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Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells.
Food and Chemical Toxicology ( IF 4.3 ) Pub Date : 2020-03-28 , DOI: 10.1016/j.fct.2020.111297
Katrin Kreuzer 1 , Linda Böhmert 1 , Deema Alhalabi 1 , Thorsten Buhrke 1 , Alfonso Lampen 1 , Albert Braeuning 1
Affiliation  

The conventional approach for testing the genotoxic potential of chemicals in vitro includes a battery of bacterial and mammalian mutagenicity tests. Toxicogenomics analyses may provide information about DNA-damaging properties of test compounds but are not routinely used for identification of a genotoxic potential. In this study, metabolically active human HepaRG hepatocarcinoma cells were exposed to five food-relevant genotoxic carcinogens. Transcriptomic responses were analyzed using RNA sequencing technology and validated by real-time polymerase chain reaction. Biostatistical approaches revealed a characteristic transcript signature of 37 differentially expressed genes, which were commonly regulated by the test chemicals. Specificity of the transcript signature was confirmed by using non-genotoxic carcinogens as comparators. Pathway analyses showed that the obtained transcript signature was closely related to DNA damage response and p53 activation. In conclusion, we have established a characteristic transcript marker pattern to monitor genotoxicity in human HepaRG cells, and to distinguish genotoxic from non-genotoxic carcinogens. Our analyses underline that a common response related to DNA damages response, cell cycle alterations and cell death is initiated in HepaRG cells upon exposure to genotoxic compounds and allows for the identification of a common transcriptomic signature for genotoxic stress.

中文翻译:

鉴定人类HepaRG肝癌细胞中与食物相关的基因毒素的转录组签名。

用于测试体外化学物质潜在遗传毒性的常规方法包括一系列细菌和哺乳动物致突变性测试。毒理基因组学分析可提供有关测试化合物的DNA破坏特性的信息,但通常不用于鉴定遗传毒性潜力。在这项研究中,具有代谢活性的人类HepaRG肝癌细胞暴露于五种与食物有关的遗传毒性致癌物。使用RNA测序技术分析转录组反应,并通过实时聚合酶链反应进行验证。生物统计学方法揭示了37种差异表达基因的特征转录本签名,这些基因通常受测试化学品的调节。转录物签名的特异性通过使用非遗传毒性致癌物作为对照来确认。途径分析表明,获得的转录本签名与DNA损伤反应和p53激活密切相关。总之,我们已经建立了一个特征性的转录标记模式,以监测人类HepaRG细胞的遗传毒性,并区分遗传毒性和非遗传毒性致癌物。我们的分析强调,与DNA损伤反应,细胞周期改变和细胞死亡相关的常见应答是在暴露于遗传毒性化合物后在HepaRG细胞中引发的,并允许鉴定遗传毒性胁迫的常见转录组特征。并区分遗传毒性和非遗传毒性致癌物。我们的分析强调,与DNA损伤反应,细胞周期改变和细胞死亡相关的常见应答是在暴露于遗传毒性化合物后在HepaRG细胞中引发的,并允许鉴定遗传毒性胁迫的常见转录组特征。并区分遗传毒性和非遗传毒性致癌物。我们的分析强调,与DNA损伤反应,细胞周期改变和细胞死亡相关的常见应答是在暴露于遗传毒性化合物后在HepaRG细胞中引发的,并允许鉴定遗传毒性胁迫的常见转录组特征。
更新日期:2020-03-28
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