Use of DNA adducts to identify human health risk from exposure to hazardous environmental pollutants: The increasing role of mass spectrometry in assessing biologically effective doses of genotoxic carcinogens
Use of DNA adducts to identify human health risk from exposure to hazardous environmental pollutants: The increasing role of mass spectrometry in assessing biologically effective doses of genotoxic carcinogens
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DOI：
10.1016/j.mrrev.2008.03.006
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发表时间：
2008-07-01
影响因子：
5.3
通讯作者：
Singh, Rajinder
中科院分区：
文献类型：
--
作者：
Farmer, Peter B.;Singh, Rajinder
人类接触的致癌物通常以复杂混合物的形式存在，人们已经做了很多努力来确定这些混合物中最重要的致癌成分的性质及其作用机制。在接触人群中实现这一目标的关键是使用生物标志物，生物标志物可以表征所涉及的致癌物的化学性质，并确定由接触引起的关键生物效应。DNA加合物是特别合适的生物标志物的情况下，遗传毒性致癌物，因为它们表明的生物有效剂量的遗传毒素在靶tissue.This审查认为，特别是使用质谱（MS），这是有越来越多的作用，在确定DNA加合物。与其他现有的DNA损伤检测方法相比，如P-32-后标记，HPLC-荧光或电化学检测，基于免疫测定的技术和改进的彗星试验，MS提供了改进的加合物的结构表征。更大的选择性分析是通过使用串联MS与选定的反应监测或恒定的中性离子损失。毛细管/纳米液相色谱和微/纳米电喷雾离子化的使用提高了分析灵敏度，并且通过使用在线柱切换可以获得更高的通量。微流体技术的应用为质谱仪的样品制备提供了令人兴奋的新可能性。尽管在使用MS进行加合物检测方面有了这些改进，但目前的主要要求是在分析和分子流行病学研究中验证这些方法。需要对储存样品的稳定性有更多的了解。开发灵敏的质谱DNA内收体筛选系统和长期生物标志物（例如，不能有效修复的磷酸三酯加合物）似乎是今后评估人类接触环境遗传毒素的影响以及研究低剂量下的剂量-反应关系的重要领域。(C)2008 Elsevier B. V.保留所有权利。
The carcinogens to which humans are exposed are normally in the form of complex mixtures, and much effort has gone into determining the nature of the most significant carcinogenic components in these mixtures and their mechanisms of action. Essential to achieving this aim in exposed populations is the use of biomarkers, which can characterize the chemical nature of the carcinogens involved and identify key biological effects that result from the exposure. DNA adducts are particularly appropriate as biomarkers in the case of genotoxic carcinogens as they indicate the biologically effective dose of the genotoxin in the target tissue under study.This review considers in particular the use of mass spectrometry (MS), which is having an increasing role in the determination of DNA adducts. Compared to other existing DNA damage detection methods, such as P-32-postlabeling, HPLC-fluorescence or electrochemical detection, immunoassay-based techniques and modified Comet assays, MS provides improved structural characterization of adducts. Greater selectivity in the analyses is achieved by the use of tandem MS with selected reaction monitoring or constant neutral loss of ions. Use of capillary/nano liquid chromatography and micro/nano electrospray ionization improves the analytical sensitivity and higher throughput may be obtained by the use of online-column switching. The application of microfluidics technology offers exciting new possibilities for interfacing sample preparation to the mass spectrometer. Despite these improvements in the use of MS for adduct detection, the main current requirement is to validate these methods both analytically and in molecular epidemiology studies. More knowledge of the stability of stored samples is required. Development of sensitive mass spectrometric DNA adductomic screening systems, and of long-term biomarkers (e.g., phosphotriester adducts that are not repaired efficiently) seems important areas for the future assessment of the effects of human exposure to environmental genotoxins, together with studies of dose-response relationships at low doses. (C) 2008 Elsevier B.V. All rights reserved.