title: Evaluation and identification of dioxin exposure biomarkers in human urine by high-resolution metabolomics, multivariate analysis and in vitro synthesis.
abstract: A previous high-resolution metabolomic study pointed out a dysregulation of urinary steroids and bile acids in human cases of acute dioxin exposure. A subset of 24 compounds was highlighted as putative biomarkers. The aim of the current study was (i) to evaluate the 24 biomarkers in an independent human cohort exposed to dioxins released from the incineration fumes of a municipal waste incinerator and; (ii) to identify them by comparison with authentic chemical standards and biosynthesised products obtained with in vitro metabolic reactions. An orthogonal projection to latent structures discriminant analysis built on biomarker profiles measured in the intoxicated cohort and the controls separated both groups with reported values of 93.8%; 100% and 87.5% for global accuracy; sensitivity and specificity; respectively. These results corroborated the 24 compounds as exposure biomarkers; but a definite identification was necessary for a better understanding of dioxin toxicity. Dehydroepiandrosterone 3β-sulfate, androsterone 3α-glucuronide, androsterone 3α-sulfate, pregnanediol 3α-glucuronide and 11-ketoetiocholanolone 3α-glucuronide were identified by authentic standards. Metabolic reactions characterised four biomarkers: glucuronide conjugates of 11β-hydroxyandrosterone; glycochenodeoxycholic acid and glycocholic acid produced in human liver microsomes and glycoursodeoxycholic acid sulfate generated in cytosol fraction. The combination of metabolomics by high-resolution mass spectrometry with in vitro metabolic syntheses confirmed a perturbed profile of steroids and bile acids in human cases of dioxin exposure.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; Human Protein Sciences Department, University of Geneva, Geneva, Switzerland; Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Jeanneret
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; Human Protein Sciences Department, University of Geneva, Geneva, Switzerland; Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Tonoli
authors.affiliation: Human Protein Sciences Department, 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: Human Protein Sciences Department, University of Geneva, Geneva, Switzerland; Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland.
authors.forename: Jean-Hilaire
authors.initials: JH
authors.lastname: Saurat
authors.affiliation: Human Protein Sciences Department, 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: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Boccard
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: D000293:Adolescent; D000328:Adult; D000368:Aged; D001647:Bile Acids and Salts / Q000652:urine; D015415:Biomarkers / Q000652:urine*; D002648:Child; D004147:Dioxins / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D015999:Multivariate Analysis; D013256:Steroids / Q000652:urine; D055815:Young Adult
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D004147:Dioxins; D013256:Steroids
keywords: Dioxin; In vitro synthesis; Mass spectrometry; Metabolomics; Steroid; UHPLC-QTOF