A proteome-wide assessment of the oxidative stress paradigm for metal and metal-oxide nanomaterials in human macrophages

Zhang, Tong; Gaffrey, Matthew J.; Thomas, Dennis G.; Weber, Thomas J.; Hess, Becky M.; Weitz, Karl K.; Piehowski, Paul D.; Petyuk, Vladislav A.; Moore, Ronald J.; Qian, Wei-Jun; Thrall, Brian D.

doi:10.1016/j.impact.2019.100194

Title: A proteome-wide assessment of the oxidative stress paradigm for metal and metal-oxide nanomaterials in human macrophages

Journal Article · 23 November 2019 · NanoImpact

DOI: https://doi.org/10.1016/j.impact.2019.100194 · OSTI ID:1642069

Zhang, Tong ^[1]; Gaffrey, Matthew J. ^[1];

^[1];

^[1]; Hess, Becky M. ^[1]; Weitz, Karl K. ^[1];

^[1];

^[1]; Moore, Ronald J. ^[1];

^[1]; Thrall, Brian D. ^[1]

Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

Responsible implementation of engineered nanomaterials (ENMs) into commercial applications is an important societal issue, driving demand for new approaches for rapid and comprehensive evaluation of their bioactivity and safety. An essential part of any research focused on identifying potential hazard of ENMs is the appropriate selection of biological endpoints to evaluate. Herein, we use a tiered strategy employing both targeted biological assays and untargeted quantitative proteomics to elucidate the biological responses of human macrophages across a library of metal/metal oxide ENMs, raised as priority ENMs for investigation by NIEHS’s Nanomaterial Health Implications Research (NHIR) program. Our results show that quantitative cellular proteome profiles readily distinguish ENM types based on their cytotoxic potential according to induction of biological processes and pathways involved in the cellular antioxidant response, TCA cycle, oxidative stress, endoplasmic reticulum stress, and immune responses as major processes impacted. Interestingly, pathway analysis of differentially abundant proteins also revealed new cell processes that were influenced by all ENMs independent of cytotoxic potential. These included pathways previously implicated as cellular adaptive mechanisms to low levels of oxidative stress, including cell adhesion, protein translation and protein targeting pathways. Unsupervised clustering of all data revealed the most striking proteome changes that differentiated ENM classes involved a small subset of proteins involved in the oxidative stess response (HMOX1), protein chaperone functions (HS71B, DNJB1), and autophagy (SQSTM), providing a potential new panel of markers of ENM-induced cell stress. To our knowledge, the results represent the most comprehensive profiling of the biological responses to a library of ENMs conducted using quantitative mass spectrometry-based proteomics. The results provide a basis to identify the patterns of a diverse set of cellular pathways and cell processes impacted by ENM exposure in an important immune cell type, laying the foundation for multivariate, pathway-level structure activity assessments of ENMs in the future.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); Nanotechnology Health Implications Research (NHIR) Consortium

Grant/Contract Number:: AC05-76RL01830; UO1ES027292; P41GM103494; U24ES026946

OSTI ID:: 1642069

Report Number(s):: PNNL-SA-147217

Journal Information:: NanoImpact, Vol. 17; ISSN 2452-0748

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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