Institute of Pharmacology and Toxicology, University of Wuerzburg, Versbacher Str. 9, 97078, Wuerzburg, Germany.
Bavarian Health and Food Safety Authority, Eggenreuther Weg 43, 91058, Erlangen, Germany.
Sci Rep. 2018 Feb 20;8(1):3371. doi: 10.1038/s41598-018-21680-8.
For mutagenicity testing, primary lymphocytes or mammalian cell lines are employed. However, the true target for carcinogenic action of mutagenic chemicals may be stem cells. Since hematopoietic cancers induced by chemical agents originate at the hematopoietic stem cell (HSC) stage and since one of the side effects of chemotherapeutic cancer treatment is the induction of secondary tumors, often leukemias, HSC may be a suitable cell system. We compared the sensitivity of HSC with the genotoxicity testing cell line TK6 for chromosomal mutations. HSC were less sensitive than TK6 cells for the genotoxic effects of the model genotoxins and chemotherapeutic agents doxorubicin, vinblastine, methyl methanesulfonate (MMS) and equally sensitive for mitomycin C (MMC). However, loss of viability after mitomycin C treatment was higher in HSC than in TK6 cells. Among the factors that may influence sensitivity for genomic damage, the generation or response to reactive oxygen species (ROS) and the effectiveness of DNA damage response can be discussed. Here we show that HSC can be used in a standard micronucleus test protocol for chromosomal mutations and that their sensitivity was not higher than that of a classical testing cell line.
对于致突变性测试，通常使用原代淋巴细胞或哺乳动物细胞系。然而，致突变化学物质致癌作用的真正靶标可能是干细胞。由于化学试剂诱导的血液系统癌症起源于造血干细胞（HSC）阶段，并且化学疗法癌症治疗的副作用之一是诱导继发性肿瘤，通常是白血病，因此 HSC 可能是一种合适的细胞系统。我们比较了 HSC 与 TK6 细胞系的染色体突变的遗传毒性测试细胞的敏感性。与 TK6 细胞相比，HSC 对模型遗传毒物和化疗药物阿霉素、长春新碱、甲磺酸甲酯（MMS）的遗传毒性作用的敏感性较低，而对丝裂霉素 C（MMC）的敏感性相同。然而，在用丝裂霉素 C 处理后 HSC 的存活率下降高于 TK6 细胞。在可能影响基因组损伤敏感性的因素中，可以讨论活性氧（ROS）的产生或反应以及 DNA 损伤反应的有效性。在这里，我们表明 HSC 可以用于标准的微核试验方案以检测染色体突变，并且它们的敏感性并不高于经典的测试细胞系。
