16 - Human Lung Disease-Associated Proteins Are Oxidized in Mouse Lung by Cadmium Levels Found in Human Environmental and Dietary Exposures

Abstract

Cd accumulates in humans from dietary, environmental including cigarette smoke, and occupational sources, and has a twenty-year biologic half-life. Our previous studies show that environmental low dose Cd oxidizes protein redox states and stimulates inflammatory signaling and actin cytoskeleton disruption; these results suggest that Cd could impact multiple disease mechanisms. Although considerable information is available concerning effects of high dose occupational Cd exposures and cigarette smoking, little is known about the relative sensitivities of subcellular compartmental redox proteome and the effect of its disruption on lung physiology and pathophysiology at low environmental and dietary levels. In the present study lung tissues from mice exposed to low dose Cd by drinking water (3.3 mg/L, 16 weeks), compared to Cd-free drinking, were examined for redox proteomics (n=3 per group). Redox proteomics was performed by a mass spectrometry-based Isotope Coded Affinity Tag (ICAT) method to measure oxidation of cysteine residues, and pathway and network analyses were performed using MetaCore software. Results showed that 545 protein peptides of two groups were identified and redox states of all 545 were measured (mean % oxidation, control, 32.3%; Cd, 36.4%). Of these, 173 were oxidized 1.3 fold or more by Cd compared to respective protein peptides in control. The results of subcellular compartmental analysis of these 173 showed that mitochondrial proteins were relatively more susceptible to oxidation (1.8 fold) by Cd than proteins in other compartments. Pathway analysis showed that pathways for cystic fibrosis, lung cancer and asthma were associated with the 173 proteins oxidized by Cd, suggesting that exposure to environmental and diet levels of Cd could alter lung redox proteome and impact pulmonary health and diseases.