Mitochondrial Genetic Background Modifies the Relationship between Traffic-Related Air Pollution Exposure and Systemic Biomarkers of Inflammation

Mitochondrial Genetic Background Modifies the Relationship between Traffic-Related Air Pollution Exposure and Systemic Biomarkers of Inflammation Sharine Wittkopp 1 , Norbert Staimer 2 , Thomas Tjoa 2 , Daniel Gillen 3 , Nancy Daher 4 , Martin Shafer 5 , James J. Schauer 5 , Constantinos Sioutas 4 , Ralph J. Delfino 2 * 1 Occupational and Environmental Medicine Division, Department of Medicine, School of Medicine, University of California Irvine, Irvine, California, United States of America, 2 Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, California, United States of America, 3 Department of Statistics, School of Information and Computer Sciences, University of California Irvine, Irvine, California, United States of America, 4 Department of Civil and Environmental Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California, United States of America, 5 University of Wisconsin-Madison, Environmental Chemistry and Technology Program, Madison, Wisconsin, United States of America Abstract Background: Mitochondria are the main source of reactive oxygen species (ROS). Human mitochondrial haplogroups are linked to differences in ROS production and oxidative-stress induced inflammation that may influence disease pathogenesis, including coronary artery disease (CAD). We previously showed that traffic-related air pollutants were associated with biomarkers of systemic inflammation in a cohort panel of subjects with CAD in the Los Angeles air basin. Objective: We tested whether air pollutant exposure-associated inflammation was stronger in mitochondrial haplogroup H than U (high versus low ROS production) in this panel (38 subjects and 417 observations). Methods: Inflammation biomarkers were measured weekly in each subject (#12 weeks), including interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), C-reactive protein, interleukin-6 soluble receptor and tumor necrosis factor-soluble receptor II. We determined haplogroup by restriction fragment length polymorphism analysis. Air pollutants included nitrogen oxides (NO x ), carbon monoxide (CO), organic carbon, elemental and black carbon (EC, BC); and particulate matter mass, three size fractions (,0.25 m m, 0.25–2.5 m m, and 2.5–10 m m in aerodynamic diameter). Particulate matter extracts were analyzed for organic compounds, including polycyclic aromatic hydrocarbons (PAH), and in vitro oxidative potential of aqueous extracts. Associations between exposures and biomarkers, stratified by haplogroup, were analyzed by mixed- effects models. Results: IL-6 and TNF-a were associated with traffic-related air pollutants (BC, CO, NO x and PAH), and with mass and oxidative potential of quasi-ultrafine particles ,0.25 m m. These associations were stronger for haplogroup H than haplogroup U. Conclusions: Results suggest that mitochondrial haplogroup U is a novel protective factor for air pollution-related systemic inflammation in this small group of subjects. Citation: Wittkopp S, Staimer N, Tjoa T, Gillen D, Daher N, et al. (2013) Mitochondrial Genetic Background Modifies the Relationship between Traffic-Related Air Pollution Exposure and Systemic Biomarkers of Inflammation. PLoS ONE 8(5): e64444. doi:10.1371/journal.pone.0064444 Editor: Thomas Behrens, Universita¨t Bochum, Germany Received December 7, 2012; Accepted April 15, 2013; Published May 23, 2013 Copyright: s 2013 Wittkopp et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The present project was supported by U.S. National Institutes of Health grant numbers R01 ES12243, R21 ES016420, and F30 ES021107-01A1 from the National Institute of Environmental Health Sciences, MO1 RR00827 from the National Center for Research Resources and California Air Resources Board contracts 03-329 and 09-341. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies and no official endorsement should be inferred. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: C.S. receives royalties from SKC Inc. for the air sampling device (Sioutas Personal Cascade Impactor Sampler) used in this research. The remaining authors declare they have no actual or potential competing financial interests.This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: rdelfino@uci.edu exposure times of hours to days, have been associated with major cardiovascular events such as MI [3,4] and stroke, as well as cardiovascular hospital admissions and mortality [1]. In addition, there are associations between exposure and subclinical effects such as increases in blood pressure, ST-segment depression and increases in blood biomarkers of cardiovascular risk (reviewed by Brook et al. [1]). Introduction Traffic-related air pollution has been shown to be associated with cardiovascular and respiratory morbidity and mortality in many epidemiological studies [1,2]. These associations hold for both long- and, importantly, short-term exposure-response rela- tions [1]. Increases in short-term air pollutant exposures, with PLOS ONE | www.plosone.org May 2013 | Volume 8 | Issue 5 | e64444