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Reddy R. Gottipolu,^1,* J. Grace Wallenborn,² Edward D. Karoly,³ Mette C. Schladweiler,¹ Allen D. Ledbetter,¹ Todd Krantz,¹ William P. Linak,⁴ Abraham Nyska,⁵ Jo Anne Johnson,⁶ Ronald Thomas,¹ Judy E. Richards,¹ Richard H. Jaskot,¹ and Urmila P. Kodavanti¹

¹Experimental Toxicology Division, National Health & Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; ²School of Public Health, University of North Carolina, Chapel Hill, North Carolina, USA; ³Human Studies Division, National Health & Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Chapel Hill, North Carolina, USA; ⁴Air Pollution Prevention and Control Division, National Risk Management Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; ⁵Tel Aviv University, Tel Aviv, Israel; ⁶Laboratory 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

Abstract
Background: Exposure to diesel exhaust (DE) is linked to vasoconstriction, endothelial dysfunction, and myocardial ischemia in compromised individuals.

Objective: We hypothesized that DE inhalation would cause greater inflammation, hematologic alterations, and cardiac molecular impairment in spontaneously hypertensive (SH) rats than in healthy Wistar Kyoto (WKY) rats.

Methods and results: Male rats (12–14 weeks of age) were exposed to air or DE from a 30-kW Deutz engine at 500 or 2,000 µg/m³, 4 hr/day, 5 days/week for 4 weeks. Neutrophilic influx was noted in the lung lavage fluid of both strains, but injury markers were minimally changed. Particle-laden macrophages were apparent histologically in DE-exposed rats. Lower baseline cardiac antioxidant enzyme activities were present in SH than in WKY rats ; however, no DE effects were noted. Cardiac mitochondrial aconitase activity decreased after DE exposure in both strains. Electron microscopy indicated abnormalities in cardiac mitochondria of control SH but no DE effects. Gene expression profiling demonstrated alterations in 377 genes by DE in WKY but none in SH rats. The direction of DE-induced changes in WKY mimicked expression pattern of control SH rats without DE. Most genes affected by DE were down-regulated in WKY. The same genes were down-regulated in SH without DE producing a hypertensive-like expression pattern. The down-regulated genes included those that regulate compensatory response, matrix metabolism, mitochondrial function, and oxidative stress response. No up-regulation of inflammatory genes was noted.

Conclusions: We provide the evidence that DE inhalation produces a hypertensive-like cardiac gene expression pattern associated with mitochondrial oxidative stress in healthy rats.

Key words: air pollution, cardiac gene expression profile, diesel exhaust, hypertension, mitochondria, particulate matter. Environ Health Perspect 117:38–46 (2009) . doi:10.1289/ehp.11647 available via http://dx.doi.org/ [Online 12 September 2008]

Address correspondence to U.P. Kodavanti, MD: B143-01, ETD/NHEERL, U.S. EPA, 109 T.W. Alexander Dr., Research Triangle Park, NC 27709 USA. Telephone: (919) 541-4963. Fax: (919) 541-0026. E-mail: kodavanti.urmila@epa.gov

*Current address: Department of Zoology, SV University, Tirupati, India.

Supplemental Material is available online at http://www.ehponline.org/members/2008/11647/suppl.pdf

We thank C. King and D. Janek (Arcadis G&M Inc., Highlands Ranch, CO, USA) for their help with the operation of the engine and exposure facilities ; M. I. Gilmour for help in organizing diesel exhaust exposures ; S.-H. Cho and D. Winsett (U.S. EPA) for their help in particle analysis, data acquisition, and data reduction ; D. Malarkey (NIEHS) for help with pathology evaluation ; and J. Dunnick (NIEHS) , D. Diaz-Sanchez, D. Costa, G. Hatch, and L. Birnbaum (U.S. EPA) for their critical review of this manuscript.

Portions of the exposure efforts were sponsored under contract EP-C-04-023 with Arcadis G&M Inc., Highlands Ranch, CO, USA. This study was also supported in part by the U.S. EPA/University of North Carolina Research Agreement CT829471 (J.G.W.) , NRC Research Associateship Award at NHEERL, U.S. EPA (R.R.G.) , and a Senior Environmental Employment Program via Cooperative Agreement between the National Caucus and Center on Black Aged, Inc. and the U.S. EPA (R.T.) .

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 30 April 2008 ; accepted 11 September 2008.