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首页> 外文期刊>Archives of Toxicology >A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure
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A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure

机译：用于定量硫芥末诱导的核酸加合物作为机械相关的曝光生物标志物的质谱平台

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摘要

Despite its worldwide ban, the warfare agent sulfur mustard (SM) still represents a realistic threat, due to potential release in terroristic attacks and asymmetric conflicts. Therefore, the rigorous and quantitative detection of SM exposure is crucial for diagnosis, health risk assessment, and surveillance of international law. Alkylation adducts of nucleic acids can serve as valuable toxicologically relevant biomarkers of SM exposure'. Here, we developed a robust and versatile bioanalytical platform based on isotope dilution UPLC-MS/MS to quantify major SM-induced DNA and RNA adducts, as well as adducts induced by the monofunctional mustard 2-chloroethylethylsulfide. We synthesized N-15/C-13-labeled standards, which allowed absolute quantitation with full chemical specificity and subfemtomole sensitivities. DNA and RNA mono-alkylation adducts and crosslinks were carefully analyzed in a dose- and time-dependent manner in various matrices, including human cancer and primary cells, derived of the main SM-target tissues. Nucleic acid adducts were detected up to 6days post-exposure, indicating long persistence, which highlights their toxicological relevance and proves their suitability as forensic and medical biomarkers. Finally, we investigated ex vivo-treated rat skin biopsies and human blood samples, which set the basis for the implementation into the method portfolio of Organization for the Prohibition of Chemical Weapons-designated laboratories to analyze authentic samples from SM-exposed victims.
机译：尽管其全球禁令，因此由于恐怖袭击和不对称冲突的潜在释放，战争代理硫磺芥末（SM）仍然是一种现实的威胁。因此，SM暴露的严格和定量检测对于诊断，健康风险评估和国际法监测至关重要。核酸的烷基化加合物可以作为SM暴露的有价值的毒理学相关生物标志物。在这里，我们开发了一种基于同位素稀释UPLC-MS / MS的强大和通用的生物分析平台，以量化主要的SM诱导的DNA和RNA加合物，以及单官能芥菜2-氯乙基硫化物诱导的加合物。我们合成了N-15 / C-13标记的标准，其允许具有全部化学特异性和次麦粉敏感性的绝对定量。在各种基质中以剂量和时间依赖性方式分析DNA和RNA单烷基化加合物和交联，包括主要SM-靶组织的人类癌症和原代细胞。检测到核酸加合物的暴露后6天，表明长期持久性，突出了它们的毒理学相关性，并证明了它们作为法医和医学生物标志物的适用性。最后，我们研究了离体疗法的大鼠皮肤活检和人血样，为禁止化学武器指定实验室的禁止化学武器，分析了来自SM暴露的受害者的真实样本的方法组织组合的实施依据。

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