Special Issue "Adductomics: Elucidating the Environmental Causes of Disease"

A special issue of High-Throughput (ISSN 2571-5135).

Deadline for manuscript submissions: closed (31 March 2019).

Special Issue Editors

Prof. Alexandra Antunes
E-Mail Website
Guest Editor
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
Interests: protein covalent adducts; adductomics, chemical toxicology; mechanisms of chemically-induced cancer; drug-induced adverse effects; metabolic pathways of endogenous and exogenous chemicals; mass spectrometry; biomimetic catalysts; sythetic organic chemistry tools for toxicology studies
Prof. Sofia A. Pereira
E-Mail
Guest Editor
CEDOC, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-006 Lisboa, Portugal

Special Issue Information

Dear Colleagues,

It is widely accepted that cumulative exposure to chemical agents from diet, medication and environmental sources leads to a wide range of deleterious health outcomes, including adverse drug events, cancer, cardiovascular, respiratory, neurologic and autoimmune diseases. Therefore, investigating exposure-related adverse health outcomes and their underlying mechanisms is currently a major societal challenge.

Bioactivation is one of the most frequent events at the onset of chemically-induced toxicity. Indeed, chemicals are frequently metabolized to reactive (primarily electrophilic) species capable of reacting with biomacromolecules to afford covalent protein, peptides and DNA adducts. Once formed, these adducts may elicit direct cell toxicity, trigger an immune response, and/or initiate mutagenic/carcinogenic processes. Additionally, external exposure can also interfere with the metabolism of endogenous compounds, leading to dysregulation of biological processes which can be on the onset of multiple diseases via the formation of covalent adducts. In fact, reactive electrophiles of endogenous or exogenous sources constitute an important but understudied class of human exposures. One of main challenge to investigate reactive metabolites is their short-life, preventing direct detection. However, exposure to reactive electrophiles can be characterized by adductomics tools: identification and quantification of covalent adducts from reactions between electrophiles and bionucleophiles (DNA, peptides or proteins). Adductomics is a powerful tool to link exposure with the occurrence of diseases, constituting an opportunity for the identification of risk factors, molecular mechanisms of adverse outcomes and biomarkers for early disease diagnosis. Additionally, adductomics can guide regulatory and preventive actions, thereby leading to the minimization of exposure-related health adverse outcomes.

This Special Issue on “Adductomics” will focus on the state-of-the-art of this emerging field that puts together human exposure and disease. However, the successful understanding of this linkage implies to overcome technological challenges and investigate the multiple applications of adductomics. There are still several open questions in this field, including the contribution of endogenous and exogenous electrophilic metabolites, the identification of adequate translational models to identify mechanisms linking adductomics-disease and the usefulness of covalent adducts as biomarkers of effect. Manuscripts addressing these issues are welcome.

Prof. Alexandra Antunes
Prof. Sofia A. Pereira
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 papers will be 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. High-Throughput is an international peer-reviewed open access quarterly 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 1000 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

  • Adductome
  • Bioactivation
  • Biomarkers of exposure
  • Biomarkers of disease
  • Covalent adducts
  • Electrophilic species
  • Exposome
  • Mass spectrometry
  • Human biomonitoring
  • Reactive metabolites

Published Papers (6 papers)

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Editorial

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Open AccessEditorial
Special Issue “Adductomics: Elucidating the Environmental Causes of Disease”
High-Throughput 2019, 8(3), 17; https://doi.org/10.3390/ht8030017 - 31 Jul 2019
Abstract
Adductomics studies represent effective tools for providing additional insights into how exposure to reactive metabolites can underlie disease mechanisms. This special issue is focused not only on summarizing the analytical methodologies used for DNA, protein, and mercapturic acid adductomics tools but also on [...] Read more.
Adductomics studies represent effective tools for providing additional insights into how exposure to reactive metabolites can underlie disease mechanisms. This special issue is focused not only on summarizing the analytical methodologies used for DNA, protein, and mercapturic acid adductomics tools but also on highlighting the opportunities and challenges for the application of this type of studies in biomedical research. Full article
(This article belongs to the Special Issue Adductomics: Elucidating the Environmental Causes of Disease)

Research

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Open AccessFeature PaperArticle
The Adductomics of Isolevuglandins: Oxidation of IsoLG Pyrrole Intermediates Generates Pyrrole–Pyrrole Crosslinks and Lactams
High-Throughput 2019, 8(2), 12; https://doi.org/10.3390/ht8020012 - 10 May 2019
Cited by 2
Abstract
Isoprostane endoperoxides generated by free radical-induced oxidation of arachidonates, and prostaglandin endoperoxides generated through enzymatic cyclooxygenation of arachidonate, rearrange nonenzymatically to isoprostanes and a family of stereo and structurally isomeric γ-ketoaldehyde seco-isoprostanes, collectively known as isolevuglandins (isoLGs). IsoLGs are stealthy toxins, and free [...] Read more.
Isoprostane endoperoxides generated by free radical-induced oxidation of arachidonates, and prostaglandin endoperoxides generated through enzymatic cyclooxygenation of arachidonate, rearrange nonenzymatically to isoprostanes and a family of stereo and structurally isomeric γ-ketoaldehyde seco-isoprostanes, collectively known as isolevuglandins (isoLGs). IsoLGs are stealthy toxins, and free isoLGs are not detected in vivo. Rather, covalent adducts are found to incorporate lysyl ε-amino residues of proteins or ethanolamino residues of phospholipids. In vitro studies have revealed that adduction occurs within seconds and is uniquely prone to cause protein–protein crosslinks. IsoLGs accelerate the formation of the type of amyloid beta oligomers that have been associated with neurotoxicity. Under air, isoLG-derived pyrroles generated initially are readily oxidized to lactams and undergo rapid oxidative coupling to pyrrole–pyrrole crosslinked dimers, and to more highly oxygenated derivatives of those dimers. We have now found that pure isoLG-derived pyrroles, which can be generated under anoxic conditions, do not readily undergo oxidative coupling. Rather, dimer formation only occurs after an induction period by an autocatalytic oxidative coupling. The stable free-radical TEMPO abolishes the induction period, catalyzing rapid oxidative coupling. The amine N-oxide TMAO is similarly effective in catalyzing the oxidative coupling of isoLG pyrroles. N-acetylcysteine abolishes the generation of pyrrole–pyrrole crosslinks. Instead pyrrole-cysteine adducts are produced. Two unified single-electron transfer mechanisms are proposed for crosslink and pyrrole-cysteine adduct formation from isoLG-pyrroles, as well as for their oxidation to lactams and hydroxylactams. Full article
(This article belongs to the Special Issue Adductomics: Elucidating the Environmental Causes of Disease)
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Review

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Open AccessFeature PaperReview
Emerging Technologies in Mass Spectrometry-Based DNA Adductomics
High-Throughput 2019, 8(2), 13; https://doi.org/10.3390/ht8020013 - 14 May 2019
Cited by 2
Abstract
The measurement of DNA adducts, the covalent modifications of DNA upon the exposure to the environmental and dietary genotoxicants and endogenously produced electrophiles, provides molecular evidence for DNA damage. With the recent improvements in the sensitivity and scanning speed of mass spectrometry (MS) [...] Read more.
The measurement of DNA adducts, the covalent modifications of DNA upon the exposure to the environmental and dietary genotoxicants and endogenously produced electrophiles, provides molecular evidence for DNA damage. With the recent improvements in the sensitivity and scanning speed of mass spectrometry (MS) instrumentation, particularly high-resolution MS, it is now feasible to screen for the totality of DNA damage in the human genome through DNA adductomics approaches. Several MS platforms have been used in DNA adductomic analysis, each of which has its strengths and limitations. The loss of 2′-deoxyribose from the modified nucleoside upon collision-induced dissociation is the main transition feature utilized in the screening of DNA adducts. Several advanced data-dependent and data-independent scanning techniques originated from proteomics and metabolomics have been tailored for DNA adductomics. The field of DNA adductomics is an emerging technology in human exposure assessment. As the analytical technology matures and bioinformatics tools become available for analysis of the MS data, DNA adductomics can advance our understanding about the role of chemical exposures in DNA damage and disease risk. Full article
(This article belongs to the Special Issue Adductomics: Elucidating the Environmental Causes of Disease)
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Open AccessFeature PaperReview
Mass Spectrometry-Based Methodologies for Targeted and Untargeted Identification of Protein Covalent Adducts (Adductomics): Current Status and Challenges
High-Throughput 2019, 8(2), 9; https://doi.org/10.3390/ht8020009 - 23 Apr 2019
Cited by 4
Abstract
Protein covalent adducts formed upon exposure to reactive (mainly electrophilic) chemicals may lead to the development of a wide range of deleterious health outcomes. Therefore, the identification of protein covalent adducts constitutes a huge opportunity for a better understanding of events underlying diseases [...] Read more.
Protein covalent adducts formed upon exposure to reactive (mainly electrophilic) chemicals may lead to the development of a wide range of deleterious health outcomes. Therefore, the identification of protein covalent adducts constitutes a huge opportunity for a better understanding of events underlying diseases and for the development of biomarkers which may constitute effective tools for disease diagnosis/prognosis, for the application of personalized medicine approaches and for accurately assessing human exposure to chemical toxicants. The currently available mass spectrometry (MS)-based methodologies, are clearly the most suitable for the analysis of protein covalent modifications, providing accuracy, sensitivity, unbiased identification of the modified residue and conjugates along with quantitative information. However, despite the huge technological advances in MS instrumentation and bioinformatics tools, the identification of low abundant protein covalent adducts is still challenging. This review is aimed at summarizing the MS-based methodologies currently used for the identification of protein covalent adducts and the strategies developed to overcome the analytical challenges, involving not only sample pre-treatment procedures but also distinct MS and data analysis approaches. Full article
(This article belongs to the Special Issue Adductomics: Elucidating the Environmental Causes of Disease)
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Open AccessReview
The Mercapturomic Profile of Health and Non-Communicable Diseases
High-Throughput 2019, 8(2), 10; https://doi.org/10.3390/ht8020010 - 23 Apr 2019
Cited by 3
Abstract
The mercapturate pathway is a unique metabolic circuitry that detoxifies electrophiles upon adducts formation with glutathione. Since its discovery over a century ago, most of the knowledge on the mercapturate pathway has been provided from biomonitoring studies on environmental exposure to toxicants. However, [...] Read more.
The mercapturate pathway is a unique metabolic circuitry that detoxifies electrophiles upon adducts formation with glutathione. Since its discovery over a century ago, most of the knowledge on the mercapturate pathway has been provided from biomonitoring studies on environmental exposure to toxicants. However, the mercapturate pathway-related metabolites that is formed in humans—the mercapturomic profile—in health and disease is yet to be established. In this paper, we put forward the hypothesis that these metabolites are key pathophysiologic factors behind the onset and development of non-communicable chronic inflammatory diseases. This review goes from the evidence in the formation of endogenous metabolites undergoing the mercapturate pathway to the methodologies for their assessment and their association with cancer and respiratory, neurologic and cardiometabolic diseases. Full article
(This article belongs to the Special Issue Adductomics: Elucidating the Environmental Causes of Disease)
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Open AccessFeature PaperReview
Protein Adductomics: Methodologies for Untargeted Screening of Adducts to Serum Albumin and Hemoglobin in Human Blood Samples
High-Throughput 2019, 8(1), 6; https://doi.org/10.3390/ht8010006 - 08 Mar 2019
Cited by 6
Abstract
The reaction products of electrophiles in vivo can be measured as adducts to the abundant proteins, hemoglobin (Hb), and human serum albumin (HSA), in human blood samples. During the last decade, methods for untargeted screening of such adducts, called “adductomics”, have used liquid [...] Read more.
The reaction products of electrophiles in vivo can be measured as adducts to the abundant proteins, hemoglobin (Hb), and human serum albumin (HSA), in human blood samples. During the last decade, methods for untargeted screening of such adducts, called “adductomics”, have used liquid chromatography-mass spectrometry to detect large numbers of previously unknown Hb and HSA adducts. This review presents methodologies that were developed and used in our laboratories for Hb and HSA adductomics, respectively. We discuss critical aspects regarding choice of target protein, sample preparation, mass spectrometry, data evaluation, and strategies for identification of detected unknown adducts. With this review we give an overview of these two methodologies used for protein adductomics and the precursor electrophiles that have been elucidated from the adducts. Full article
(This article belongs to the Special Issue Adductomics: Elucidating the Environmental Causes of Disease)
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