Transcriptomics pave the way into mechanisms of cobalt and nickel toxicity: Nrf2-mediated cellular responses in liver carcinoma cells.

Autor:	Thiel A; Food Chemistry with Focus on Toxicology, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, 42119, Wuppertal, Germany., Drews F; Molecular Cell Biology and Microbiology, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, 42119, Wuppertal, Germany., Pirritano M; Molecular Cell Biology and Microbiology, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, 42119, Wuppertal, Germany., Schumacher F; Freie Universität Berlin, Institute of Pharmacy, Königin-Luise-Str. 2+4, Berlin, Germany., Michaelis V; Food Chemistry with Focus on Toxicology, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, 42119, Wuppertal, Germany., Schwarz M; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena-Wuppertal, 14558, Nuthetal, Germany; Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Dornburger Str. 24, 07743, Jena, Germany., Franzenburg S; Competence Centre for Genomic Analysis CCGA, Kiel, Germany., Schwerdtle T; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena-Wuppertal, 14558, Nuthetal, Germany; German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589, Berlin, Germany., Michalke B; Research Unit Analytical BioGeoChemistry, Helmholz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Kipp AP; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena-Wuppertal, 14558, Nuthetal, Germany; Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Dornburger Str. 24, 07743, Jena, Germany., Kleuser B; Freie Universität Berlin, Institute of Pharmacy, Königin-Luise-Str. 2+4, Berlin, Germany., Simon M; Molecular Cell Biology and Microbiology, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, 42119, Wuppertal, Germany., Bornhorst J; Food Chemistry with Focus on Toxicology, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, 42119, Wuppertal, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena-Wuppertal, 14558, Nuthetal, Germany. Electronic address: bornhorst@uni-wuppertal.de.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2024 Sep; Vol. 75, pp. 103290. Date of Electronic Publication: 2024 Jul 27.
DOI:	10.1016/j.redox.2024.103290
Abstrakt:	Cobalt (Co) and Nickel (Ni) are used nowadays in various industrial applications like lithium-ion batteries, raising concerns about their environmental release and public health threats. Both metals are potentially carcinogenic and may cause neurological and cardiovascular dysfunctions, though underlying toxicity mechanisms have to be further elucidated. This study employs untargeted transcriptomics to analyze downstream cellular effects of individual and combined Co and Ni toxicity in human liver carcinoma cells (HepG2). The results reveal a synergistic effect of Co and Ni, leading to significantly higher number of differentially expressed genes (DEGs) compared to individual exposure. There was a clear enrichment of Nrf2 regulated genes linked to pathways such as glycolysis, iron and glutathione metabolism, and sphingolipid metabolism, confirmed by targeted analysis. Co and Ni exposure alone and combined caused nuclear Nrf2 translocation, while only combined exposure significantly affects iron and glutathione metabolism, evidenced by upregulation of HMOX-1 and iron storage protein FTL. Both metals impact sphingolipid metabolism, increasing dihydroceramide levels and decreasing ceramides, sphingosine and lactosylceramides, along with diacylglycerol accumulation. By combining transcriptomics and analytical methods, this study provides valuable insights into molecular mechanisms of Co and Ni toxicity, paving the way for further understanding of metal stress. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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