Limoli C L, Corcoran J J, Milligan J R, Ward J F, Morgan W F
Department of Radiology, University of California, San Francisco 94143-0750, USA.
Radiat Res. 1999 Jun;151(6):677-85.
To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.
为了研究电离辐射诱导染色体不稳定的关键靶点、剂量反应和剂量率反应，将溴脱氧尿苷（BrdU）取代和未取代的GM10115细胞暴露于一系列剂量（0.1 - 10 Gy）和不同剂量率（0.092 - 17.45 Gy min⁻¹）下。在急性暴露后存活的单个祖细胞衍生的克隆群体中，大约照射20代后，通过荧光原位杂交确定染色体稳定性状态。总体而言，分析了代表超过140,000个中期相的近700个单个克隆。在未用BrdU取代的细胞中，发现了剂量反应，即在任何给定克隆中观察到延迟染色体不稳定的概率为每格雷X射线3%。然而，对于用25% - 66%BrdU取代的细胞，仅在低剂量（<1.0 Gy）下观察到剂量反应；在高剂量（>1.0 Gy）下，染色体不稳定的发生率趋于平稳。与未用BrdU取代的细胞相比，单位剂量下染色体不稳定的频率和复杂性增加。染色体不稳定的频率似乎在约30%左右达到饱和，在存在BrdU的情况下，这种效应在低得多的剂量下就会出现。将γ射线剂量率改变190倍（0.092至17.45 Gy min⁻¹），染色体不稳定频率没有显著差异。BrdU的存在促进了染色体不稳定的增强表明，DNA至少包含对诱导基因组不稳定这一终点很重要的关键靶点之一。
