title: Systematic proteomic approach to characterize the impacts of chemical interactions on protein and cytotoxicity responses to metal mixture exposures.
abstract: 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-1α 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.
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency , 109 T. W. Alexander Drive, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ge
authors.forename: Maribel
authors.initials: M
authors.lastname: Bruno
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wallace
authors.forename: Sharon
authors.initials: S
authors.lastname: Leavitt
authors.forename: Debora
authors.initials: D
authors.lastname: Andrews
authors.forename: Maria A
authors.initials: MA
authors.lastname: Spassova
authors.forename: Mingyu
authors.initials: M
authors.lastname: Xi
authors.forename: Anindya
authors.initials: A
authors.lastname: Roy
authors.forename: Najwa
authors.initials: N
authors.lastname: Haykal-Coates
authors.forename: William
authors.initials: W
authors.lastname: Lefew
authors.forename: Adam
authors.initials: A
authors.lastname: Swank
authors.forename: Witold M
authors.initials: WM
authors.lastname: Winnik
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: Jonne
authors.initials: J
authors.lastname: Woodard
authors.forename: Aimen
authors.initials: A
authors.lastname: Farraj
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Teichman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ross
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D002460:Cell Line; D002857:Chromium / Q000633:toxicity*; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D018570:Risk Assessment
chemical_list: D004785:Environmental Pollutants; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020543:Proteome; D002104:Cadmium; D002857:Chromium; D009532:Nickel
keywords: chemical interactions; chemical mixtures; cytotoxicity; dose response; metals; mixture toxicity; proteomics; risk assessment; systems biology