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Metabolites
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Toxicometabolomics
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Toxicometabolomics

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 15147

Special Issue Editors

Dr. Márcia Carvalho

E-Mail Website
Guest Editor
Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia, 4200-150 Porto, Portugal
Interests: toxicology; drugs of abuse; amphetamines; synthetic cathinones; psychoactive substances; toxicometabolomics; cancer metabolomics; biomarkers; hepatotoxicity; nephrotoxicity; cardiotoxicity; oxidative stress
Special Issues, Collections and Topics in MDPI journals
Dr. Ana Margarida Araújo

E-Mail Website
Guest Editor
UCIBIO/REQUIMTE, Department of Biological Sciences, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal
Interests: toxicology; toxicometabolomics; hepatotoxicity; drugs of abuse; GC-MS
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent technological developments in metabolomics have created a whole new avenue of opportunities to address current gaps and challenges in the safety assessment of chemicals with potential impact on human health. Toxicometabolomics, a rapidly emerging branch of metabolomics, has proven to be a powerful tool to evaluate the mode of action and toxicological effects of multiple challenging conditions. By using a toxicometabolomics approach, it is possible to detect dynamic variations in the identity and quantity of low-molecular-weight compounds (metabolites) in a biological system in response to a specific stimulus (e.g., xenobiotics), allowing a more comprehensive understanding of the biochemical mechanisms disrupted by the challenge under study and, thus, providing new insights into the cellular and organ-specific pathways of toxicity. Moreover, in vitro and in vivo metabolomic studies have shown that this approach allows the assessment of adverse effects at a very early stage, demonstrating to be a more sensitive tool than traditional toxicological studies in understanding specific toxicological outcomes and mechanisms of action.

Toxicometabolomic potentialities have been widely applied in the study of several xenobiotics such as anticancer drugs, analgesics, pesticides, drugs of abuse, chemical carcinogens, antibiotics, and nanomaterials, among others.

This Special Issue of Metabolites on “Toxicometabolomics” will be dedicated to recent metabolomic applications in the field of toxicological research, including in the mapping of toxicity-related pathways and consequently in the understanding of the modes of action of xenobiotics, in the screening of drug-induced cellular or organ toxicity, in the construction of toxicity prediction models, in the safety assessment of new drugs, and in the discovery of new injury biomarkers. Original research articles or review papers covering these topics are highly welcomed, and we would like to invite you to contribute to this Special Issue, which will be of great value to all researchers working in this field.

Prof. Dr. Márcia Carvalho
Dr. Ana Margarida Araújo
Guest Editors

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
  • Safety assessment
  • Toxicometabolomics
  • Mechanisms of toxicity
  • Injury biomarkers
  • Xenobiotics
  • Metabolic pathways

Published Papers (5 papers)

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Research

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17 pages, 4900 KiB  
Article
Comparative Metabolomics Study of the Impact of Articaine and Lidocaine on the Metabolism of SH-SY5Y Neuronal Cells
by Gustavo H. Rodrigues da Silva, Luís F. Mendes, Fabíola V. de Carvalho, Eneida de Paula and Iola F. Duarte
Metabolites 2022, 12(7), 581; https://doi.org/10.3390/metabo12070581 - 23 Jun 2022
Cited by 5 | Viewed by 2190
Abstract
Articaine (ATC) and lidocaine (LDC) are the local anesthetics (LAs) currently most employed in dentistry. Cases of paresthesia, reported more frequently for ATC, have raised concerns about their potential neurotoxicity, calling for further investigation of their biological effects in neuronal cells. In this [...] Read more.
Articaine (ATC) and lidocaine (LDC) are the local anesthetics (LAs) currently most employed in dentistry. Cases of paresthesia, reported more frequently for ATC, have raised concerns about their potential neurotoxicity, calling for further investigation of their biological effects in neuronal cells. In this work, the impact of ATC and LDC on the metabolism of SH-SY5Y cells was investigated through 1H NMR metabolomics. For each LA, in vitro cultured cells were exposed to concentrations causing 10 and 50% reductions in cell viability, and their metabolic intracellular and extracellular profiles were characterized. Most effects were common to ATC and LDC, although with varying magnitudes. The metabolic variations elicited by the two LAs suggested (i) downregulation of glycolysis and of glucose-dependent pathways (e.g., one-carbon metabolism and hexosamine biosynthetic pathway), (ii) disturbance of branched chain amino acids (BCAA) catabolism, (iii) downregulation of TCA cycle anaplerotic fueling and activation of alternative energy producing pathways, (iv) interference with choline metabolism and (v) lipid droplet build-up. Interestingly, LDC had a greater impact on membrane phospholipid turnover, as suggested by higher phosphatidylcholine to phosphocholine conversion. Moreover, LDC elicited an increase in triglycerides, whereas cholesteryl esters accumulated in ATC-exposed cells, suggesting a different composition and handling of lipid droplets. Full article
(This article belongs to the Special Issue Toxicometabolomics)
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26 pages, 5016 KiB  
Article
HBM4EU Chromates Study: Urinary Metabolomics Study of Workers Exposed to Hexavalent Chromium
by Lucyna Kozłowska, Tiina Santonen, Radu Corneliu Duca, Lode Godderis, Karolina Jagiello, Beata Janasik, An Van Nieuwenhuyse, Katrien Poels, Tomasz Puzyn, Paul T. J. Scheepers, Monika Sijko, Maria João Silva, Anita Sosnowska, Susana Viegas, Jelle Verdonck, Wojciech Wąsowicz, on behalf of HBM4EU Chromates Study Team and on behalf of Statistical Team
Metabolites 2022, 12(4), 362; https://doi.org/10.3390/metabo12040362 - 18 Apr 2022
Cited by 6 | Viewed by 2980
Abstract
Exposure to hexavalent chromium Cr(VI) may occur in several occupational activities, placing workers in many industries at risk for potential related health outcomes. Untargeted metabolomics was applied to investigate changes in metabolic pathways in response to Cr(VI) exposure. We obtained our data from [...] Read more.
Exposure to hexavalent chromium Cr(VI) may occur in several occupational activities, placing workers in many industries at risk for potential related health outcomes. Untargeted metabolomics was applied to investigate changes in metabolic pathways in response to Cr(VI) exposure. We obtained our data from a study population of 220 male workers with exposure to Cr(VI) and 102 male controls from Belgium, Finland, Poland, Portugal and the Netherlands within the HBM4EU Chromates Study. Urinary metabolite profiles were determined using liquid chromatography mass spectrometry, and differences between post-shift exposed workers and controls were analyzed using principal component analysis. Based on the first two principal components, we observed clustering by industrial chromate application, such as welding, chrome plating, and surface treatment, distinct from controls and not explained by smoking status or alcohol use. The changes in the abundancy of excreted metabolites observed in workers reflect fatty acid and monoamine neurotransmitter metabolism, oxidative modifications of amino acid residues, the excessive formation of abnormal amino acid metabolites and changes in steroid and thyrotropin-releasing hormones. The observed responses could also have resulted from work-related factors other than Cr(VI). Further targeted metabolomics studies are needed to better understand the observed modifications and further explore the suitability of urinary metabolites as early indicators of adverse effects associated with exposure to Cr(VI). Full article
(This article belongs to the Special Issue Toxicometabolomics)
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12 pages, 2450 KiB  
Article
An Analysis of the Serum Metabolomic Profile for the Radiomitigative Effect of the Thrombopoietin Receptor Agonist Romiplostim in Lethally Whole-Body-Irradiated Mice
by Yoshiaki Sato, Masaru Yamaguchi and Ikuo Kashiwakura
Metabolites 2022, 12(2), 161; https://doi.org/10.3390/metabo12020161 - 08 Feb 2022
Cited by 3 | Viewed by 1895
Abstract
The thrombopoietin receptor agonist romiplostim (RP) was recently approved by the US Food and Drug Administration for improving survival in patients acutely exposed to myelosuppressive doses of radiation. Our previous studies with mice have shown that RP administration after lethal irradiation not only [...] Read more.
The thrombopoietin receptor agonist romiplostim (RP) was recently approved by the US Food and Drug Administration for improving survival in patients acutely exposed to myelosuppressive doses of radiation. Our previous studies with mice have shown that RP administration after lethal irradiation not only completely rescues irradiated mice but also shows mitigative effects on their hematopoiesis and multiple organ injury, including that of the lung, bone marrow, small intestine, and liver. However, the mechanism by which RP functions as a radiomitigator remains unclear. In the present study, we applied a metabolomics approach, which has the ability to reflect the status of an organism directly and accurately, helping to elucidate the biology of treatment responses. Our results showed that the disruption of several metabolites and pathways in response to total body irradiation was partially corrected by RP administration. Notably, RP-corrected metabolites and pathways have been reported to be indicators of DNA damage and lung, bone marrow, small intestine, and liver injury. Taken together, the present findings suggested that the radiomitigative effect of RP is partially involved in the recovery of organ injury, and the identified metabolites may be a useful biomarker of the survival likelihood following radiation exposure. Full article
(This article belongs to the Special Issue Toxicometabolomics)
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20 pages, 2247 KiB  
Article
An Extensive Metabolomics Workflow to Discover Cardiotoxin-Induced Molecular Perturbations in Microtissues
by Tara J. Bowen, Andrew R. Hall, Gavin R. Lloyd, Ralf J. M. Weber, Amanda Wilson, Amy Pointon and Mark R. Viant
Metabolites 2021, 11(9), 644; https://doi.org/10.3390/metabo11090644 - 21 Sep 2021
Cited by 3 | Viewed by 2648
Abstract
Discovering modes of action and predictive biomarkers of drug-induced structural cardiotoxicity offers the potential to improve cardiac safety assessment of lead compounds and enhance preclinical to clinical translation during drug development. Cardiac microtissues are a promising, physiologically relevant, in vitro model, each composed [...] Read more.
Discovering modes of action and predictive biomarkers of drug-induced structural cardiotoxicity offers the potential to improve cardiac safety assessment of lead compounds and enhance preclinical to clinical translation during drug development. Cardiac microtissues are a promising, physiologically relevant, in vitro model, each composed of ca. 500 cells. While untargeted metabolomics is capable of generating hypotheses on toxicological modes of action and discovering metabolic biomarkers, applying this technology to low-biomass microtissues in suspension is experimentally challenging. Thus, we first evaluated a filtration-based approach for harvesting microtissues and assessed the sensitivity and reproducibility of nanoelectrospray direct infusion mass spectrometry (nESI-DIMS) measurements of intracellular extracts, revealing samples consisting of 28 pooled microtissues, harvested by filtration, are suitable for profiling the intracellular metabolome and lipidome. Subsequently, an extensive workflow combining nESI-DIMS untargeted metabolomics and lipidomics of intracellular extracts with ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) analysis of spent culture medium, to profile the metabolic footprint and quantify drug exposure concentrations, was implemented. Using the synthetic drug and model cardiotoxin sunitinib, time-resolved metabolic and lipid perturbations in cardiac microtissues were investigated, providing valuable data for generating hypotheses on toxicological modes of action and identifying putative biomarkers such as disruption of purine metabolism and perturbation of polyunsaturated fatty acid levels. Full article
(This article belongs to the Special Issue Toxicometabolomics)
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Review

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31 pages, 2000 KiB  
Review
Toxicometabolomics: Small Molecules to Answer Big Toxicological Questions
by Ana Margarida Araújo, Félix Carvalho, Paula Guedes de Pinho and Márcia Carvalho
Metabolites 2021, 11(10), 692; https://doi.org/10.3390/metabo11100692 - 09 Oct 2021
Cited by 20 | Viewed by 3673
Abstract
Given the high biological impact of classical and emerging toxicants, a sensitive and comprehensive assessment of the hazards and risks of these substances to organisms is urgently needed. In this sense, toxicometabolomics emerged as a new and growing field in life sciences, which [...] Read more.
Given the high biological impact of classical and emerging toxicants, a sensitive and comprehensive assessment of the hazards and risks of these substances to organisms is urgently needed. In this sense, toxicometabolomics emerged as a new and growing field in life sciences, which use metabolomics to provide new sets of susceptibility, exposure, and/or effects biomarkers; and to characterize in detail the metabolic responses and altered biological pathways that various stressful stimuli cause in many organisms. The present review focuses on the analytical platforms and the typical workflow employed in toxicometabolomic studies, and gives an overview of recent exploratory research that applied metabolomics in various areas of toxicology. Full article
(This article belongs to the Special Issue Toxicometabolomics)
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