title: Human urinary biomarkers of dioxin exposure: analysis by metabolomics and biologically driven data dimensionality reduction.
abstract: 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).
authors.affiliation: 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.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Jeanneret
authors.affiliation: AgroParisTech UMR 1145, Laboratoire de Chimie Analytique, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Boccard
authors.affiliation: Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland.
authors.forename: Flavia
authors.initials: F
authors.lastname: Badoud
authors.affiliation: Department of Human Protein Sciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sorg
authors.affiliation: Department of Human Protein Sciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Tonoli
authors.affiliation: Charles University Prague, Department of Occupational Medicine of the First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pelclova
authors.affiliation: Charles University Prague, Department of Occupational Medicine of the First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
authors.forename: Stepanka
authors.initials: S
authors.lastname: Vlckova
authors.affiliation: AgroParisTech UMR 1145, Laboratoire de Chimie Analytique, Paris, France.
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Rutledge
authors.affiliation: Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland; Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Samer
authors.affiliation: Department of Human Protein Sciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Hochstrasser
authors.affiliation: Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland.
authors.forename: Jean-Hilaire
authors.initials: JH
authors.lastname: Saurat
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland. Electronic address: serge.rudaz@unige.ch.
authors.forename: Serge
authors.initials: S
authors.lastname: Rudaz
mesh_terms: D015415:Biomarkers / Q000652:urine*; D002851:Chromatography, High Pressure Liquid; D057225:Data Mining; D004784:Environmental Monitoring / Q000379:methods*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D055432:Metabolomics / Q000379:methods*; D016273:Occupational Exposure / Q000032:analysis*; D018384:Oxidative Stress / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D000072317:Polychlorinated Dibenzodioxins
keywords: Biomarkers; Dimensionality reduction; Dioxin; Extreme phenotype; Steroidomics; Toxicity