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首页> 外文期刊>Archives of Toxicology >Development of in vitro 3D cell model from hepatocellular carcinoma (HepG2) cell line and its application for genotoxicity testing
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Development of in vitro 3D cell model from hepatocellular carcinoma (HepG2) cell line and its application for genotoxicity testing

机译：肝细胞癌（HepG2）细胞系中体外3D细胞模型的研制及其对遗传毒性试验的应用

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The evaluation of genotoxicity plays an important role within hazard identification and risk assessment of chemicals and consumer products. For genotoxicity assessment, in vitro hepatic cells are often used as they have retained certain level of xenobiotic metabolic activity. However, current protocols are designed for the use on 2D monolayer models that are associated with several limitations due to the lack of numerous biological functions, which results in the loss of many hepatic properties. In this respect, an attractive alternative are three-dimensional (3D) models. The aim of our study was to develop physiologically more relevant 3D cell model (spheroids) from the human hepatocellular carcinoma (HepG2) cell line for genotoxicity testing. The spheroids were prepared by the forced floating method, which had been optimized for the production of a large number of uniform spheroids. The sensitivity of the spheroids to detect genotoxicity was determined by the comet assay after the exposure of spheroids to non-cytotoxic concentrations of model indirect acting genotoxic compounds, namely polycyclic aromatic hydrocarbon (B(a)P), mycotoxin (AFB1), two heterocyclic aromatic amines (PhIP and IQ) and a direct acting etoposide (ET). All five tested compounds concentration dependently induced DNA damage. Higher sensitivity of 3D cell model compared to 2D monolayer culture was noticed particularly for detection of the genotoxicity of the heterocyclic aromatic amines and BaP. Deregulation of mRNA expression (qPCR) by genotoxic compounds revealed that HepG2 cells in 3D express important genes encoding phase I and II metabolic enzymes, as well as DNA damage responsive genes in an inducible form. The newly developed HepG2 3D model shows improved sensitivity for detecting genotoxic compounds compared to 2D cultures and can provide a suitable experimental model for genotoxicity assessment.
机译：遗传毒性的评估在危害识别和化学品和消费品风险评估中起着重要作用。对于遗传毒性评估，通常使用体外肝细胞，因为它们保留了一定水平的异蛋白代谢活性。然而，目前的协议被设计用于在2D单层模型上使用，由于缺乏许多生物学功能，这与几个限制相关联，这导致许多肝脏特性的损失。在这方面，有吸引力的替代方案是三维（3D）模型。我们的研究目的是从人肝细胞癌（HepG2）细胞系进行生理上更相关的3D细胞模型（球状体）用于基因毒性测试。通过强制浮动方法制备球状体，该方法已经针对生产大量均匀的球状体进行了优化。彗星测定在球形间接作用遗传毒性化合物的非细胞毒性浓度暴露于非细胞毒性浓度之后的彗星测定来测定球体对遗传毒性的敏感性，即多环芳烃（B（a）p），霉菌毒素（afb1），两个杂环芳族胺（PHIP和IQ）和直接作用依托泊苷（ET）。所有五种测试的化合物浓度依赖性诱导DNA损伤。对于2D单层培养，3D细胞模型的较高灵敏度被注意到，特别是检测杂环芳族胺和壳体的遗传毒性。通过遗传毒性化合物进行MRNA表达（QPCR）的放松管制显示，在3D表达3D中的HEPG2细胞编码I和II代谢酶的重要基因，以及诱导形式的DNA损伤响应基因。与2D培养物相比，新开发的HEPG2 3D模型显示出检测遗传毒性化合物的改善灵敏度，并可提供适当的基因毒性评估实验模型。

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