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Courtney D. Kozul,^1,2 Thomas H. Hampton,^1,2 Jennifer C. Davey,^1,2 Julie A. Gosse,^1,2,* Athena P. Nomikos,^1,2 Phillip L. Eisenhauer,³ Daniel J. Weiss,³ Jessica E. Thorpe,⁴ Michael A. Ihnat,⁴ and Joshua W. Hamilton^1,2,**

¹Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA; ²Center for Environmental Health Sciences, Dartmouth College, Hanover, New Hampshire, USA; ³Vermont Lung Center, University of Vermont College of Medicine, Burlington, Vermont, USA; ⁴Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Abstract
Background: Chronic exposure to drinking water arsenic is a significant worldwide environmental health concern. Exposure to As is associated with an increased risk of lung disease, which may make it a unique toxicant, because lung toxicity is usually associated with inhalation rather than ingestion.

Objectives: The goal of this study was to examine mRNA and protein expression changes in the lungs of mice exposed chronically to environmentally relevant concentrations of As in the food or drinking water, specifically examining the hypothesis that As may preferentially affect gene and protein expression related to immune function as part of its mechanism of toxicant action.

Methods: C57BL/6J mice fed a casein-based AIN-76A defined diet were exposed to 10 or 100 ppb As in drinking water or food for 5–6 weeks.

Results: Whole genome transcriptome profiling of animal lungs revealed significant alterations in the expression of many genes with functions in cell adhesion and migration, channels, receptors, differentiation and proliferation, and, most strikingly, aspects of the innate immune response. Confirmation of mRNA and protein expression changes in key genes of this response revealed that genes for interleukin 1β, interleukin 1 receptor, a number of toll-like receptors, and several cytokines and cytokine receptors were significantly altered in the lungs of As-exposed mice.

Conclusions: These findings indicate that chronic low-dose As exposure at the current U.S. drinking-water standard can elicit effects on the regulation of innate immunity, which may contribute to altered disease risk, particularly in lung.

Key words: arsenic, inflammation, innate immune system, lung, migration. Environ Health Perspect 117:1108–1115 (2009) . doi:10.1289/ehp.0800199 available via http://dx.doi.org/ [Online 4 March 2009]

Address correspondence to J.W. Hamilton, Bay Paul Center in Comparative Molecular Biology and Evolution, Marine Biological Laboratory, 7 MBL St., Woods Hole, MA 02543 USA. Telephone: (508) 289-7300. Fax: (508) 289-7934. E-mail: jhamilton@mbl.edu

Supplemental Material is available online at http://www.ehponline.org/members/2009/0800199/suppl.pdf

*Current address: Department of Biochemistry, Microbiology, and Molecular Biology, University of Maine, Orono.

**Current address: Bay Paul Center in Comparative Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, MA.

We thank A. Milano, C. Tomlinson, and J. Dionne at Dartmouth’s Genomics Shared Resource Center (Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA) for running the microarray samples.

This work was supported by National Institute of Environmental Health Science grant P42 ES007373 [J.W.H., Superfund Basic Research Program (SBRP) project 2]. C.D.K., A.P.N., and J.A.G. were supported by graduate and postdoctoral fellowships from P42 ES007373 (SBRP, Training Core) . C.D.K. was also supported by National Institutes of Health training grant predoctoral fellowship T32-DF007301. P.L.E. and D.J.W. were supported by Cystic Fibrosis Foundation Research grant HL081289.

The authors declare they have no competing financial interests.

Received 17 September 2008 ; accepted 4 March 2009.