Knowledge-driven approaches to create the MTox700+ metabolite panel for predicting toxicity

Elena Sostare, Thomas N Lawson, Lucy R Saunders, John K Colbourne, Ralf J M Weber, Tomasz Sobanski, Mark R Viant

Research output: Contribution to journalArticlepeer-review

Abstract

Endogenous metabolite levels describe the molecular phenotype that is most downstream from chemical exposure. Consequently, quantitative changes in metabolite levels have the potential to predict mode-of-action and adversity, with regulatory toxicology predicated on the latter. However, toxicity-related metabolic biomarker resources remain highly fragmented and incomplete. Although development of the S1500+ gene biomarker panel has accelerated the application of transcriptomics to toxicology, a similar initiative for metabolic biomarkers is lacking. Our aim was to define a publicly available metabolic biomarker panel, equivalent to S1500+, capable of predicting pathway perturbations and/or adverse outcomes. We conducted a systematic review of multiple toxicological resources, yielding 189 proposed metabolic biomarkers from existing assays (BASF, Bowes-44, and Tox21), 342 biomarkers from databases (Adverse Outcome Pathway Wiki, Comparative Toxicogenomics Database, QIAGEN Ingenuity Pathway Analysis, and Toxin and Toxin-Target Database), and 435 biomarkers from the literature. Evidence mapping across all 8 resources generated a panel of 722 metabolic biomarkers for toxicology (MTox700+), of which 462 (64%) are associated with molecular pathways and 575 (80%) with adverse outcomes. Comparing MTox700+ and S1500+ revealed that 418 (58%) metabolic biomarkers associate with pathways shared across both panels, with further metabolites mapping to unique pathways. Metabolite reference standards are commercially available for 646 (90%) of the panel metabolites, and assays exist for 578 (80%) of these biomarkers. This study has generated a publicly available metabolic biomarker panel for toxicology, which through its future laboratory deployment, is intended to help build foundational knowledge to support the generation of molecular mechanistic data for chemical hazard assessment.
Original languageEnglish
Pages (from-to)208-220
Number of pages13
JournalToxicological Sciences
Volume186
Issue number2
Early online date30 Jan 2022
DOIs
Publication statusPublished - Apr 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.

Keywords

  • systematic review
  • metabolite
  • metabolomics
  • biomarker
  • adverse outcome
  • molecular pathway
  • Phenotype
  • Transcriptome
  • Biomarkers
  • Databases, Factual

ASJC Scopus subject areas

  • Toxicology

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