Jeanneret Fabienne, Boccard Julien, Badoud Flavia, Sorg Olivier, Tonoli David, Pelclova Daniela, Vlckova Stepanka, Rutledge Douglas N, Samer Caroline F, Hochstrasser Denis, Saurat Jean-Hilaire, Rudaz Serge
Department of Human Protein Sciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland; School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland.
AgroParisTech UMR 1145, Laboratoire de Chimie Analytique, Paris, France.
Toxicol Lett. 2014 Oct 15;230(2):234-43. doi: 10.1016/j.toxlet.2013.10.031. Epub 2013 Nov 4.
Untargeted metabolomic approaches offer new opportunities for a deeper understanding of the molecular events related to toxic exposure. This study proposes a metabolomic investigation of biochemical alterations occurring in urine as a result of dioxin toxicity. Urine samples were collected from Czech chemical workers submitted to severe dioxin occupational exposure in a herbicide production plant in the late 1960s. Experiments were carried out with ultra-high pressure liquid chromatography (UHPLC) coupled to high-resolution quadrupole time-of-flight (QTOF) mass spectrometry. A chemistry-driven feature selection was applied to focus on steroid-related metabolites. Supervised multivariate data analysis allowed biomarkers, mainly related to bile acids, to be highlighted. These results supported the hypothesis of liver damage and oxidative stress for long-term dioxin toxicity. As a second step of data analysis, the information gained from the urine analysis of Victor Yushchenko after his poisoning was examined. A subset of relevant urinary markers of acute dioxin toxicity from this extreme phenotype, including glucuro- and sulfo-conjugated endogenous steroid metabolites and bile acids, was assessed for its ability to detect long-term effects of exposure. The metabolomic strategy presented in this work allowed the determination of metabolic patterns related to dioxin effects in human and the discovery of highly predictive subsets of biologically meaningful and clinically relevant compounds. These results are expected to provide valuable information for a deeper understanding of the molecular events related to dioxin toxicity. Furthermore, it presents an original methodology of data dimensionality reduction by using extreme phenotype as a guide to select relevant features prior to data modeling (biologically driven data reduction).
非靶向代谢组学方法为更深入了解与有毒物质暴露相关的分子事件提供了新机会。本研究提出对二噁英毒性导致尿液中发生的生化改变进行代谢组学研究。尿液样本取自20世纪60年代末在一家除草剂生产厂遭受严重二噁英职业暴露的捷克化学工人。实验采用超高压液相色谱（UHPLC）与高分辨率四极杆飞行时间（QTOF）质谱联用。应用化学驱动的特征选择来聚焦于类固醇相关代谢物。有监督的多变量数据分析突出了主要与胆汁酸相关的生物标志物。这些结果支持了长期二噁英毒性导致肝损伤和氧化应激的假说。作为数据分析的第二步，对维克托·尤先科中毒后尿液分析获得的信息进行了检查。评估了这一极端表型中急性二噁英毒性的一组相关尿液标志物，包括葡萄糖醛酸和硫酸酯结合的内源性类固醇代谢物以及胆汁酸，以确定其检测暴露长期影响的能力。本研究中提出的代谢组学策略能够确定与二噁英对人类影响相关的代谢模式，并发现具有生物学意义和临床相关性的高度预测性化合物子集。这些结果有望为更深入了解与二噁英毒性相关的分子事件提供有价值的信息。此外，它还提出了一种原始的数据降维方法，即利用极端表型作为指导，在数据建模之前选择相关特征（生物驱动的数据降维）。
