A serum metabolomics signature of hypothermia fatalities involving arginase activity, tryptophan content, and phosphatidylcholine saturation

Guillaume Rousseau, Juan Manuel Chao de la Barca, Clotilde Rougé-Maillart, Grzegorz Teresiński, Nathalie Jousset, Xavier Dieu, Floris Chabrun, Delphine Prunier-Mirabeau, Gilles Simard, Pascal Reynier, Cristian Palmiere

Hypothermia is a potentially lethal condition whose postmortem diagnosis is often complex to perform due to the absence of pathognomonic lesions and biomarkers. Our first study of human serum and urinary metabolome in hypothermia fatalities sought novel biomarkers with better diagnostic performances than those already existing. Thirty-two cases of hypothermia deaths and 16 cases excluding known antemortem exposure to cold or postmortem elements suggesting hypothermia were selected. A targeted metabolomic study allowing the detection and quantitation of 188 metabolites was performed on collected serum and urine using direct flow injection (FIA) and liquid chromatography (LC) separation, both coupled to tandem mass spectrometry (MS/MS). Amino acid quantification was also carried on using an in-house LC-MS/MS method in order to replicate the results obtained with the metabolomic study. A discriminant metabolic signature allowing a clear separation between hypothermia and control groups was obtained in the serum. This signature was characterized by increased arginase activity and fatty acid unsaturation along with decreased levels of tryptophan in hypothermia fatalities compared to controls. By contrast, no discriminant metabolic signature separating hypothermia from control fatalities was found in urines. The serum metabolic signature of hypothermia fatalities herein observed pointed toward metabolic adaptations that likely aimed at heat production enhancement, endothelial function, and cell membrane fluidity preservation. Novel biomarkers potentially useful in a hypothermia diagnosis were also identified.