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Proteomic Assessment of Biochemical Pathways That Are Critical to Nickel-Induced Toxicity Responses in Human Epithelial Cells
Citation:
Ge, Y., M. Bruno, N. Coates, K. Wallace, D. Andrews, A. Swank, W. Winnik, AND J. Ross. Proteomic Assessment of Biochemical Pathways That Are Critical to Nickel-Induced Toxicity Responses in Human Epithelial Cells. PLOS ONE . Public Library of Science, San Francisco, CA, 11(9):1-20, (2016).
Impact/Purpose:
Nickel compounds are present in various industrial and environmental exposures. They are ubiquitous, highly toxic, and carcinogenic, and pose serious environmental and human health concerns. Understanding the mechanisms underlying toxicity initiated by nickel, a ubiquitous environmental contaminant and known human carcinogen is necessary for proper assessment of its risks to human and environment. The present study extended and expanded the previous Ni (II) toxicity pathway studies by profiling the expression and phosphorylation changes of both upstream pathway regulating proteins using ELISA and downstream functional proteins using 2-D gel electrophoresis in one experimental system. this integrated proteomic approach used in the present study identified key proteins and toxicity pathways that were modulated in the cellular response to Ni (II) exposure, and the likely determinants of nickel-induced cellular toxicity. This small set of key proteins were mainly involved in glycolysis and gluconeogenesis pathways, apoptosis, protein degradation, and stress responses including inflammation and oxidative stress. Thus, the identification of key pathways involved in specific toxicity response enables the use of such proteomic signatures as predictive tools to facilitate toxicity screening of nickel and other chemicals.
Description:
Understanding the mechanisms underlying toxicity initiated by nickel, a ubiquitous environmental contaminant and known human carcinogen is necessary for proper assessment of its risks to human and environment. Among a variety of toxic mechanisms, disruption of protein responses and protein response-based biochemical pathways represents a key mechanism through which nickel induces cytotoxicity and carcinogenesis. To identify protein responses and bio-chemical pathways that are critical to nickel-induced toxicity responses, we measured cytotoxicity and changes in expression and phosphorylation status of 21 critical biochemical pathway regulators in human BEAS-2B cells exposed to four concentrations of nickel using an integrated proteomic approach. A subset of the pathway regulators, including Interleukin 6, and JNK, were found to be linearly correlated with cell viability, and may function as molecular determinants of cytotoxic responses of BEAS-2B cells to nickel exposures. In addition, 129 differentially ex-pressed proteins were identified by two dimensional electrophoresis (2-DE) and mass spectrometry. Principal component analysis, hierarchical cluster analyses, and ingenuity signaling pathway analysis (IPA) identified putative nickel toxicity pathways. Some of the proteins and pathways identified have not previously been linked to nickel toxicity. Based on the consistent results obtained from both ELISA and 2-DE proteomic analysis, we propose a core signaling pathway regulating cytotoxic responses of human BEAS-2B cells to nickel exposures, which integrates a small set of proteins involved in glycolysis and gluconeogenesis pathways, apoptosis, protein degradation, and stress responses including inflammation and oxidative stress.
