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.

中文翻译：

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转录组学为钴和镍毒性机制铺平了道路：肝癌细胞中 Nrf2 介导的细胞反应


如今，钴 (Co) 和镍 (Ni) 用于锂离子电池等各种工业应用，引发了人们对其环境释放和公共健康威胁的担忧。这两种金属都具有潜在的致癌性，并可能导致神经和心血管功能障碍，尽管潜在的毒性机制有待进一步阐明。本研究采用非靶向转录组学来分析人肝癌细胞 (HepG2) 中单独和组合的 Co 和 Ni 毒性的下游细胞效应。结果揭示了 Co 和 Ni 的协同效应，与单独暴露相比，导致差异表达基因 (DEG) 的数量显着增加。靶向分析证实，与糖酵解、铁和谷胱甘肽代谢以及鞘脂代谢等途径相关的 Nrf2 调节基因明显富集。 Co和Ni单独暴露和联合暴露引起核Nrf2易位，而仅联合暴露显着影响铁和谷胱甘肽代谢，HMOX-1和铁储存蛋白FTL的上调证明了这一点。这两种金属都会影响鞘脂代谢，增加二氢神经酰胺水平并减少神经酰胺、鞘氨醇和乳糖神经酰胺以及二酰基甘油的积累。通过结合转录组学和分析方法，这项研究为钴和镍毒性的分子机制提供了有价值的见解，为进一步了解金属应力铺平了道路。