醛类标志物的化学衍生化色谱-质谱分析方法进展

doi:10.3724/SP.J.1123.2021.02023

摘要/Abstract

摘要：

人体接触环境中的化学污染物会导致多种疾病,包括癌症、糖尿病、心血管疾病、神经退行性疾病(阿尔茨海默症、帕金森病等)等。作为一类具有高反应活性的亲电化合物,醛类(包括外源性醛类或环境污染物暴露后产生的内源性醛类)可与人体中多种重要生物分子形成共价修饰产物而产生毒害作用。暴露组研究自2005年被首次提出以来一直是一个前沿热门领域,暴露组研究可绘制生物标志物与疾病风险之间的复杂关系,因此,所有生物标志物的可测量的和特征性的变化共同构成了暴露组研究的关键基础。醛类是化学暴露组的主要成分之一。由于醛类化合物自身物理化学性质和样品大量基质干扰存在,对它们进行分析和表征特别困难。醛类化合物的分析检测方法主要有传感分析法、电化学法、荧光成像、色谱法、质谱法、色谱-质谱联用法等。基于色谱-质谱的分析技术已成为化学暴露组研究的主要方法之一。化学衍生化,特别是稳定同位素标记衍生化(亦称化学同位素标记)结合液相色谱-质谱(LC-MS)技术能够解决靶向和非靶向代谢组和暴露组分析工作中的诸多问题。化学衍生化联合色谱-质谱的分析策略是复杂体系中醛类精准分析非常重要的解决方案之一。特别是近5年,基于化学衍生化的色谱-质谱分析方法开发与应用已成为醛类分析方法中的热点和亮点。该文主要总结与评述了近5年基于化学衍生化的气相色谱-质谱(GC-MS)和LC-MS最新进展,重点关注生物基质(血液、尿液、唾液、生物组织等)中醛类暴露标志物的分析方法进展。通过探讨标记小分子醛的各种衍生试剂、定性/定量分析方法及应用价值,评述醛类暴露标志物不同分析方法的优缺点以及未来发展趋势,为暴露组学、代谢组学、脂质组学的整合发展和环境生态健康研究提供一定的帮助。为了阐明外源性和内源性醛类化合物在生理和病理事件中所起的复杂作用,需要大力改进研究醛组学(aldehydome)的分析表征技术和工具。随着更先进的质谱仪的研发和使用,以及高效色谱分离和不断进步的生物信息学手段,并同时伴随着单细胞分析、质谱成像的兴起,未来的醛类暴露组分析方法会具有更高的灵敏度、更高的分析通量,更有希望筛选鉴定未知醛类化合物并发现新的暴露组生物标志物。

关键词: 醛, 标志物, 色谱-质谱, 衍生化, 同位素标记, 综述

Abstract:

Human exposure to chemical pollutants in the environment can cause a variety of diseases, including cancer, diabetes, cardiovascular disease, and neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, etc.). Exogenous and environmental pollutant exposure-induced endogenous aldehydes are highly reactive electrophilic compounds that can form covalently modified products with a variety of important biological molecules in the human body, thus inducing toxic effects. Exposome research has become a hotspot since it was first proposed in 2005. Exposure studies can map the complex relationships between biomarkers and disease risk. Therefore, the measurable and characteristic changes of all biomarkers together constitute a key basis for exposome research. Aldehydes are among the main components of chemical exposure. Because of the physical and chemical properties of aldehydes and the existence of multiple matrix interferences in the samples, it is particularly difficult to analyze and characterize them. The analysis and detection methods for aldehydes mainly include sensing analysis, electrochemical methods, fluorescence imaging, chromatography, mass spectrometry (MS), and chromatography-MS. Analytical techniques based on gas chromatography-MS (GC-MS) and liquid chromatography-MS (LC-MS) have emerged as the main methods for chemical exposome research. Chemical derivatization, especially stable isotope labeling derivatization (also known as chemical isotope labeling) combined with LC-MS analytical techniques, can help circumvent the problems encountered in targeted and non-targeted metabolome and exposome analysis. The combination of chemical derivatization with chromatography-MS is one of the most important solutions for the accurate analysis of aldehydes in complex samples. Over the past five years, the development and application of chromatography-MS analytical methods based on chemical derivatization have become key topics in aldehyde analysis. This paper summarizes and reviews the latest progress in GC-MS and LC-MS methods based on chemical derivatization (2015-2020). The review focuses on analytical method development for aldehyde exposure biomarkers in bio-matrices (blood, urine, saliva, biological tissue, etc.). Various derivatization reagents for labeling small-molecule aldehydes, qualitative/quantitative analytical methods and their application value, advantages/disadvantages of different analytical methods for aldehyde exposure biomarkers, and future development trends are also included. The manuscript contents may aid the integrated development of exposome, metabolomics, and lipidomics, as well as research on the environment, ecology, and health. To clarify the complex actions of exogenous and endogenous aldehydes in physiological and pathological events, it is necessary to improve the analysis and characterization techniques and tools for studying the “aldehydome.” With the development and application of sophisticated mass spectrometers, advances in high-performance chromatographic separation and bioinformatics, and advent of single-cell analysis and MS imaging, future aldehyde exposome analytical methods will have higher sensitivity and throughput. This in turn would be more useful for screening and identifying unknown aldehyde compounds and discovering new exposome biomarkers.

Key words: aldehydes, biomarkers, chromatography-mass spectrometry, derivatization, isotope labeling, review

中图分类号:

O658

朱树芸, 赵先恩, 刘虎威. 醛类标志物的化学衍生化色谱-质谱分析方法进展[J]. 色谱, 2021, 39(8): 845-854.

ZHU Shuyun, ZHAO Xian-En, LIU Huwei. Recent advances in chemical derivatization-based chromatography-mass spectrometry methods for analysis of aldehyde biomarkers[J]. Chinese Journal of Chromatography, 2021, 39(8): 845-854.

图/表 8

图1 人甲状腺组织中脂肪醛的季铵化增敏衍生与MS/MS特异性检测[32]

Fig. 1 Quaternization sensitizing derivatization of fatty aldehydes in human thyroid tissues and the MS/MS specific detection[32]

图2 醛的柱后衍生与MRM定量分析和母离子扫描非靶向筛选[35]

Fig. 2 Post column derivatization and MRM quantitation of aldehydes and their non-targeted screening by precursor ion scan[35]

图3 (a)14重LHMTs试剂的设计、合成以及(b)MTCIL的衍生化条件[42]

Fig. 3 (a) Design and synthesis procedure of 14-plex LHMTs reagents and (b) MTCIL derivatization conditions[42] MTCIL: multiplex tags chemical isotope labeling.

图4 多标签化学同位素标记分析策略流程及其14种LHMTs质量标签作用[42]

Fig. 4 Analytic strategy workflow of multiplex tags chemical isotope labeling and the application of 14 LHMTs reagents[42] MDSPE: magnetic dispersive solid phase extraction.

图5 (a)4种标记试剂的化学结构和(b)d0/d7-HIQB对羰基化合物的标记[44]

Fig. 5 (a) Structures of the four labeling reagents and (b) labeling of carbonyl compounds by HIQB and d7-HIQB[44] HIQB: (2-(2-hydrazinyl-2-oxoethyl)isoquinolin-2-ium bromide; THB: N,N,N-triethyl-2-hydrazinyl-2-oxoethanaminium bromide; GT: Girard reagent T; GP: Girard reagent P.

图6 LC-DPIS-MS策略用于羰基化合物轮廓分析[44]

Fig. 6 Schematic diagram for profiling of carbonyl compounds by LC-DPIS-MS[44] CID: collision-induced dissociation; DPIS: double precursor ion scan.

图7 12C/13C-DnsHz标记CIL-LC-MS羰基代谢亚组相对定量分析流程[45]

Fig. 7 Workflow of 12C-/13C-dansylhydrazine labeling for relative quantification of the carbonyl submetabolome differences in comparative samples by CIL-LC-MS[45] CIL: chemical isotope labeling.

图8 高分辨精确质量数MS3中性丢失扫描策略[47]

Fig. 8 High resolution accurate mass data-dependent MS3 neutral loss screening strategy[47] The high resolution accurate mass of ·OH (17.0027 Da) was used to screen for all 2,4-dinitrophenylhydrazine (DNPH)-derivatized carbonyls. In addition, monitoring specific fragment ions (m/z 78.0332 and 164.0323) minimize possible false positive identification.

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