Hirabayashi Yoko, Tsuboi Isao, Nakachi Kei, Kusunoki Yoichiro, Inoue Tohru
Cellular and Molecular Toxicology Division, National Center for Biological Safety and Research, National Institute of Health Sciences, 1-18-1 Kamiyohga, Setagayaku, Tokyo, 158-8501, Japan.
J Appl Toxicol. 2015 Mar;35(3):230-40. doi: 10.1002/jat.3088. Epub 2014 Nov 21.
The number of murine mature blood cells recovered within 6 weeks after 2-Gy whole-body irradiation at 6 weeks of age, whereas in the case of the undifferentiated hematopoietic stem/progenitor cell (HSC/HPC) compartment [cells in the lineage-negative, c-kit-positive and stem-cell-antigen-1-positive (LKS) fraction], the numerical differences between mice with and without irradiation remained more than a year, but conclusively the cells showed numerical recovery. When mice were exposed to radiation at 6 months of age, acute damages of mature blood cells were rather milder probably because of their maturation with age; but again, cells in the LKS fraction were specifically damaged, and their numerical recovery was significantly delayed probably as a result of LKS-specific cellular damages. Interestingly, in contrast to the recovery of the number of cells in the LKS fraction, their quality was not recovered, which was quantitatively assessed on the basis of oxidative-stress-related fluorescence intensity. To investigate why the recovery in the number of cells in the LKS fraction was delayed, expression levels of genes related to cellular proliferation and apoptosis of cells in the bone marrow and LKS fraction were analyzed by real-time polymerase chain reaction (RT-PCR). In the case of 21-month-old mice after radiation exposure, Ccnd1, PiK3r1 and Fyn were overexpressed solely in cells in the LKS fraction. Because Ccnd1and PiK3r1 upregulated by aging were further upregulated by radiation, single-dose radiation seemed to induce the acceleration of aging, which is related to the essential biological responses during aging based on a lifetime-dependent relationship between a living creature and xenobiotic materials.
6周龄小鼠在接受2 Gy全身照射后6周内恢复的成熟血细胞数量，而在未分化造血干/祖细胞（HSC/HPC）区室[谱系阴性、c-kit阳性和干细胞抗原-1阳性（LKS）部分的细胞]中，照射组和未照射组小鼠之间的数量差异持续了一年多，但最终细胞数量出现了恢复。当6月龄小鼠受到辐射时，成熟血细胞的急性损伤可能由于其随年龄成熟而相对较轻；但同样，LKS部分的细胞受到特异性损伤，其数量恢复可能由于LKS特异性细胞损伤而显著延迟。有趣的是，与LKS部分细胞数量的恢复相反，其质量并未恢复，这是根据氧化应激相关荧光强度进行定量评估的。为了研究LKS部分细胞数量恢复延迟的原因，通过实时聚合酶链反应（RT-PCR）分析了骨髓和LKS部分细胞中与细胞增殖和凋亡相关的基因表达水平。在21月龄小鼠辐射暴露后，Ccnd1、PiK3r1和Fyn仅在LKS部分的细胞中过度表达。由于衰老上调的Ccnd1和PiK3r1因辐射而进一步上调，单剂量辐射似乎诱导了衰老加速，这与基于生物与异源物质之间寿命依赖关系的衰老过程中的基本生物学反应有关。
