Megid Wael Abdel, Ensenberger Martin G, Halberg Richard B, Stanhope Stephen A, Kent-First Marijo G, Prolla Tomas A, Bacher Jeff W
Department of Animal Sciences, University of Wisconsin, Madison, WI, USA.
Radiat Environ Biophys. 2007 Jun;46(2):147-54. doi: 10.1007/s00411-006-0072-1. Epub 2006 Oct 27.
Accurate methods for measuring the biological effects of radiation are critical for estimating an individual's health risk from radiation exposure. We investigated the feasibility of using radiation-induced mutations in repetitive DNA sequences to measure genetic damage caused by radiation exposure. Most repetitive sequences are in non-coding regions of the genome and alterations in these loci are usually not deleterious. Thus, mutations in non-coding repetitive sequences might accumulate, providing a stable molecular record of DNA damage caused by all past exposures. To test this hypothesis, we screened repetitive DNA sequences to identify the loci most sensitive to radiation-induced mutations and then investigated whether these mutations were stable in vivo over time and after multiple exposures. Microsatellite repeat markers were identified that exhibited a linear dose response up to 1 Gy of 1 GeV/nucleon 56Fe ions and 137Cs gamma rays in mouse and human cells. Short tandem repeats on the Y chromosome and mononucleotide repeats on autosomal chromosomes exhibited significant increases in mutations at >or= 0.5 Gy of 56Fe ions with frequencies averaging 4.3-10.3 x 10(-3) mutations/locus/Gy/cell, high enough for direct detection of mutations in irradiated cells. A significant increase in radiation-induced mutations in extended mononucleotide repeats was detectible in vivo in mouse blood and cheek samples 10 and 26 weeks after radiation exposure and these mutations were additive over multiple exposures. This study demonstrates the feasibility of a novel method for biodosimetry that is applicable to humans and other species. This new approach should complement existing methods of biodosimetry and might be useful for measuring radiation exposure in circumstances that are not amenable to current methods.
准确测量辐射生物效应的方法对于评估个体因辐射暴露而面临的健康风险至关重要。我们研究了利用重复DNA序列中的辐射诱导突变来测量辐射暴露所致遗传损伤的可行性。大多数重复序列位于基因组的非编码区，这些位点的改变通常无害。因此，非编码重复序列中的突变可能会积累，为过去所有暴露所造成的DNA损伤提供一个稳定的分子记录。为了验证这一假设，我们筛选了重复DNA序列，以确定对辐射诱导突变最敏感的位点，然后研究这些突变在体内随时间以及多次暴露后是否稳定。我们鉴定出了微卫星重复标记，在小鼠和人类细胞中，对于1 GeV/核子的56Fe离子和137Csγ射线，剂量高达1 Gy时，这些标记呈现出线性剂量反应。Y染色体上的短串联重复序列和常染色体上的单核苷酸重复序列在56Fe离子剂量≥0.5 Gy时突变显著增加，频率平均为4.3 - 10.3×10(-3)突变/位点/Gy/细胞，高到足以直接检测受辐照细胞中的突变。在辐射暴露后10周和26周，在小鼠血液和颊部样本中可检测到扩展单核苷酸重复序列中辐射诱导突变显著增加，且这些突变在多次暴露后具有累加性。本研究证明了一种适用于人类和其他物种的新型生物剂量测定方法的可行性。这种新方法应能补充现有的生物剂量测定方法，并且可能有助于在当前方法不适用的情况下测量辐射暴露。
