| Acute Ozone-Induced Differential Gene Expression Profiles in Rat Lung Srikanth S. Nadadur,1 Daniel L. Costa,1 Ralph Slade,1 Robert
Silbjoris,2 and Gary E. Hatch1 1Pulmonary Toxicology Branch, Experimental Toxicology Division,
and 2Clinical Research Branch, Human Studies Division, National
Health Environmental Effects Research Laboratory, Office of Research and Development,
U.S. Environmental Protection Agency, Research Triangle Park, North Carolina,
USA Abstract
Ozone (O3) is an oxidant gas that can directly induce lung injury. Knowledge of the initial molecular events of the acute O3 response would be useful in developing biomarkers of exposure or response. Toward this goal, we exposed rats to toxic concentrations of O3 (2 and 5 ppm) for 2 hr and the molecular changes were assessed in lung tissue 2 hr postexposure using a rat cDNA expression array containing 588 characterized genes. Gene array analysis indicated differential expression in almost equal numbers of genes for the two exposure groups: 62 at 2 ppm and 57 at 5 ppm. Most of these genes were common to both exposure groups, suggesting common roles in the initial toxicity response. However, we also identified the induction of nine genes specific to 2-ppm (thyroid hormone-β receptor c-erb-A-β and glutathione reductase) or 5-ppm exposure groups (c-jun, induced nitric oxide synthase, macrophage inflammatory protein-2, and heat shock protein 27) . Injury markers in bronchoalveolar lavage fluid (BALF) were used to assess immediate toxicity and inflammation in rats similarly exposed. At 2 ppm, injury was marked by significant increases in BALF total protein, N-acetylglucosaminidase, and lavageable ciliated cells. Because infiltration of neutrophils was observed only at the higher 5 ppm concentration, the distinctive genes suggested a potential amplification role for inflammation in the gene profile. Although the specific gene interactions remain unclear, this is the first report indicating a dose-dependent direct and immediate induction of gene expression that may be separate from those genes involved in inflammation after acute O3 exposure. Key words: acute exposure, gene expression profiles, lung, microarray, ozone, rat. Environ Health Perspect 113:1717-1722 (2005) . doi:10.1289/ehp.7413 available via http://dx.doi.org/ [Online 23 June 2005]
Address correspondence to S.S. Nadadur, National Center for Environmental Assessment, U.S. EPA, Mail Drop B243-01, Research Triangle Park, NC 27711 USA. Telephone: (919) 541-0672. Fax: (919) 541-2985. E-mail: nadadur.srikanth@epa.gov We thank J. Richards for protein and NAG analyses and J. McKee for engineering assistance with ozone exposures. We also thank K. Dreher, M. Madden, and L. Birnbaum for critical review of the manuscript. This article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA, and approved for publication. Approval does not signify that the contents necessarily reflect the views and 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 13 July 2004 ; accepted 23 June 2005.
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