Untargeted metabolomics approaches to improve casework in clinical and forensic toxicology—“Where are we standing and where are we heading?”

Steuer, Andrea E.; Brockbals, Lana; Kræmer, Thomas

doi:10.1002/wfs2.1449

Cited by 13 publications

(5 citation statements)

References 178 publications

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“…Each step of a common untargeted metabolome workflow (pre-analytics, analytics, data processing and interpretation) should be as stringent as possible and thoroughly documented. This figure and the legend were taken from the open access article [ 65 ] distributed under the terms of the Creative Commons CC BY license.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics of Human Semen: A Review of Different Analytical Methods to Unravel Biomarkers for Male Fertility Disorders

Blaurock

Baumann

Grunewald

et al. 2022

IJMS

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Background: Human life without sperm is not possible. Therefore, it is alarming that the fertilizing ability of human spermatozoa is continuously decreasing. The reasons for that are widely unknown, but there is hope that metabolomics-based investigations may be able to contribute to overcoming this problem. This review summarizes the attempts made so far. Methods: We will discuss liquid chromatography–mass spectrometry (LC-MS), gas chromatography (GC), infrared (IR) and Raman as well as nuclear magnetic resonance (NMR) spectroscopy. Almost all available studies apply one of these methods. Results: Depending on the methodology used, different compounds can be detected, which is (in combination with sophisticated methods of bioinformatics) helpful to estimate the state of the sperm. Often, but not in all cases, there is a correlation with clinical parameters such as the sperm mobility. Conclusions: LC-MS detects the highest number of metabolites and can be considered as the method of choice. Unfortunately, the reproducibility of some studies is poor, and, thus, further improvements of the study designs are needed to overcome this problem. Additionally, a stronger focus on the biochemical consequences of the altered metabolite concentrations is also required.

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Section: Discussionmentioning

confidence: 99%

Metabolomics of Human Semen: A Review of Different Analytical Methods to Unravel Biomarkers for Male Fertility Disorders

Blaurock

Baumann

Grunewald

et al. 2022

IJMS

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“…However, recently developed non-targeted analysis (NTA) methods now allow for the simultaneous identification of many chemicals in a given sample ( Sobus et al, 2018 ). These methods can be used to enhance studies of xenobiotic metabolism via identification of novel metabolites ( Steuer et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Identifying xenobiotic metabolites with in silico prediction tools and LCMS suspect screening analysis

Boyce

Favela²,

Bonzo³

et al. 2023

Front. Toxicol.

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Understanding the metabolic fate of a xenobiotic substance can help inform its potential health risks and allow for the identification of signature metabolites associated with exposure. The need to characterize metabolites of poorly studied or novel substances has shifted exposure studies towards non-targeted analysis (NTA), which often aims to profile many compounds within a sample using high-resolution liquid-chromatography mass-spectrometry (LCMS). Here we evaluate the suitability of suspect screening analysis (SSA) liquid-chromatography mass-spectrometry to inform xenobiotic chemical metabolism. Given a lack of knowledge of true metabolites for most chemicals, predictive tools were used to generate potential metabolites as suspect screening lists to guide the identification of selected xenobiotic substances and their associated metabolites. Thirty-three substances were selected to represent a diverse array of pharmaceutical, agrochemical, and industrial chemicals from Environmental Protection Agency’s ToxCast chemical library. The compounds were incubated in a metabolically-active in vitro assay using primary hepatocytes and the resulting supernatant and lysate fractions were analyzed with high-resolution LCMS. Metabolites were simulated for each compound structure using software and then combined to serve as the suspect screening list. The exact masses of the predicted metabolites were then used to select LCMS features for fragmentation via tandem mass spectrometry (MS/MS). Of the starting chemicals, 12 were measured in at least one sample in either positive or negative ion mode and a subset of these were used to develop the analysis workflow. We implemented a screening level workflow for background subtraction and the incorporation of time-varying kinetics into the identification of likely metabolites. We used haloperidol as a case study to perform an in-depth analysis, which resulted in identifying five known metabolites and five molecular features that represent potential novel metabolites, two of which were assigned discrete structures based on in silico predictions. This workflow was applied to five additional test chemicals, and 15 molecular features were selected as either reported metabolites, predicted metabolites, or potential metabolites without a structural assignment. This study demonstrates that in some–but not all–cases, suspect screening analysis methods provide a means to rapidly identify and characterize metabolites of xenobiotic chemicals.

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“…Application of (un)targeted metabolomics approaches, a strategy that aims at the simultaneous analysis and identification of a large variety of different small molecular weight compounds (<1000 Da) from endogenous and exogenous origin, gained interest in GHB research. Initial studies focused on biological pathways and mechanisms of GHB's drug action, 16–21 moving to the search for new biomarkers of its consumption 20,22–25 . Applying such untargeted metabolome strategies either by high‐resolution MS or nuclear magnetic resonance (NMR) revealed changes in endogenous compounds such as diyhdroxybutyric acid (DHB), glycolate (GA), GA‐taurine conjugate, SA, or succinylcarnitine 18,20,23,25 .…”

Section: Introductionmentioning

confidence: 99%

“…Initial studies focused on biological pathways and mechanisms of GHB's drug action, [16][17][18][19][20][21] moving to the search for new biomarkers of its consumption. 20,[22][23][24][25] Applying such untargeted metabolome strategies either by high-resolution MS or nuclear magnetic resonance (NMR) revealed changes in endogenous compounds such as diyhdroxybutyric acid (DHB), glycolate (GA), GAtaurine conjugate, SA, or succinylcarnitine. 18,20,23,25 Also based on former targeted findings of elevated concentrations of 2,4-and 3,4-DHB, 26,27 these organic acids, resulting either from GHB's initial degradation to SSA or its beta-oxidation, gained attention as additional markers for GHB detection.…”

mentioning

confidence: 99%

New gamma‐hydroxybutyric acid (GHB) biomarkers: Development and validation of a liquid chromatography–tandem mass spectrometry method for the determination of GHB amino acid, carnitine, and fatty acid conjugates in urine

Steuer

Sutter

Kræmer

2023

Drug Testing and Analysis

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Gamma‐hydroxybutyric acid (GHB) represents an important drug in clinical and forensic toxicology, particularly in the context of drug‐facilitated crimes. Analytically, GHB remains a major challenge given its endogenous occurrence and short detection window. Previous studies identified a number of potential interesting novel conjugates of GHB with carnitine, amino acids (AA, glutamate, glycine, and taurine), or fatty acids. As a basis for comprehensive studies on the suitability of these novel biomarkers, we developed and validated a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method in human urine. Additionally, already known markers 2,4‐dihydroxy butyric acid (2,4‐DHB), 3,4‐DHB, glycolic acid, succinic acid, succinylcarnitine, and GHB glucuronide were included. The method was fully validated according to (inter)national guidelines. Synthetic urine proved suitable as a surrogate matrix for calibration. Matrix effects were observed for all analytes with suppression effects of about 50% at QC LOW, and approximately 20% to 40% at QC HIGH, but with consistent standard deviation of <25% at QC LOW and <15% at QC HIGH, respectively. All analytes showed acceptable intra‐ and inter‐day imprecision of below 20%, except for inter‐day variation of GHB taurine and FA conjugates at the lowest QC. Preliminary applicability studies proved the usefulness of the method and pointed towards GHB glycine, followed by other AA conjugates as the most promising candidates to improve GHB detection. FA conjugates were not detected in urine samples yet. The method can be used now for comprehensive sample analysis on (controlled) GHB administration to prove the usefulness of the novel GHB biomarkers.

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Untargeted metabolomics approaches to improve casework in clinical and forensic toxicology—“Where are we standing and where are we heading?”

Cited by 13 publications

References 178 publications

Metabolomics of Human Semen: A Review of Different Analytical Methods to Unravel Biomarkers for Male Fertility Disorders

Metabolomics of Human Semen: A Review of Different Analytical Methods to Unravel Biomarkers for Male Fertility Disorders

Identifying xenobiotic metabolites with in silico prediction tools and LCMS suspect screening analysis

New gamma‐hydroxybutyric acid (GHB) biomarkers: Development and validation of a liquid chromatography–tandem mass spectrometry method for the determination of GHB amino acid, carnitine, and fatty acid conjugates in urine

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