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Donald C. Malins,¹ Katie M. Anderson,¹ John J. Stegeman,² Pawel Jaruga,^3,4 Virginia M. Green,¹ Naomi K. Gilman,¹ and Miral Dizdaroglu⁴

¹Biochemical Oncology Program, Pacific Northwest Research Institute, Seattle, Washington, USA; ²Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, USA; ³Department of Chemical and Biochemical Engineering, University of Maryland Baltimore County, Baltimore, Maryland, USA; ⁴Chemical Science and Technology Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland, USA

Abstract
Fish living in contaminated environments accumulate toxic chemicals in their tissues. Biomarkers are needed to identify the resulting health effects, particularly focusing on early changes at a subcellular level. We used a suite of complementary biomarkers to signal contaminant-induced changes in the DNA structure and cellular physiology of the livers and gills of English sole (Parophrys vetulus) . These sediment-dwelling fish were obtained from the industrialized lower Duwamish River (DR) in Seattle, Washington, and from Quartermaster Harbor (QMH) , a relatively clean reference site in south Puget Sound. Fourier transform-infrared (FT-IR) spectroscopy, liquid chromatography/mass spectrometry (LC/MS) , and gas chromatography/mass spectrometry (GC/MS) identified potentially deleterious alterations in the DNA structure of the DR fish livers and gills, compared with the QMH fish. Expression of CYP1A (a member of the cytochrome P450 multigene family of enzymes) signaled changes in the liver associated with the oxidation of organic xenobiotics, as previously found with the gill. The FT-IR models demonstrated that the liver DNA of the DR fish had a unique structure likely arising from exposure to environmental chemicals. Analysis by LC/MS and GC/MS showed higher concentrations of DNA base lesions in the liver DNA of the DR fish, suggesting that these base modifications contributed to this discrete DNA structure. A comparable analysis by LC/MS and GC/MS of base modifications provided similar results with the gill. The biomarkers described are highly promising for identifying contaminant-induced stresses in fish populations from polluted and reference sites and, in addition, for monitoring the progress of remedial actions. Key words: cyclopurine nucleosides, cytochrome P4501A, DNA markers, DNA structure, Fourier transform-infrared spectroscopy, liquid chromatography/mass spectrometry. Environ Health Perspect 114: 823-829 (2006) . doi:10.1289/ehp.8544 available via http://dx.doi.org/ [Online 2 February 2006]

Address correspondence to D.C. Malins, Biochemical Oncology Program, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122 USA. Telephone: (206) 726-1240. Fax: (206) 726-1235. E-mail: dcmalins@dcmalins.com

We thank R. Smolowitz for confirmation of histopathologies and B. Woodin and S. Vest for technical assistance.

This study was supported by grants P42-ES04696 (D.C.M.) and P42-ES07381 (J.J.S.) from the National Institute of Environmental Health Sciences (NIEHS) , National Institutes of Health (NIH) ; funding was also received from the Woods Hole Oceanographic Institution (contribution no. 11411) .

The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS or the NIH. Certain commercial equipment or materials are identified in this article in order to specify adequately the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose.

The authors declare they have no competing financial interests.

Received 27 July 2005 ; accepted 2 February 2006.