the National Institutes of Health, National Institute of Environmental Health Sciences. Gene expression data were available for 43 subjects with up to 12 weekly repeated measures conducted in three of the four retirement communities in the Los Angeles Air basin where the exposure measurement work took place. Whole blood samples were collected weekly, RNA was isolated and then it was reversed transcribed into complementary DNA for subsequent gene expression analysis using the polymerase chain reaction method. Candidate genes (35) were selected a priori based on biological function and reported pollutant exposure effects. Exposure measurements were conducted in the indoor and outdoor environment of each community and included daily size-fractionated PM mass and PM organic chemical composition, including polycyclic aromatic hydrocarbons (PAH). We also measured hourly criteria pollutant gases, total particle number concentration, PM2.5 organic carbon (OC), and PM2.5 markers of primary combustion products, namely elemental carbon (EC), and black carbon (BC). The present ARB-funded study provided accumulation mode PM data for: 1) chemical composition; 2) in vitro generation of reactive oxygen species (ROS) by alveolar (lung) macrophages that were exposed to extracts of the weekly PM samples; and 3) source apportionment work, including estimations of photochemically-related secondary organic aerosols. Within-subject relations between air pollutant exposures and normalized gene expression levels were analyzed using mixed-effects regression models adjusted for weather, community and study season.

Results: Source apportionment results in the four retirement communities showed that although people spend most of their time indoors, this does not shield them from outdoor pollutants since a sizeable portion of indoor PM2.5 particles originate from outdoor mobile sources. Expression levels of 30 genes from the 43 subjects were suitable for analysis and provided around 360 samples. Results of regression models showed that traffic-related air pollutants were associated with the expression of 7 genes in important pathways including Nrf2-mediated oxidative stress response, xenobiotic response, inflammation, and platelet activation. Although many relationships were not statistically significant, associations were consistent with respect to their magnitude and direction (positive). PAH and/or ROS from quasi-ultrafine PM ( < 0.25 micrometers) generally showed stronger associations with gene expression than did accumulation mode PM (0.25-2.5 micrometers). In secondary analyses we found some evidence of effect modification of these and other associations by polymorphisms in selected candidate genes, including NFE2L2, SELP, and SOD2. Secondary air pollutant exposures were not associated with gene expression. Other air pollutants (metals, total OC and CO) were not associated with the expression of genes. Source-apportioned biomass smoke was positively associated with expression of the hemoxenase-1 gene and was positively, but not significantly, associated with expression of seven others. None of the air pollutant exposures were associated with expression of 15 genes linked to most of the biological pathways studied.

Conclusions: Results revealed numerous positive associations with gene expression among genes that are part of the Nrf2-mediated oxidative stress response, xenobiotic response, inflammation, and platelet activation pathways. This supports our hypothesis that traffic-related air pollutant exposures affect the expression of genes in pathways that are relevant to adverse cardiovascular effects. Our findings are relevant to ambient air quality standards, which do not include ultrafine PM or the general class of organic components from fossil fuel combustion sources that have been associated with gene expression outcomes in this study as well as with cardiovascular outcomes in other analyses involving the same cohort.

For questions regarding this research project, including available data and progress status, contact: Research Division staff at (916) 445-0753

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