| The Role of Particulate Matter-Associated
Zinc in Cardiac Injury in Rats Urmila P. Kodavanti,1 Mette C.
Schladweiler,1 Peter S. Gilmour,2* J. Grace Wallenborn,3 Bhaskar S. Mandavilli,4** Allen
D. Ledbetter,1 David C. Christiani,5 Marschall S.
Runge,4 Edward D. Karoly,6 Daniel L. Costa,1 Shyamal Peddada,7 Richard Jaskot,1 Judy H. Richards,1
Ronald Thomas,1
Nageswara R. Madamanchi,4 and Abraham Nyska7,8 1National
Health and Environmental Effects Research Laboratory, Office of
Research and Development (ORD), U.S. Environmental Protection
Agency, Research Triangle Park, North Carolina, USA; 2Center
for Environmental Medicine, Asthma and Lung Biology, School of
Medicine, 3Department of Environmental Science and
Engineering, School of Public Health, and 4Carolina
Cardiovascular Biology Center, Department of Medicine,
University of North Carolina, Chapel Hill, North Carolina, USA;
5Harvard School of Public Health, Boston,
Massachusetts, USA; 6Human Studies Division, National Health and
Environmental Effects Research Laboratory, ORD, U.S.
Environmental Protection Agency, Chapel Hill, North Carolina,
USA; 7Laboratory of Experimental Pathology, National
Institute of Environmental Health Sciences, National Institutes
of Health, Department of Health and Human Services, Research
Triangle Park, North Carolina, USA; 8Tel Aviv
University, Tel Aviv, Israel Abstract
Background: Exposure to particulate matter (PM) has been associated with increased cardiovascular morbidity ; however, causative components are unknown. Zinc is a major element detected at high levels in urban air. Objective: We investigated the role of PM-associated zinc in cardiac injury. Methods: We repeatedly exposed 12- to 14-week-old male Wistar Kyoto rats intratracheally (1x/week for 8 or16 weeks) to a) saline (control) ; b) PM having no soluble zinc (Mount St. Helens ash, MSH) ; or c) whole-combustion PM suspension containing 14.5 µg/mg of water-soluble zinc at high dose (PM-HD) and d) low dose (PM-LD) , e) the aqueous fraction of this suspension (14.5 µg/mg of soluble zinc) (PM-L) , or f) zinc sulfate (rats exposed for 8 weeks received double the concentration of all PM components of rats exposed for 16 weeks) . Results: Pulmonary inflammation was apparent in all exposure groups when compared with saline (8 weeks > 16 weeks) . PM with or without zinc, or with zinc alone caused small increases in focal subepicardial inflammation, degeneration, and fibrosis. Lesions were not detected in controls at 8 weeks but were noted at 16 weeks. We analyzed mitochondrial DNA damage using quantitative polymerase chain reaction and found that all groups except MSH caused varying degrees of damage relative to control. Total cardiac aconitase activity was inhibited in rats receiving soluble zinc. Expression array analysis of heart tissue revealed modest changes in mRNA for genes involved in signaling, ion channels function, oxidative stress, mitochondrial fatty acid metabolism, and cell cycle regulation in zinc but not in MSH-exposed rats. Conclusion: These results suggest that water-soluble PM-associated zinc may be one of the causal components involved in PM cardiac effects. Key words: aconitase, air pollution, cardiac gene expression profile , mitochondria, particulate matter, zinc. Environ Health Perspect 116:13–20 (2008) . doi:10.1289/ehp.10379 available via http://dx.doi.org/ [Online 24 October 2007]
Address correspondence to U.P. Kodavanti, Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. EPA, MD B143-01, 109 TW Alexander Dr., Research Triangle Park, NC 27711 USA. Telephone: (919) 541-4963. Fax: (919) 541-0026. E-mail: kodavanti.urmila@epa.gov Supplemental Material is available online at http://www.ehponline.org/members/2007/10379/suppl.pdf *Current address: Astra Zeneca, Loughborough, Leicestershire, UK. **Current address: Life Sciences Research, Thermo Fisher Scientific, Rockford, IL. We thank J. Lehmann and D. Winsett of the U.S. EPA for intratracheal instillations. We also thank J. Samet, A. LaGier, G. Hatch, and L. Birnbaum (U.S. EPA) for critical review of this manuscript. This work was supported in part by U.S. EPA/University of North Carolina Training Agreements CT829471 and CR829522. The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and the policies of the agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The authors declare they have no competing financial interests. Received 18 April 2007 ; accepted 23 October 2007.
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