P 253 - Integrative omics-defined redox, metabolic and functional responses to environmental metal exposure

Abstract

Our previous studies showed that low dose cadmium (Cd) altered protein redox states resulting in inflammatory signaling, actin cytoskeleton disruption, and fibrosis. However, little is known about low-level Cd effects on the redox proteomic and metabolic regulation in pulmonary fibroblasts and potential impact on pulmonary health. To address this issue, we investigated low dose Cd effects using an integrative omics approach with biochemical and functional analyses. Redox proteomics was performed on lung fibroblasts and lung tissues of C57BL/6 male mice exposed to Cd (3.3 mg/L, 16 weeks). Lung tissues were also analyzed for metabolomics. Both redox proteomics and metabolomics identified a large number of mitochondrial proteins and metabolites altered by Cd, suggesting that mitochondria are sensitive to Cd-induced oxidation. Cd also increased nuclear translocation of thioredoxin-1 and stimulated myofibroblast differentiation and fibrosis as shown by smad transcription factor activity and subsequent differentiation marker proteins. Pathway analysis showed that PIP2 metabolism, carbohydrate metabolism with pyruvate and TCA metabolism, are significantly affected by Cd. The integrative redox proteomics and metabolomics with mechanistic and functional pathways provide a powerful approach to understand complex mechanisms of low environmental Cd in lung disease.