title: Alteration in circulating metabolites during and after heat stress in the conscious rat: potential biomarkers of exposure and organ-specific injury.
abstract: BACKGROUND
  Heat illness is a debilitating and potentially life-threatening condition. Limited data are available to identify individuals with heat illness at greatest risk for organ damage. We recently described the transcriptomic and proteomic responses to heat injury and recovery in multiple organs in an in vivo model of conscious rats heated to a maximum core temperature of 41.8°C (Tc,Max). In this study, we examined changes in plasma metabolic networks at Tc,Max, 24, or 48 hours after the heat stress stimulus.
  
  
  RESULTS
  Circulating metabolites were identified by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry. Bioinformatics analysis of the metabolomic data corroborated proteomics and transcriptomics data in the tissue at the pathway level, supporting modulations in metabolic networks including cell death or catabolism (pyrimidine and purine degradation, acetylation, sulfation, redox alterations and glutathione metabolism, and the urea cycle/creatinine metabolism), energetics (stasis in glycolysis and tricarboxylic acid cycle, β-oxidation), cholesterol and nitric oxide metabolism, and bile acids. Hierarchical clustering identified 15 biochemicals that differentiated animals with histopathological evidence of cardiac injury at 48 hours from uninjured animals. The metabolic networks perturbed in the plasma corroborated the tissue proteomics and transcriptomics pathway data, supporting a model of irreversible cell death and decrements in energetics as key indicators of cardiac damage in response to heat stress.
  
  
  CONCLUSIONS
  Integrating plasma metabolomics with tissue proteomics and transcriptomics supports a diagnostic approach to assessing individual susceptibility to organ injury and predicting recovery after heat stress.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Ippolito
authors.forename: John A
authors.initials: JA
authors.lastname: Lewis
authors.forename: Chenggang
authors.initials: C
authors.lastname: Yu
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Leon
authors.affiliation: The United States Army Center for Environmental Health Research, Environmental Health Program, Bldg, 568 Doughten Drive, Fort Detrick, Frederick 21702-5010, MD, USA. jonathan.d.stallings.mil@mail.mil.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Stallings
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001833:Body Temperature Regulation; D016923:Cell Death; D006335:Heart Injuries / Q000378:metabolism; D006359:Heat Exhaustion / Q000097:blood* / Q000473:pathology; D018869:Heat-Shock Response; D007668:Kidney / Q000293:injuries / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism; D055370:Lung Injury / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000097:blood
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species