High-performance metabolic profiling of plasma from seven mammalian species for simultaneous environmental chemical surveillance and bioeffect monitoring

Abstract

High-performance metabolic profiling (HPMP) by Fourier-transform mass spectrometry coupled to liquid chromatography gives relative quantification of thousands of chemicals in biologic samples but has had little development for use in toxicology research. In principle, the approach could be useful to detect complex metabolic response patterns to toxicologic exposures and to detect unusual abundances or patterns of potentially toxic chemicals. As an initial study to develop these possible uses, we applied HPMP and bioinformatics analysis to plasma of humans, rhesus macaques, marmosets, pigs, sheep, rats and mice to determine: 1) whether more chemicals are detected in humans living in a less controlled environment than captive species, and 2) whether a subset of plasma chemicals with similar inter-species and intra-species variation could be identified for use in comparative toxicology. Results show that the number of chemicals detected was similar in humans (3221) and other species (range 2537 to 3373). Metabolite patterns were most similar within species and separated samples according to family and order. A total of 1485 chemicals were common to all species; 37% of these matched chemicals in human metabolomic databases and included chemicals in 137 out of 146 human metabolic pathways. Probability-based modularity clustering separated 644 chemicals, including many endogenous metabolites, with inter-species variation similar to intra-species variation. The remaining chemicals had greater inter-species variation and included environmental chemicals as well as GSH and methionine. Together, the data suggest that HPMP provides a platform that can be useful within human populations and controlled animal studies to simultaneously evaluate environmental exposures and biological responses to such exposures.

Metabolome-wide association study of peripheral parasitemia in Plasmodium vivax malaria

“…Sample processing and high-resolution mass spectrometry analysis was performed as described previously (Park et al, 2012; Soltow et al, 2013; Go et al, 2015b; Jin et al, 2016; Walker et al, 2016; Cribbs et al, 2016; Li et al, 2017). Acetonitrile (2:1, v/v) was added to 65 μL of plasma containing 14 stable isotope internal standards ([13C6]-D-glucose, [15N]-indole, [2-15N]-L-lysine dihydrochloride, [13C5]-L-glutamic acid, [13C7]-benzoic acid, [3,4-13C2] cholesterol, [15N]-L-tyrosine, [trimethyl-13C3]-caffeine, [15N2]-uracil, [3,3-13C2]-cystine, [1,2-13C2]-palmitic acid, [15N, 13C5]-L-methionine, [15N]-choline chloride, and 2′-deoxyguanosine-15N2,13C10-5′-monophosphate).…”

New Exposure Biomarkers as Tools for Breast Cancer Epidemiology, Biomonitoring, and Prevention: A Systematic Approach Based on Animal Evidence

“…For example, metabolomics techniques, widely used to investigate pharmaceuticals’ effects on levels of small molecules in blood, have been used to identify exposure biomarkers (Park et al 2012). These exposome approaches are an especially promising tool for identifying exposure biomarkers for complex mixtures such as vehicle exhaust.…”

Deployment-Associated Exposure Surveillance With High-Resolution Metabolomics

“…Here, we focus on metabolomics as a general approach to provide a cost-effective means to measure body burden of known chemicals, detect unidentified exposures, and monitor a broad spectrum of metabolic perturbations that could predict potential adverse health outcomes. We first describe high-resolution metabolomics (HRM) using liquid chromatography (LC) coupled to high-resolution mass spectrometry (MS) as an analytical platform to simultaneously evaluate perturbations in metabolism and detect chemicals present at very low levels in biological samples (12). This methodology has been developed for precision medicine (13, 14), and is being refined for use to sequence exposures as part of a human exposome project (15).…”

“…Over 90% of metabolites in the Kyoto Encyclopedia of Genes and Genomes (KEGG) have accurate mass m/z values that differ by >10 ppm (12). HRM profiling of blood plasma samples obtained from healthy individuals has indicated measure of metabolites from >80% of the pathways present in the KEGG database (Figure 2), enabling quantification with >85% accuracy based upon ion intensity in terms of the integral of precursor ions (MS 1 ) (15, 38).…”

“…For instance, metabolic indicators of nutrition (vitamins, amino acids), liver function (bilirubin), renal function (creatinine, uric acid) and other health phenotypes can be readily measured using routine analysis. At the same time, a range of PAH metabolites, persistent halogenated chemicals, insecticides, herbicides, flame retardants and other chemicals are detected (12, 15, 41, 51, 63, 78, 79). Thus, implementation of routine HRM for exposure surveillance would provide a means to address uncertainties concerning exposure.…”