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Metabolites
Special Issues
Method Development in Metabolomics and Exposomics
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Method Development in Metabolomics and Exposomics

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Bioinformatics and Data Analysis".

Deadline for manuscript submissions: closed (15 April 2025) | Viewed by 8757

Special Issue Editor

Prof. Dr. Facundo M. Fernandez

E-Mail Website
Guest Editor
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA
Interests: bioanalytical mass spectrometry; ambient sampling/ionization & molecular imaging; ion mobility spectrometry; metabolomics; pharmaceutical forensics

Special Issue Information

Dear Colleagues,

Metabolomics continues to deepen our understanding of complex biological processes and environmental influences on organisms. The Metabolomics Innovation Centre is Canada’s distributed metabolomics core facility, hosting nine principal investigators at the forefront of developing cutting-edge analytical and bioinformatic methodologies to advance the field of metabolomics. This Special Issue aims to showcase the latest research and developments in analytical techniques, bioinformatics tools, and their applications in metabolomics studies.

We invite contributions that highlight innovative approaches to metabolome and exposome analysis, including but not limited to the following:

  • The development and application of targeted or quantitative assays for reliable metabolite measurements in various biological matrices, including human serum, urine, and spinal cord tissue.
  • The development and application of untargeted or semiquantitative assays for enhanced metabolite detectability, submetabolome profiling, and complex sample analysis.
  • Explorations into lipidomics and its applications in understanding disordered biology.
  • Advanced workflows and metabolite library construction for deep metabolome/exposome annotation and interpretation.
  • Investigations into the metabolic impact of environmental exposures.

We welcome high-quality original research articles, review articles, and short communications that contribute to the advancement of metabolomics methodologies. By sharing these insights, this Special Issue aims to foster collaboration and innovation in the metabolomics community, ultimately enhancing our understanding of the metabolome, the exposome, and the role that the chemical environment plays in health and disease.

Prof. Dr. Facundo M. Fernandez
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolomics
  • exposomics
  • lipidomics
  • metabolite
  • environmental exposure

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Published Papers (6 papers)

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Research

13 pages, 764 KiB  
Article
Multiplexed Dilute-and-Shoot Liquid Chromatography–Multiple-Reaction Monitoring Mass Spectrometry Clinical Assay for Metanephrines and Catecholamines in Human Urine
by Deema O. Qasrawi, Adriano M. C. Pimenta, Evgeniy V. Petrotchenko, Shaun Eintracht and Christoph H. Borchers
Metabolites 2025, 15(1), 30; https://doi.org/10.3390/metabo15010030 - 8 Jan 2025
Viewed by 846
Abstract
Background: Quantifying urinary catecholamines and metanephrines is essential for the clinical screening and diagnosis of neuroendocrine tumours. HPLC with electrochemical detection (HPLC-ECD) is commonly used for this type of analysis but requires extensive sample cleanup. Simple and rapid dilute-and-shoot LC–multiple-reaction monitoring (MRM)-MS assays [...] Read more.
Background: Quantifying urinary catecholamines and metanephrines is essential for the clinical screening and diagnosis of neuroendocrine tumours. HPLC with electrochemical detection (HPLC-ECD) is commonly used for this type of analysis but requires extensive sample cleanup. Simple and rapid dilute-and-shoot LC–multiple-reaction monitoring (MRM)-MS assays have been developed for quantitating these analytes in urine but have not yet been validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Methods: A simple dilute-and-shoot sample preparation without derivatization was used. C18 RP-UPLC-MRM-MS and positive-ion ESI were used, usually with two transitions per analyte being monitored. Certified deuterated internal standards were used for each analyte. Results: This assay was validated according to the CLSI C62-A guidelines, including accuracy/trueness, imprecision, sensitivity, specificity, carryover, stability, and linearity. The final MRM-MS method was compared to the established HPLC-ECD clinical chemistry reference method. The run time was reduced from 25 min to 5 min. Conclusions: A simple, robust, rapid, and cost-effective LC-MRM-MS assay for measuring urinary catecholamines and metanephrines was developed and validated according to the CLSI guidelines. This validated method requires minimal sample manipulation before analysis and provides sensitivity, specificity, and improved precision. The implementation of this assay in clinical laboratories will facilitate early and accurate diagnosis. Full article
(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)
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18 pages, 7658 KiB  
Article
Comprehensive Blood Metabolome and Exposome Analysis, Annotation, and Interpretation in E-Waste Workers
by Zhiqiang Pang, Charles Viau, Julius N. Fobil, Niladri Basu and Jianguo Xia
Metabolites 2024, 14(12), 671; https://doi.org/10.3390/metabo14120671 - 2 Dec 2024
Viewed by 1114
Abstract
Background: Electronic and electrical waste (e-waste) production has emerged to be of global environmental public health concern. E-waste workers, who are frequently exposed to hazardous chemicals through occupational activities, face considerable health risks. Methods: To investigate the metabolic and exposomic changes in these [...] Read more.
Background: Electronic and electrical waste (e-waste) production has emerged to be of global environmental public health concern. E-waste workers, who are frequently exposed to hazardous chemicals through occupational activities, face considerable health risks. Methods: To investigate the metabolic and exposomic changes in these workers, we analyzed whole blood samples from 100 male e-waste workers and 49 controls from the GEOHealth II project (2017–2018 in Accra, Ghana) using LC-MS/MS. A specialized computational workflow was established for exposomics data analysis, incorporating two curated reference libraries for metabolome and exposome profiling. Two feature detection algorithms, asari and centWave, were applied. Results: In comparison to centWave, asari showed better sensitivity in detecting MS features, particularly at trace levels. Principal component analysis demonstrated distinct metabolic profiles between e-waste workers and controls, revealing significant disruptions in key metabolic pathways, including steroid hormone biosynthesis, drug metabolism, bile acid biosynthesis, vitamin metabolism, and prostaglandin biosynthesis. Correlation analyses linked metal exposures to alterations in hundreds to thousands of metabolic features. Functional enrichment analysis highlighted significant perturbations in pathways related to liver function, vitamin metabolism, linoleate metabolism, and dynorphin signaling, with the latter being observed for the first time in e-waste workers. Conclusions: This study provides new insights into the biological impact of prolonged metal exposure in e-waste workers. Full article
(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)
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13 pages, 3168 KiB  
Article
Global Lipidomics Reveals the Lipid Composition Heterogeneity of Extracellular Vesicles from Drug-Resistant Leishmania
by Sehyeon (Erica) Kim, Ana Victoria Ibarra-Meneses, Christopher Fernandez-Prada and Tao Huan
Metabolites 2024, 14(12), 658; https://doi.org/10.3390/metabo14120658 - 25 Nov 2024
Viewed by 1224
Abstract
Background: The rise of drug-resistant Leishmania strains presents a significant challenge in the treatment of Leishmaniasis, a neglected tropical disease. Extracellular vesicles (EVs) produced by these parasites have gained attention for their role in drug resistance and host–pathogen interactions. Methods: This [...] Read more.
Background: The rise of drug-resistant Leishmania strains presents a significant challenge in the treatment of Leishmaniasis, a neglected tropical disease. Extracellular vesicles (EVs) produced by these parasites have gained attention for their role in drug resistance and host–pathogen interactions. Methods: This study developed and applied a novel lipidomics workflow to explore the lipid profiles of EVs from three types of drug-resistant Leishmania infatum strains compared to a wild-type strain. EVs were isolated through ultracentrifugation, and their lipid content was extracted using a modified Matyash protocol. LC-MS analysis was performed, and data processing in MS-DIAL enabled lipid identification and quantification. Statistical analysis in MetaboAnalyst revealed strain-specific lipid alterations, highlighting potential links between lipid composition and drug resistance mechanisms. Results: Our results show distinct alterations in lipid composition associated with drug resistance. Specifically, drug-resistant strains exhibited reduced levels of phosphatidylcholine (PC) and phosphatidylglycerol (PG), particularly in the amphotericin B-resistant strain LiAmB1000.1. Sterol and glycerolipid species, including cholesteryl ester (CE) and triacylglycerol (TG) were also found to be diminished in LiAmB1000.1. These changes suggest significant lipid remodeling under drug pressure, potentially altering the biophysical properties of EV membranes and their capacity for molecule transfer. Furthermore, the lipidomic profiles of EVs from the other resistant strains, LiSb2000.1 and LiMF200.5, also displayed unique alterations, underscoring strain-specific adaptations to different drug resistance mechanisms. Conclusions: These significant alterations in lipid composition suggest potential lipid-based mechanisms underlying drug resistance in Leishmania, providing new avenues for therapeutic intervention. Full article
(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)
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13 pages, 2892 KiB  
Article
Analysis of In Vivo Plant Volatiles Using Active Sampling and TD-GC×GC-TOFMS
by Sheri A. Schmidt, Ewenet Yemane Mesfin, Chaminda De Silva Weeraddana, A. Paulina de la Mata, Alejandro C. Costamagna and James J. Harynuk
Metabolites 2024, 14(11), 623; https://doi.org/10.3390/metabo14110623 - 14 Nov 2024
Cited by 1 | Viewed by 1114
Abstract
Background: Plants constantly produce primary and secondary metabolites, and a significant fraction of these are volatile organic compounds (VOCs). Factors including the life stage of the plant, temperature, environment, and stress influence the abundance and types of VOCs emitted. The analysis of VOCs [...] Read more.
Background: Plants constantly produce primary and secondary metabolites, and a significant fraction of these are volatile organic compounds (VOCs). Factors including the life stage of the plant, temperature, environment, and stress influence the abundance and types of VOCs emitted. The analysis of VOCs released by plants during different stages or with different conditions provides insight into plant metabolism and stress responses. Collecting the VOC profiles of plants in vivo makes it possible to obtain a representative sample of the entire plant volatilome under controlled conditions with minimal invasiveness. In addition, in vivo sampling can also be used to compare the impacts of different environmental conditions or stressors on plants, i.e., the presence/absence of a pest or amount of nitrogen in soil. Methods: In this study, an in vivo plant sampling technique is introduced and validated using active sampling and thermal desorption (TD) tubes with comprehensive two-dimensional gas chromatography coupled to a time-of-flight mass spectrometer (TD-GC×GC-TOFMS). The purpose of this work is to highlight a novel technique to analyze headspace secondary plant metabolites with a minimal invasiveness. Results: It was concluded that in vivo active sampling onto TD tubes provides a wider global coverage of compounds and larger peak areas when compared to extraction by solid-phase microextraction (SPME). Additionally, the Horwitz ratio of active sampling onto TD tubes was 0.893, demonstrating this technique to be a reliable and reproducible method. Lastly, a variety of plants were sampled to assess the versatility of this technique across various plant species with different sizes and volatile profiles. Hundreds of compounds were measured with this analysis, including terpenes, aldehydes, ketones, terpenoids, and alcohols. Conclusions: This novel in vivo active sampling method provides an additional technique for extracting and analyzing volatile secondary plant metabolites. Full article
(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)
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17 pages, 2798 KiB  
Article
A Comprehensive LC–MS Metabolomics Assay for Quantitative Analysis of Serum and Plasma
by Lun Zhang, Jiamin Zheng, Mathew Johnson, Rupasri Mandal, Meryl Cruz, Miriam Martínez-Huélamo, Cristina Andres-Lacueva and David S. Wishart
Metabolites 2024, 14(11), 622; https://doi.org/10.3390/metabo14110622 - 14 Nov 2024
Viewed by 2612
Abstract
Background/Objectives: Targeted metabolomics is often criticized for the limited metabolite coverage that it offers. Indeed, most targeted assays developed or used by researchers measure fewer than 200 metabolites. In an effort to both expand the coverage and improve the accuracy of metabolite quantification [...] Read more.
Background/Objectives: Targeted metabolomics is often criticized for the limited metabolite coverage that it offers. Indeed, most targeted assays developed or used by researchers measure fewer than 200 metabolites. In an effort to both expand the coverage and improve the accuracy of metabolite quantification in targeted metabolomics, we decided to develop a comprehensive liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay that could quantitatively measure more than 700 metabolites in serum or plasma. Methods: The developed assay makes use of chemical derivatization followed by reverse phase LC–MS/MS and/or direct flow injection MS (DFI–MS) in both positive and negative ionization modes to separate metabolites. Multiple reaction monitoring (MRM), in combination with isotopic standards and multi-point calibration curves, is used to detect and absolutely quantify the targeted metabolites. The assay has been adapted to a 96-well plate format to enable automated, high-throughput sample analysis. Results: The assay (called MEGA) is able to detect and quantify 721 metabolites in serum/plasma, covering 20 metabolite classes and many commonly used clinical biomarkers. The limits of detection were determined to range from 1.4 nM to 10 mM, recovery rates were from 80% to 120%, and quantitative precision was within 20%. LC–MS/MS metabolite concentrations of the NIST® SRM®1950 plasma standard were found to be within 15% of NMR quantified levels. The MEGA assay was further validated in a large dietary intervention study. Conclusions: The MEGA assay should make comprehensive quantitative metabolomics much more affordable, accessible, automatable, and applicable to large-scale clinical studies. Full article
(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)
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13 pages, 2623 KiB  
Article
Metabolomics of Papanicolaou Tests for the Discovery of Ovarian Cancer Biomarkers
by Samyukta Sah, Elisabeth M. Schwiebert, Samuel G. Moore, Ying Liu, David A. Gaul, Kristin L. M. Boylan, Amy P. N. Skubitz and Facundo M. Fernández
Metabolites 2024, 14(11), 600; https://doi.org/10.3390/metabo14110600 - 7 Nov 2024
Viewed by 1305
Abstract
Background: Ovarian cancer (OC) remains one of the most lethal cancers among women due to most cases going undiagnosed until later stages. The early detection and treatment of this malignancy provides the best prognosis, but the lack of an accurate and sensitive [...] Read more.
Background: Ovarian cancer (OC) remains one of the most lethal cancers among women due to most cases going undiagnosed until later stages. The early detection and treatment of this malignancy provides the best prognosis, but the lack of an accurate and sensitive screening tool combined with ambiguous symptoms hinders these diagnoses. In contrast, screening for cervical cancer via Papanicolaou (Pap) tests is a widespread practice that greatly reduces the cancer’s mortality rates. Interestingly, previous studies show evidence of OC cells in Pap tests, suggesting that proteins, and potentially lipids, shed from ovarian tumors end up in the cervix. The goal of this study is to evaluate the practicality of using Pap tests as biospecimens for OC-screening-related metabolomics. Methods: To evaluate the effectiveness of using residual Pap test samples as biospecimens for potential metabolomics work, 29 Pap test samples, collected from women over the age of 50 with normal cytology and no visible blood contamination, were first obtained from the University of Minnesota, with IRB approval. These samples were centrifuged to recover the cell pellets from the supernatants. The cell pellets underwent a biphasic extraction, followed by an RP-LC-MS analysis, while the supernatants underwent two separate extractions and analyses, including RP-LC-MS and HILIC-LC-MS. Non-targeted features were detected in the range of 220–1000 m/z to determine the sensitivity and scope of the various extraction and analytical workflows, as well as evaluating residual Pap test samples as viable metabolomics biospecimens. Results: The biphasic extraction and subsequent RP-LC-MS analysis of the isolated cell pellets from all 29 samples yielded informative, exploratory data, highlighting the potential of using residual Pap test samples as biospecimens for metabolomics, specifically lipidomics, studies. Each sample was analyzed in both the positive and negative ion mode, yielding the detection of 7318 in the positive ion mode and 3733 in the negative ion mode. Using multiple reference libraries, 22.85% and 36.19% of these features were annotated in the positive and negative ion mode, respectively. Among these detected features, 453 unique lipids, representative of 20 different lipid subclasses, were annotated in all 29 samples. Of the various lipid subclasses represented from the detected lipids, ceramides, triacylglycerols, hexosylceramides, and phosphatidylcholines contributed to over half (53.3%) of the detected lipids at 16.2%, 13.0%, 12.8%, and 11.3%, respectively. Conclusions: The detection of these 453 common lipids across all patients establishes a relative lipidome baseline for women over the age of 50 with normal cervical cytology. This exploratory study is the first investigation to utilize residual Pap test samples as biospecimens in a metabolomics/lipidomics workflow. Full article
(This article belongs to the Special Issue Method Development in Metabolomics and Exposomics)
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