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Multiple metabolic pathways are predictive of ricin intoxication in a rat model

Authors
  • D’Elia, Riccardo V.1
  • Goodchild, Sarah A.1
  • Winder, Catherine L.2
  • Southam, Andrew D.2
  • Weber, Ralf J. M.2
  • Stahl, Fiona M.1
  • Docx, Cerys1
  • Patel, Vikesh1
  • Green, A. Christopher1
  • Viant, Mark R.2
  • Lukaszewski, Roman A.1
  • Dunn, Warwick B.2, 3
  • 1 Dstl Porton Down, Salisbury, SP4 0JQ, UK , Salisbury (United Kingdom)
  • 2 University of Birmingham, Phenome Centre Birmingham and School of Biosciences, Edgbaston, Birmingham, B15 2TT, UK , Edgbaston, Birmingham (United Kingdom)
  • 3 University of Birmingham, Institute of Metabolism and Systems Research, Edgbaston, Birmingham, B15 2TT, UK , Edgbaston, Birmingham (United Kingdom)
Type
Published Article
Journal
Metabolomics
Publisher
Springer US
Publication Date
Jul 03, 2019
Volume
15
Issue
7
Identifiers
DOI: 10.1007/s11306-019-1547-9
Source
Springer Nature
Keywords
License
Green

Abstract

IntroductionExposure to ricin can be lethal and treatments that are under development have short windows of opportunity for administration after exposure. It is therefore essential to achieve early detection of ricin exposure to provide the best prognosis for exposed individuals. Ricin toxin can be detected in clinical samples via several antibody-based techniques, but the efficacy of these can be limited due to the rapid processing and cellular uptake of toxin in the body and subsequent low blood ricin concentrations. Other diagnostic tools that perform, in an orthogonal manner, are therefore desirable.ObjectivesTo determine time-dependent metabolic changes in Sprague–Dawley rats following intravenous exposure to ricin.MethodsSprague–Dawley rats were intravenously exposed to ricin and multiple blood samples were collected from each animal for up to 48 h following exposure in two independent studies. Plasma samples were analysed applying HILIC and C18 reversed phase UHPLC–MS assays followed by univariate and multivariate analysis.ResultsIn Sprague–Dawley rats we have demonstrated that metabolic changes measured in blood can distinguish between rats exposed intravenously to ricin and controls prior to the onset of behavioral signs of intoxication after 24 h. A total of 37 metabolites were significantly altered following exposure to ricin when compared to controls. The arginine/proline, bile acid and triacylglyceride metabolic pathways were highlighted as being important with two triacylglycerides at 8 h post exposure giving an AUROC score of 0.94. At 16 h and 24 h the AUROC score increased to 0.98 and 1.0 with the number of metabolites in the panel increasing to 5 and 7, respectively.ConclusionsThese data demonstrate that metabolites may be a useful tool to diagnose and detect ricin exposure, thus increasing the effectiveness of supportive therapy and future ricin-specific medical treatments.

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