title: Metabolomics reveals dose effects of low-dose chronic exposure to uranium in rats: identification of candidate biomarkers in urine samples.
abstract: BACKGROUND
  Data are sparse about the potential health risks of chronic low-dose contamination of humans by uranium (natural or anthropogenic) in drinking water. Previous studies report some molecular imbalances but no clinical signs due to uranium intake.
  
  
  OBJECTIVE
  In a proof-of-principle study, we reported that metabolomics is an appropriate method for addressing this chronic low-dose exposure in a rat model (uranium dose: 40 mg L-1; duration: 9 months, n = 10). In the present study, our aim was to investigate the dose-effect pattern and identify additional potential biomarkers in urine samples.
  
  
  METHODS
  Compared to our previous protocol, we doubled the number of rats per group (n = 20), added additional sampling time points (3 and 6 months) and included several lower doses of natural uranium (doses used: 40, 1.5, 0.15 and 0.015 mg L-1). LC-MS metabolomics was performed on urine samples and statistical analyses were made with SIMCA-P+ and R packages.
  
  
  RESULTS
  The data confirmed our previous results and showed that discrimination was both dose and time related. Uranium exposure was revealed in rats contaminated for 9 months at a dose as low as 0.15 mg L-1. Eleven features, including the confidently identified N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide and 4-hydroxyphenylacetylglycine, discriminated control from contaminated rats with a specificity and a sensitivity ranging from 83 to 96 %, when combined into a composite score.
  
  
  CONCLUSIONS
  These findings show promise for the elucidation of underlying radiotoxicologic mechanisms and the design of a diagnostic test to assess exposure in urine, in a dose range experimentally estimated to be above a threshold between 0.015 and 0.15 mg L-1.
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, LRTOX, 92260 Fontenay-aux-roses, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Grison
authors.affiliation: Aix Marseille Université (AMU), NORT, 13005 Marseille, France.|Inserm, UMR_S 1062, 13005 Marseille, France.|Inra, UMR_INRA 1260, 13005 Marseille, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Favé
authors.affiliation: Aix Marseille Université (AMU), NORT, 13005 Marseille, France.|Inserm, UMR_S 1062, 13005 Marseille, France.|Inra, UMR_INRA 1260, 13005 Marseille, France.|MS-Nutrition, Marseille, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Maillot
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, LRTOX, 92260 Fontenay-aux-roses, France.
authors.forename: Line
authors.initials: L
authors.lastname: Manens
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, LRTOX, 92260 Fontenay-aux-roses, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Delissen
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SDI, LEDI, 92260 Fontenay-aux-roses, France.
authors.forename: Éric
authors.initials: É
authors.lastname: Blanchardon
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, LRTOX, 92260 Fontenay-aux-roses, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dublineau
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, 92260 Fontenay-aux-roses, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Aigueperse
authors.affiliation: AREVA Mines, 92400 Courbevoie, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bohand
authors.affiliation: Aix Marseille Université (AMU), NORT, 13005 Marseille, France.|Inserm, UMR_S 1062, 13005 Marseille, France.|Inra, UMR_INRA 1260, 13005 Marseille, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Martin
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PRP-HOM, SRBE, LRTOX, 92260 Fontenay-aux-roses, France.
authors.forename: Maâmar
authors.initials: M
authors.lastname: Souidi
keywords: Chronic; Contamination; Low dose; Metabolomics; N1-methylnicotinamide; Uranium