Bellouard Marie, Gasser Marie, Lenglet Sébastien, Gilardi Federica, Bararpour Nasim, Augsburger Marc, Thomas Aurélien, Alvarez Jean-Claude
Service de Pharmacologie-Toxicologie, Groupe Hospitalier Universitaire AP-HP, Paris-Saclay, Hôpital Raymond Poincaré, FHU Sepsis, 104 bvd R. Poincaré, 92380 Garches, France.
Plateforme MasSpecLab, UMR1173, Inserm, Université Paris Saclay (Versailles Saint Quentin-en-Yvelines), 2 Avenue de le Source de la Bièvre, 78180 Montigny-le-Bretonneux, France.
Chem Res Toxicol. 2022 May 16;35(5):807-816. doi: 10.1021/acs.chemrestox.1c00429. Epub 2022 Apr 20.
Cobalt, chromium, and nickel are used in orthopedic prostheses. They can be released, accumulate in many organs, and be toxic. The aim of this study is to evaluate the cytotoxicity of these metals on human hepatocytes and to improve our knowledge of their cellular toxicity mechanisms by metabolomic analysis. HepaRG cells were incubated for 48 h with increasing concentrations of metals to determine their IC. Then, a nontargeted metabolomic study using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was done at IC and at a lower concentration (100 nM), near to those found in the blood and liver of patients with prostheses. IC were defined at 940, 2, and 1380 μM for Co, Cr, and Ni, respectively. , Cr appears to be much more toxic than Co and Ni. Metabolomic analysis revealed the disruption of metabolic pathways from the low concentration of 100 nM, in particular tryptophan metabolism and lipid metabolism illustrated by an increase in phenylacetylglycine, a marker of phospholipidosis, for all three metals. They also appear to be responsible for oxidative stress. Dysregulation of these pathways impacts hepatocyte metabolism and may result in hepatotoxicity. Further investigations on accessible biological matrices should be conducted to correlate our results with the clinical data of prostheses-bearing patients.
钴、铬和镍用于骨科假体。它们会释放出来，在许多器官中积累并具有毒性。本研究的目的是评估这些金属对人肝细胞的细胞毒性，并通过代谢组学分析增进我们对其细胞毒性机制的了解。将HepaRG细胞与浓度不断增加的金属孵育48小时以确定其半数抑制浓度（IC）。然后，在半数抑制浓度以及接近假体患者血液和肝脏中发现的较低浓度（100 nM）下，使用液相色谱-高分辨率质谱（LC-HRMS）进行非靶向代谢组学研究。钴、铬和镍的半数抑制浓度分别定义为940、2和1380 μM。铬似乎比钴和镍毒性大得多。代谢组学分析显示，从100 nM的低浓度开始代谢途径就受到破坏，特别是色氨酸代谢和脂质代谢，这三种金属均表现为磷脂质病标志物苯乙酰甘氨酸增加。它们似乎还会导致氧化应激。这些途径的失调会影响肝细胞代谢，并可能导致肝毒性。应该对可获取的生物基质进行进一步研究，以将我们的结果与佩戴假体患者的临床数据相关联。
