Systematic Proteomic Approach to Characterize the Impacts of Chemical Interactions on Protein and Cytotoxicity Responses to Metal Mixture Exposures

作者：Ge Yue^*; Bruno Maribel; Wallace Kathleen; Leavitt Sharon; Andrews Debora; Spassova Maria A; Xi Mingyu; Roy Anindya; Haykal Coates Najwa; Lefew William; Swank Adam; Winnik Witold M; Chen Chao; Woodard Jonne; Farraj Aimen; Teichman Kevin Y; Ross Jeffrey A

来源：Journal of Proteome Research, 2015, 14(1): 183-192.

DOI：10.1021/pr500795d

• chemical interactions
• dose response
• mixture toxicity
• chemical mixtures
• risk assessment
• proteomics
• cytotoxicity
• metals
• systems biology

Chemical interactions have posed a big challenge in toxicity characterization and human health risk assessment of environmental mixtures. To characterize the impacts of chemical interactions on protein and cytotoxicity responses to environmental mixtures, we established a systems biology approach integrating proteomics, bioinformatics, statistics, and computational toxicology to measure expression or phosphorylation levels of 21 critical toxicity pathway regulators and 445 downstream proteins in human BEAS-2B cells treated with 4 concentrations of nickel, 2 concentrations each of cadmium and chromium, as well as 12 defined binary and 8 defined ternary mixtures of these metals in vitro. Multivariate statistical analysis and mathematical modeling of the metal-mediated proteomic response patterns showed a high correlation between changes in protein expression or phosphorylation and cellular toxic responses to both individual metals and metal mixtures. Of the identified correlated proteins, only a small set of proteins including HIF-1 alpha is likely to be responsible for selective cytotoxic responses to different metals and metals mixtures. Furthermore, support vector machine learning was utilized to computationally predict protein responses to uncharacterized metal mixtures using experimentally generated protein response profiles corresponding to known metal mixtures. This study provides a novel proteomic approach for characterization and prediction of toxicities of metal and other chemical mixtures.

• 出版日期2015-1