Pulmonary Biomarkers Based on Alterations in Protein Expression after Exposure to Arsenic R. Clark Lantz,1,2 Brandon J. Lynch,1 Scott Boitano,1,2,3,4 Gerald S. Poplin,5 Sally Littau,5 George Tsaprailis,2,6 and Jefferey L. Burgess2,5 1Department of Cell Biology & Anatomy, 2Southwest Environmental Health Science Center, 3Department of Physiology, 4Arizona Respiratory Center, 5Division of Community, Environment and Policy, and 6Center for Toxicology, University of Arizona, Tucson, Arizona, USA Abstract Objective: Environmental exposure to arsenic results in multiple adverse effects in the lung. Our objective was to identify potential pulmonary protein biomarkers in the lung-lining fluid of mice chronically exposed to low-dose As and to validate these protein changes in human populations exposed to As. Methods: Mice were administered 10 or 50 ppb As (sodium arsenite) in their drinking water for 4 weeks. Proteins in the lung-lining fluid were identified using two-dimensional gel electrophoresis (n = 3) or multidimensional protein identification technology (MUDPIT) (n = 2) coupled with mass spectrometry. Lung-induced sputum samples were collected from 57 individuals (tap water As ranged from ~ 5 to 20 ppb) . Protein levels in sputum were determined by ELISA, and As species were analyzed in first morning void urine. Results: Proteins in mouse lung-lining fluid whose expression was consistently altered by As included glutathione-S-transferase (GST) -omega-1, contraspin, apolipoprotein A-I and A-IV, enolase-1, peroxiredoxin-6, and receptor for advanced glycation end products (RAGE) . Validation of the putative biomarkers was carried out by evaluating As-induced alterations in RAGE in humans. Regression analysis demonstrated a significant negative correlation (p = 0.016) between sputum levels of RAGE and total urinary inorganic As, similar to results seen in our animal model. Conclusion: Combinations of proteomic analyses of animal models followed by specific analysis of human samples provide an unbiased determination of important, previously unidentified putative biomarkers that may be related to human disease. Key words: arsenic, human, lavage, lung, mice, proteomics, sputum. Environ Health Perspect 115:586–591 (2007) . doi:10.1289/ehp.9611 available via http://dx.doi.org/ [Online 8 January 2007] Address correspondence to C. Lantz, Department of Cell Biology & Anatomy, University of Arizona, PO Box 245044, 1501 N. Campbell Ave., Room LSN 447, Tucson, AZ 85724-5044 USA. Telephone: (520) 626-6716. Fax: (520) 626-2097. E-mail: lantz@email.arizona.edu This research was funded in part by grants P30 ES006694 and P42 ES004940 from the National Institutes of Health and by grant R832095 from the U.S. Environmental Protection Agency. The authors declare they have no competing financial interests. Received 11 August 2006 ; accepted 8 January 2007. The full version of this article is available for free in HTML or PDF formats. |