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Mutat Res Rev Mutat Res. 2020 Oct-Dec;786:108341. doi: 10.1016/j.mrrev.2020.108341. Epub 2020 Oct 18.
An underappreciated aspect of human mutagenicity biomonitoring is tissue specificity reflected in different assays, especially those that measure events that can only occur in developing bone marrow (BM) cells. Reviewed here are 9 currently-employed human mutagenicity biomonitoring assays. Several assays measure chromosome-level events in circulating T-lymphocytes (T-cells), i.e., traditional analyses of aberrations, translocation studies involving chromosome painting and fluorescence in situ hybridization (FISH) and determinations of micronuclei (MN). Other T-cell assays measure gene mutations. i.e., hypoxanthine-guanine phosphoriboslytransferase (HPRT) and phosphoribosylinositol glycan class A (PIGA). In addition to the T-cell assays, also reviewed are those assays that measure events in peripheral blood cells that necessarily arose in BM cells, i.e., MN in reticulocytes; glycophorin A (GPA) gene mutations in red blood cells (RBCs), and PIGA gene mutations in RBC or granulocytes. This review considers only cell culture- or cytometry-based assays to describe endpoints measured, methods, optimal sampling times, and sample summaries of typical quantitative and qualitative results. However, to achieve its intended focus on the target cells where events occur, kinetics of the cells of peripheral blood that derive at some point from precursor cells are reviewed to identify body sites and tissues where the genotoxic events originate. Kinetics indicate that in normal adults, measured events in T-cells afford global assessments of in vivo mutagenicity but are not specific for BM effects. Therefore, an agent's capacity for inducing mutations in BM cells cannot be reliably inferred from T-cell assays as the magnitude of effect in BM, if any, is unknown. By contrast, chromosome or gene level mutations measured in RBCs/reticulocytes or granulocytes must originate in BM cells, i.e. in RBC or granulocyte precursors, thereby making them specific indicators for effects in BM. Assays of mutations arising directly in BM cells may quantitatively reflect the mutagenicity of potential leukemogenic agents.
人类致突变性生物监测被低估的一个方面是组织特异性，这反映在不同的检测方法中，尤其是那些只能在发育中的骨髓 (BM) 细胞中测量事件的检测方法。本文综述了目前使用的 9 种人类致突变性生物监测检测方法。几种检测方法测量循环 T 淋巴细胞 (T 细胞) 中的染色体水平事件，即传统的染色体畸变分析、涉及染色体染色和荧光原位杂交 (FISH) 的易位研究以及微核 (MN) 的测定。其他 T 细胞检测方法测量基因突变，即次黄嘌呤鸟嘌呤磷酸核糖基转移酶 (HPRT) 和磷酸核糖基肌醇聚糖 A (PIGA)。除了 T 细胞检测方法外，本文还综述了那些测量外周血细胞中必然在 BM 细胞中产生的事件的检测方法，即网织红细胞中的 MN；红细胞 (RBC) 中的糖蛋白 A (GPA) 基因突变，以及 RBC 或粒细胞中的 PIGA 基因突变。本综述仅考虑基于细胞培养或细胞计数的检测方法来描述测量的终点、方法、最佳采样时间和典型定量和定性结果的样本摘要。然而，为了实现其对发生事件的靶细胞的关注，还回顾了外周血中源自前体细胞的细胞的动力学，以确定产生遗传毒性事件的身体部位和组织。动力学表明，在正常成年人中，T 细胞中测量的事件可全面评估体内致突变性，但对 BM 效应不具有特异性。因此，不能从 T 细胞检测中可靠推断出药物诱导 BM 细胞突变的能力，因为 BM 中的效应幅度（如果有的话）是未知的。相比之下，在 RBC/网织红细胞或粒细胞中测量的染色体或基因突变必须起源于 BM 细胞，即 RBC 或粒细胞前体，从而使它们成为 BM 效应的特异性指标。直接在 BM 细胞中产生的突变检测方法可能可以定量反映潜在的白血病形成剂的致突变性。
