Amundson Sally A, Lee Richard Anthony, Koch-Paiz Christine A, Bittner Michael L, Meltzer Paul, Trent Jeffrey M, Fornace Albert J
Division of Basic Science, National Cancer Institute and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Mol Cancer Res. 2003 Apr;1(6):445-52.
In the past, most mechanistic studies of ionizing radiation response have employed very large doses, then extrapolated the results down to doses relevant to human exposure. It is becoming increasingly apparent, however, that this does not give an accurate or complete picture of the effects of most environmental exposures, which tend to be of low dose and protracted over time. We have initiated direct studies of low dose exposures, and using the relatively responsive ML-1 cell line, have shown that changes in gene expression can be triggered by doses of gamma-rays of 10 cGy and less in human cells. We have now extended these studies to investigate the effects on gene induction of reducing the rate of irradiation. In the ML-1 human myeloid leukemia cell line, we have found that reducing the dose rate over three orders of magnitude results in some protection against the induction of apoptosis, but still causes linear induction of the p53-regulated genes CDKN1A, GADD45A, and MDM2 between 2 and 50 cGy. Reducing the rate of exposure reduces the magnitude of induction of CDKN1A and GADD45A, but not the magnitude or duration of cell cycle delay. In contrast, MDM2 is induced to the same extent regardless of the rate of dose delivery. Microarray analysis has identified additional low dose-rate-inducible genes, and indicates the existence of two general classes of low dose-rate responders in ML-1. One group of genes is induced in a dose rate-dependent fashion, similar to GADD45A and CDKN1A. Functional annotation of this gene cluster indicates a preponderance of genes with known roles in apoptosis regulation. Similarly, a group of genes with dose rate-independent induction, such as seen for MDM2, was also identified. The majority of genes in this group are involved in cell cycle regulation. This apparent differential regulation of stress signaling pathways and outcomes in response to protracted radiation exposure has implications for carcinogenesis and risk assessment, and could not have been predicted from classical high dose studies.
过去，大多数关于电离辐射反应的机制研究都采用了非常高的剂量，然后将结果外推至与人类暴露相关的剂量。然而，越来越明显的是，这并不能准确或完整地呈现大多数环境暴露的影响，因为环境暴露往往是低剂量且持续较长时间的。我们已开展低剂量暴露的直接研究，并使用相对敏感的ML-1细胞系，结果表明，10 cGy及以下剂量的γ射线可在人类细胞中触发基因表达的变化。我们现在已扩展这些研究，以探究降低照射速率对基因诱导的影响。在ML-1人髓系白血病细胞系中，我们发现，将剂量率降低三个数量级可在一定程度上保护细胞免受凋亡诱导，但在2至50 cGy之间仍会导致p53调控基因CDKN1A、GADD45A和MDM2的线性诱导。降低暴露速率会降低CDKN1A和GADD45A的诱导幅度，但不会降低细胞周期延迟的幅度或持续时间。相比之下，无论剂量递送速率如何，MDM2的诱导程度相同。微阵列分析已鉴定出其他低剂量率诱导基因，并表明ML-1中存在两类一般的低剂量率反应基因。一组基因以剂量率依赖的方式被诱导，类似于GADD45A和CDKN1A。对该基因簇的功能注释表明，在凋亡调控中具有已知作用的基因占优势。同样，也鉴定出了一组剂量率不依赖诱导的基因，如MDM2。该组中的大多数基因参与细胞周期调控。这种在长期辐射暴露下应激信号通路和结果的明显差异调节对癌症发生和风险评估具有影响，而这是经典高剂量研究无法预测的。
