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Tang MK, Ostlund T, Dameh NF, Alcheva A, Cohen JD, Hegeman AD, Carmella SG, Stepanov I, Hecht SS. Reactions of [13C]-labelled tobacco smoke with DNA to generate selected adducts formed without metabolic activation. Carcinogenesis 2025; 46:bgaf008. [PMID: 40036216 PMCID: PMC12035816 DOI: 10.1093/carcin/bgaf008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 02/17/2025] [Accepted: 02/24/2025] [Indexed: 03/06/2025] Open
Abstract
DNA adducts are central in the carcinogenic process because they can cause miscoding leading to permanent mutations in important genes involved in carcinogenesis. While it is known that tobacco smoking leads to increased levels of multiple DNA adducts, most DNA adducts detected to date in humans cannot be explicitly attributed to smoking but instead have various possible exogenous and endogenous sources. We plan to probe the tobacco source of DNA adducts by providing carbon-13 labelled ([13C]-labelled) cigarettes to smokers and analyzing [13C]-labelled DNA adducts in their oral cells to determine which adducts arise from smoking. Prior to conducting studies in humans, we first report here proof-of-principle machine smoking experiments to evaluate carbon isotopologues of (a) selected carbonyls and (b) DNA adducts resulting from direct exposure of cigarette smoke vapour-phase to calf-thymus DNA. The smoke of the study cigarettes, made from a 50:50 mixture of [13C]-labelled tobacco and a popular commercial tobacco, yielded similar concentrations of carbonyl compounds and their respective DNA adducts compared with the smoke of 1R6F reference cigarettes and the popular brand of cigarettes. We detected [13C]-isotopologues of DNA adducts such as 1,N6-etheno-dA, (8R/S)-3-(2'-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dG), and (6S,8S and 6R,8R)-3-(2'-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)-one [(6S,8S)-γ-OH-Cro-dG and (6R,8R)-γ-OH-Cro-dG], proving that they have a direct source from tobacco smoke and providing important new insights regarding their mechanisms of formation. These unique results form the basis for further studies in cell culture and in cigarette smokers to establish how carcinogens in tobacco smoke cause DNA adduct formation.
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Affiliation(s)
- Mei-Kuen Tang
- Masonic Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, United States
- Graduate Program in Molecular Pharmacology and Therapeutics, University of Minnesota, 321 Chruch Street Southeast, Minneapolis, MN 55455, United States
| | - Trevor Ostlund
- Masonic Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, United States
| | - Nour F Dameh
- Masonic Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, United States
| | - Aleksandra Alcheva
- Masonic Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, United States
| | - Jerry D Cohen
- Department of Horticultural Science and the Microbial and Plant Genomics Institute, University of Minnesota, 1970 Folwell Avenue, Saint Paul, Minnesota 55108, United States
| | - Adrian D Hegeman
- Department of Horticultural Science and the Microbial and Plant Genomics Institute, University of Minnesota, 1970 Folwell Avenue, Saint Paul, Minnesota 55108, United States
| | - Steven G Carmella
- Masonic Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, United States
| | - Irina Stepanov
- Masonic Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, United States
| | - Stephen S Hecht
- Masonic Cancer Center, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455, United States
- Graduate Program in Molecular Pharmacology and Therapeutics, University of Minnesota, 321 Chruch Street Southeast, Minneapolis, MN 55455, United States
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2
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Sarmini L, Kitsera N, Meabed M, Khobta A. Transcription blocking properties and transcription-coupled repair of N 2-alkylguanine adducts as a model for aldehyde-induced DNA damage. J Biol Chem 2025; 301:108459. [PMID: 40157541 PMCID: PMC12051148 DOI: 10.1016/j.jbc.2025.108459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 02/15/2025] [Accepted: 03/23/2025] [Indexed: 04/01/2025] Open
Abstract
The N2 position of guanine is a preferential reaction site in DNA for numerous dietary and environmental carcinogens or their electrophilic metabolites, aldehydes arising from lipid peroxidation as well as reactive by-products of normal metabolism. However, DNA repair mechanisms of the resulting covalent adducts in mammalian cells are not well understood, with nucleotide excision repair (NER), base excision repair, and a dioxygenase-mediated damage reversal being discussed as likely pathways. Considering fundamentally different damage recognition principles between the global genome NER and the transcription-coupled (TC)-NER, we here assessed transcription blocking capacities of four synthetic deoxyguanosine (dGuo) adducts of variable size and geometry, using a transfection-based reporter assay. Notably, adducts as different as the aliphatic N2-ethylguanine, the exocyclic 1,N2-ethenoguanine, and the bulky polycyclic 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene, displayed robust DNA strand-specific transcription-blocking properties. The specific TC-NER components ERCC8/CSA and ERCC6/CSB were consistently required for the removal of all transcription-blocking N2-dGuo adducts, whereas the absence of XPC or DDB2/XPE (both specific to global genome NER) did not compromise the repair capacities in the isogenic human cell models. In contrast, no inhibition of the gene expression was detected for reporter constructs carrying N2-methylguanine even in the NER-deficient XP-A cell line, suggesting that this adduct is either bypassed with very high efficiency during transcription or repaired by a mechanism different from NER. Collectively, the results identify N2-dGuo adducts bigger than methylguanine as a structural subclass of transcription-blocking DNA lesions whose repair heavily relies on the TC-NER pathway.
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Affiliation(s)
- Leen Sarmini
- Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
| | - Nataliya Kitsera
- Institute of Toxicology, University Medical Center Mainz, Mainz, Germany
| | - Mohammed Meabed
- Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
| | - Andriy Khobta
- Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany.
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Fanfarillo F, Caronti B, Lucarelli M, Francati S, Tarani L, Ceccanti M, Piccioni MG, Verdone L, Caserta M, Venditti S, Ferraguti G, Fiore M. Alcohol Consumption and Breast and Ovarian Cancer Development: Molecular Pathways and Mechanisms. Curr Issues Mol Biol 2024; 46:14438-14452. [PMID: 39727994 DOI: 10.3390/cimb46120866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/16/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024] Open
Abstract
Alcohol consumption has been consistently linked to an increased risk of several cancers, including breast and ovarian cancer. Despite substantial evidence supporting this association, the precise mechanisms underlying alcohol's contribution to cancer pathogenesis remain incompletely understood. This narrative review focuses on the key current literature on the biological pathways through which alcohol may influence the development of breast and ovarian cancer. Key mechanisms discussed include the modulation of estrogen levels, the generation of reactive oxygen species, the production of acetaldehyde, the promotion of chronic inflammation, and the induction of epigenetic changes. Alcohol's impact on estrogenic signaling, particularly in the regulation of estrogen and progesterone, is explored in the context of hormone-dependent cancers. Additionally, the role of alcohol-induced DNA damage, mutagenesis, and immune system modulation in tumor initiation and progression is examined. Overall, this review emphasizes the importance of alcohol as a modifiable risk factor for breast and ovarian cancer and highlights the need for further research to clarify its role in cancer biology.
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Affiliation(s)
- Francesca Fanfarillo
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Brunella Caronti
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Marco Lucarelli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Silvia Francati
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Luigi Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Mauro Ceccanti
- SITAC, Società Italiana per il Trattamento dell'Alcolismo e le sue Complicanze, 00185 Rome, Italy
| | - Maria Grazia Piccioni
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Loredana Verdone
- Institute of Molecular Biology and Pathology (IBPM-CNR), 00161 Rome, Italy
| | - Micaela Caserta
- Institute of Molecular Biology and Pathology (IBPM-CNR), 00161 Rome, Italy
| | - Sabrina Venditti
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00161 Rome, Italy
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology (IBBC-CNR), Department of Sensory Organs, Sapienza University of Rome, 00161 Rome, Italy
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4
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Thapa MJ, Chan K. The mutagenic properties of formaldehyde and acetaldehyde: Reflections on half a century of progress. Mutat Res 2024; 830:111886. [PMID: 39549522 DOI: 10.1016/j.mrfmmm.2024.111886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 10/20/2024] [Accepted: 10/28/2024] [Indexed: 11/18/2024]
Abstract
Formaldehyde and acetaldehyde are reactive, small compounds that humans are exposed to routinely, variously from endogenous and exogenous sources. Both small aldehydes are classified as human carcinogens. Investigation of the DNA damaging properties of these two compounds began some 50 years ago. In this review, we summarize progress in this field since its inception over half a century ago, distilling insights gained by the collective efforts of many research groups while highlighting areas for future directions. Over the decades, general consensus about aspects of the mutagenicity of formaldehyde and acetaldehyde has been reached. But other characteristics of formaldehyde and acetaldehyde remain incompletely understood and require additional investigation. These include crucial details about the mutational signature(s) induced and possible mechanistic role(s) during carcinogenesis.
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Affiliation(s)
- Mahanish Jung Thapa
- Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa Faculty of Medicine, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Kin Chan
- Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa Faculty of Medicine, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
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Thomas LA, Hopkinson RJ. The biochemistry of the carcinogenic alcohol metabolite acetaldehyde. DNA Repair (Amst) 2024; 144:103782. [PMID: 39566398 DOI: 10.1016/j.dnarep.2024.103782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 10/14/2024] [Accepted: 10/30/2024] [Indexed: 11/22/2024]
Abstract
Acetaldehyde (AcH) is the first metabolite of ethanol and is proposed to be responsible for the genotoxic effects of alcohol consumption. As an electrophilic aldehyde, AcH can form multiple adducts with DNA and other biomolecules, leading to function-altering and potentially toxic and carcinogenic effects. In this review, we describe sources of AcH in humans, including AcH biosynthesis mechanisms, and outline the structures, properties and functions of AcH-derived adducts with biomolecules. We also describe human AcH detoxification mechanisms and discuss ongoing challenges in the field.
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Affiliation(s)
- Liam A Thomas
- Institute of Structural and Chemical Biology, School of Chemistry, University of Leicester, Leicester LE1 7RH, UK
| | - Richard J Hopkinson
- Institute of Structural and Chemical Biology, School of Chemistry, University of Leicester, Leicester LE1 7RH, UK.
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Prayuda D, Harahap Y, Wardhani BWK. Ultra high-performance liquid chromatography tandem mass spectrometry: Development and validation of an analytical method for N2-Ethyl-2'-deoxyguanosine in dried blood spot. Heliyon 2024; 10:e38610. [PMID: 39430525 PMCID: PMC11489359 DOI: 10.1016/j.heliyon.2024.e38610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 10/22/2024] Open
Abstract
In the body, ethanol is metabolized to acetaldehyde by alcohol dehydrogenase and CYP2E1. Acetaldehyde is the main carcinogen that forms DNA adducts, N2-Ethylidene-2'-deoxyguanosine (N2-Ethylidene-dG), which can cause DNA damage and lead to cancer. However, N2-Ethylidene-dG is an unstable form at the nucleoside level and is difficult to measure. So it needs to be reduced using NaBH4 to become N2-Ethyl-2'-deoxyguanosine (N2-Et-dG). This study aims to obtain a selective, sensitive, and validated analytical method to determine N2-Et-dG using ultra-high-performance liquid chromatography-tandem mass spectrometry with allopurinol as the internal standard. The N2-Et-dG analysis was performed using a C18 Acquity® Bridged Ethylene Hybrid column of (1.7 μm, 100 mm × 2.1 mm). The sample matrix used was dried blood spots, and then the DNA sample was extracted using the QIAamp DNA Mini Kit. The optimum analysis conditions were obtained in a combination eluent of 0.1 % acetic acid and methanol (60:40 v/v) with a flow rate of 0.1 mL/min and eluted isocratically for 5 min. Quantification analysis was performed using triple quadrupole mass spectrometry with electrospray ionization in positive mode, with detection at m/z 296.16 > 180.16 for N2-Et-dG and 137.03 > 110.05 for allopurinol, respectively. The validated analytical method follows the 2018 USA Food and Drug Administration guidelines with a linear concentration range of 5-200 ng/mL.
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Affiliation(s)
- Dimas Prayuda
- Faculty of Pharmacy, University of Indonesia, Indonesia
| | - Yahdiana Harahap
- Faculty of Pharmacy, University of Indonesia, Indonesia
- Faculty of Military Pharmacy, Republic of Indonesia Defense University, Indonesia
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Blouin T, Saini N. Aldehyde-induced DNA-protein crosslinks- DNA damage, repair and mutagenesis. Front Oncol 2024; 14:1478373. [PMID: 39328207 PMCID: PMC11424613 DOI: 10.3389/fonc.2024.1478373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
Aldehyde exposure has been shown to lead to the formation of DNA damage comprising of DNA-protein crosslinks (DPCs), base adducts and interstrand or intrastrand crosslinks. DPCs have recently drawn more attention because of recent advances in detection and quantification of these adducts. DPCs are highly deleterious to genome stability and have been shown to block replication forks, leading to wide-spread mutagenesis. Cellular mechanisms to prevent DPC-induced damage include excision repair pathways, homologous recombination, and specialized proteases involved in cleaving the covalently bound proteins from DNA. These pathways were first discovered in formaldehyde-treated cells, however, since then, various other aldehydes have been shown to induce formation of DPCs in cells. Defects in DPC repair or aldehyde clearance mechanisms lead to various diseases including Ruijs-Aalfs syndrome and AMeD syndrome in humans. Here, we discuss recent developments in understanding how aldehydes form DPCs, how they are repaired, and the consequences of defects in these repair pathways.
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Affiliation(s)
| | - Natalie Saini
- Department of Biochemistry and Molecular Biology, Medical University of South
Carolina, Charleston, SC, United States
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8
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Möller C, Virzi J, Chang YJ, Keidel A, Chao MR, Hu CW, Cooke MS. DNA modifications: Biomarkers for the exposome? ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2024; 108:104449. [PMID: 38636743 DOI: 10.1016/j.etap.2024.104449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/25/2024] [Accepted: 04/12/2024] [Indexed: 04/20/2024]
Abstract
The concept of the exposome is the encompassing of all the environmental exposures, both exogenous and endogenous, across the life course. Many, if not all, of these exposures can result in the generation of reactive species, and/or the modulation of cellular processes, that can lead to a breadth of modifications of DNA, the nature of which may be used to infer their origin. Because of their role in cell function, such modifications have been associated with various major human diseases, including cancer, and so their assessment is crucial. Historically, most methods have been able to only measure one or a few DNA modifications at a time, limiting the information available. With the development of DNA adductomics, which aims to determine the totality of DNA modifications, a far more comprehensive picture of the DNA adduct burden can be gained. Importantly, DNA adductomics can facilitate a "top-down" investigative approach whereby patterns of adducts may be used to trace and identify the originating exposure source. This, together with other 'omic approaches, represents a major tool for unraveling the complexities of the exposome and hence allow a better a understanding of the environmental origins of disease.
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Affiliation(s)
- Carolina Möller
- Oxidative Stress Group, Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA.
| | - Jazmine Virzi
- Oxidative Stress Group, Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA
| | - Yuan-Jhe Chang
- Department of Occupational Safety and Health, Chung Shan Medical University, Taichung 402, Taiwan
| | - Alexandra Keidel
- Oxidative Stress Group, Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA
| | - Mu-Rong Chao
- Department of Occupational Safety and Health, Chung Shan Medical University, Taichung 402, Taiwan; Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chiung-Wen Hu
- Department of Public Health, Chung Shan Medical University, Taichung 402, Taiwan
| | - Marcus S Cooke
- Oxidative Stress Group, Department of Molecular Biosciences, University of South Florida, Tampa, FL 33620, USA; College of Public Health, University of South Florida, Tampa, FL 33620, USA; Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
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Wang J, Takyi NA, Hsiao YC, Tang Q, Chen YT, Liu CW, Ma J, Qi R, Bian K, Peng Z, Essigmann JM, Lu K, Wetmore SD, Li D. Stable Interstrand Cross-Links Generated from the Repair of 1, N6-Ethenoadenine in DNA by α-Ketoglutarate/Fe(II)-Dependent Dioxygenase ALKBH2. J Am Chem Soc 2024; 146:10381-10392. [PMID: 38573229 PMCID: PMC11060877 DOI: 10.1021/jacs.3c12890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2024]
Abstract
DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1,N6-ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC-MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic N6-amino group of adenine or the N4-amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC-MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.
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Affiliation(s)
- Jie Wang
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States
| | - Nathania A Takyi
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge, Alberta T1K 3M4, Canada
| | - Yun-Chung Hsiao
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Qi Tang
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States
| | - Yi-Tzai Chen
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States
| | - Chih-Wei Liu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Jian Ma
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States
| | - Rui Qi
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States
| | - Ke Bian
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States
| | - Zhiyuan Peng
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States
| | - John M Essigmann
- Departments of Biological Engineering, Chemistry, and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Kun Lu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Stacey D Wetmore
- Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge, Alberta T1K 3M4, Canada
| | - Deyu Li
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, United States
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Mao J, Tan L, Tian C, Wang W, Zhang H, Zhu Z, Li Y. Research progress on rodent models and its mechanisms of liver injury. Life Sci 2024; 337:122343. [PMID: 38104860 DOI: 10.1016/j.lfs.2023.122343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
The liver is the most important organ for biological transformation in the body and is crucial for maintaining the body's vital activities. Liver injury is a serious pathological condition that is commonly found in many liver diseases. It has a high incidence rate, is difficult to cure, and is prone to recurrence. Liver injury can cause serious harm to the body, ranging from mild to severe fatty liver disease. If the condition continues to worsen, it can lead to liver fibrosis and cirrhosis, ultimately resulting in liver failure or liver cancer, which can seriously endanger human life and health. Therefore, establishing an rodent model that mimics the pathogenesis and severity of clinical liver injury is of great significance for better understanding the pathogenesis of liver injury patients and developing more effective clinical treatment methods. The author of this article summarizes common chemical liver injury models, immune liver injury models, alcoholic liver injury models, drug-induced liver injury models, and systematically elaborates on the modeling methods, mechanisms of action, pathways of action, and advantages or disadvantages of each type of model. The aim of this study is to establish reliable rodent models for researchers to use in exploring anti-liver injury and hepatoprotective drugs. By creating more accurate theoretical frameworks, we hope to provide new insights into the treatment of clinical liver injury diseases.
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Affiliation(s)
- Jingxin Mao
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Lihong Tan
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Cheng Tian
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Wenxiang Wang
- Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Hao Zhang
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Zhaojing Zhu
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Yan Li
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China.
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11
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De Graeve M, Van de Walle E, Van Hecke T, De Smet S, Vanhaecke L, Hemeryck LY. Exploration and optimization of extraction, analysis and data normalization strategies for mass spectrometry-based DNA adductome mapping and modeling. Anal Chim Acta 2023; 1274:341578. [PMID: 37455087 DOI: 10.1016/j.aca.2023.341578] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/23/2023] [Accepted: 06/29/2023] [Indexed: 07/18/2023]
Abstract
Although interest in characterizing DNA damage by means of DNA adductomics has substantially grown, the field of DNA adductomics is still in its infancy, with room for optimization of methods for sample analysis, data processing and DNA adduct identification. In this context, the first objective of this study was to evaluate the use of hydrophilic interaction (HILIC) vs. reversed phase liquid chromatography (RPLC) coupled to high resolution mass spectrometry (HRMS) and thermal acidic vs. enzymatic hydrolysis of DNA followed by DNA adduct purification and enrichment using solid-phase extraction (SPE) or fraction collection for DNA adductome mapping. The second objective was to assess the use of total ion count (TIC) and median intensity (MedI) normalization compared to QC (quality control), iQC (internal QC) and quality control-based robust locally estimated scatterplot smoothing (LOESS) signal correction (QC-RLSC) normalization for processing of the acquired data. The results demonstrate that HILIC compared to RPLC allowed better modeling of the tentative DNA adductome, particularly in combination with thermal acidic hydrolysis and SPE (more valid models, with an average Q2(Y) and R2(Y) of 0.930 and 0.998, respectively). Regarding the need for data normalization and the management of (limited) system instability and signal drift, QC normalization outperformed TIC, MedI, iQC and LOESS normalization. As such, QC normalization can be put forward as the default data normalization strategy. In case of momentous signal drift and/or batch effects however, comparison to other normalization strategies (like e.g. LOESS) is recommended. In future work, further optimization of DNA adductomics may be achieved by merging of HILIC and RPLC datasets and/or application of 2D-LC, as well as the inclusion of Schiff base stabilization and/or fraction collection in the thermal acidic hydrolysis-SPE sample preparation workflow.
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Affiliation(s)
- Marilyn De Graeve
- Laboratory of Integrative Metabolomics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820, Merelbeke, Belgium.
| | - Emma Van de Walle
- Laboratory of Integrative Metabolomics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820, Merelbeke, Belgium.
| | - Thomas Van Hecke
- Laboratory for Animal Nutrition and Animal Product Quality, Faculty of Bioscience Engineering, Ghent University, Coupure Links, 653, B-9000, Ghent, Belgium.
| | - Stefaan De Smet
- Laboratory for Animal Nutrition and Animal Product Quality, Faculty of Bioscience Engineering, Ghent University, Coupure Links, 653, B-9000, Ghent, Belgium.
| | - Lynn Vanhaecke
- Laboratory of Integrative Metabolomics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820, Merelbeke, Belgium; Institute for Global Food Security, School of Biological Sciences, Queen's University, University Road, Belfast, United Kingdom.
| | - Lieselot Y Hemeryck
- Laboratory of Integrative Metabolomics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820, Merelbeke, Belgium.
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12
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Vijayraghavan S, Saini N. Aldehyde-Associated Mutagenesis─Current State of Knowledge. Chem Res Toxicol 2023. [PMID: 37363863 DOI: 10.1021/acs.chemrestox.3c00045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
Aldehydes are widespread in the environment, with multiple sources such as food and beverages, industrial effluents, cigarette smoke, and additives. The toxic effects of exposure to several aldehydes have been observed in numerous studies. At the molecular level, aldehydes damage DNA, cross-link DNA and proteins, lead to lipid peroxidation, and are associated with increased disease risk including cancer. People genetically predisposed to aldehyde sensitivity exhibit severe health outcomes. In various diseases such as Fanconi's anemia and Cockayne syndrome, loss of aldehyde-metabolizing pathways in conjunction with defects in DNA repair leads to widespread DNA damage. Importantly, aldehyde-associated mutagenicity is being explored in a growing number of studies, which could offer key insights into how they potentially contribute to tumorigenesis. Here, we review the genotoxic effects of various aldehydes, focusing particularly on the DNA adducts underlying the mutagenicity of environmentally derived aldehydes. We summarize the chemical structures of the aldehydes and their predominant DNA adducts, discuss various methodologies, in vitro and in vivo, commonly used in measuring aldehyde-associated mutagenesis, and highlight some recent studies looking at aldehyde-associated mutation signatures and spectra. We conclude the Review with a discussion on the challenges and future perspectives of investigating aldehyde-associated mutagenesis.
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Affiliation(s)
- Sriram Vijayraghavan
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, United States
| | - Natalie Saini
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, United States
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13
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Smędra A, Berent J. The Influence of the Oral Microbiome on Oral Cancer: A Literature Review and a New Approach. Biomolecules 2023; 13:biom13050815. [PMID: 37238685 DOI: 10.3390/biom13050815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/01/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
In our recent article (Smędra et al.: Oral form of auto-brewery syndrome. J Forensic Leg Med. 2022; 87: 102333), we showed that alcohol production can occur in the oral cavity (oral auto-brewery syndrome) due to a disruption in the microbiota (dysbiosis). An intermediate step on the path leading to the formation of alcohol is acetaldehyde. Typically, acetic aldehyde is transformed into acetate particles inside the human body via acetaldehyde dehydrogenase. Unfortunately, acetaldehyde dehydrogenase activity is low in the oral cavity, and acetaldehyde remains there for a long time. Since acetaldehyde is a recognised risk factor for squamous cell carcinoma arising from the oral cavity, we decided to analyse the relationship linking the oral microbiome, alcohol, and oral cancer using the narrative review method, based on browsing articles in the PubMed database. In conclusion, enough evidence supports the speculation that oral alcohol metabolism must be assessed as an independent carcinogenic risk. We also hypothesise that dysbiosis and the production of acetaldehyde from non-alcoholic food and drinks should be treated as a new factor for the development of cancer.
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Affiliation(s)
- Anna Smędra
- Department of Forensic Medicine, Medical University of Lodz, 91-304 Lodz, Poland
| | - Jarosław Berent
- Department of Forensic Medicine, Medical University of Lodz, 91-304 Lodz, Poland
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14
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Cheng G, Guo J, Wang R, Yuan JM, Balbo S, Hecht SS. Quantitation by Liquid Chromatography-Nanoelectrospray Ionization-High-Resolution Tandem Mass Spectrometry of Multiple DNA Adducts Related to Cigarette Smoking in Oral Cells in the Shanghai Cohort Study. Chem Res Toxicol 2023; 36:305-312. [PMID: 36719849 PMCID: PMC10148603 DOI: 10.1021/acs.chemrestox.2c00393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
We developed a liquid chromatography-nanoelectrospray ionization-high-resolution tandem mass spectrometry (LC-NSI-HRMS/MS) method for simultaneous quantitative analysis of 5 oral cell DNA adducts associated with cigarette smoking: (8R/S)-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dGuo, 1) from acrolein; (6S,8S and 6R,8R)-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)-one [(6S,8S)γ-OH-Cro-dGuo, 2; and (6R,8R)γ-OH-Cro-dGuo, 3] from crotonaldehyde; 1,N6-etheno-dAdo (4) from acrylonitrile, vinyl chloride, lipid peroxidation, and inflammation; and 8-oxo-dGuo (5) from oxidative damage. Oral cell DNA was isolated in the presence of glutathione to prevent artifact formation. Clear LC-NSI-HRMS/MS chromatograms were obtained allowing quantitation of each adduct using the appropriately labeled internal standards. The accuracy and precision of the method were validated, and the assay limit of quantitation was 5 fmol/μmol dGuo for adducts 1-4 and 20 fmol/μmol for adduct 5. The assay was applied to 80 buccal cell samples selected from those collected in the Shanghai Cohort Study: 40 from current smokers and 40 from never smokers. Significant differences were found in all adduct levels between smokers and nonsmokers. Levels of 8-oxo-dGuo (5) were at least 3000 times greater than those of the other adducts in both smokers and nonsmokers, and the difference between amounts of this adduct in smokers versus nonsmokers, while significant (P = 0.013), was not as great as the differences of the other DNA adducts between smokers and nonsmokers (P-values all less than 0.001). No significant relationship of adduct levels to risk of lung cancer incidence was found. This study provides a new LC-NSI-HRMS/MS methodology for the quantitation of diverse DNA adducts resulting from exposure to the α,β-unsaturated aldehydes acrolein and crotonaldehyde, inflammation, and oxidative damage which are all associated with carcinogenesis. We anticipate application of this assay in ongoing studies of the molecular epidemiology of cancers of the lung and oral cavity related to cigarette smoking.
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Affiliation(s)
- Guang Cheng
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Jiehong Guo
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Renwei Wang
- UPMC Hillman Cancer Center and Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15232, United States
| | - Jian-Min Yuan
- UPMC Hillman Cancer Center and Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15232, United States
| | - Silvia Balbo
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Stephen S Hecht
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
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15
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Safeguarding DNA Replication: A Golden Touch of MiDAS and Other Mechanisms. Int J Mol Sci 2022; 23:ijms231911331. [PMID: 36232633 PMCID: PMC9570362 DOI: 10.3390/ijms231911331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 11/21/2022] Open
Abstract
DNA replication is a tightly regulated fundamental process allowing the correct duplication and transfer of the genetic information from the parental cell to the progeny. It involves the coordinated assembly of several proteins and protein complexes resulting in replication fork licensing, firing and progression. However, the DNA replication pathway is strewn with hurdles that affect replication fork progression during S phase. As a result, cells have adapted several mechanisms ensuring replication completion before entry into mitosis and segregating chromosomes with minimal, if any, abnormalities. In this review, we describe the possible obstacles that a replication fork might encounter and how the cell manages to protect DNA replication from S to the next G1.
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16
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Can gene therapy be used to prevent cancer? Gene therapy for aldehyde dehydrogenase 2 deficiency. Cancer Gene Ther 2022; 29:889-896. [PMID: 34799722 PMCID: PMC9117562 DOI: 10.1038/s41417-021-00399-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/24/2021] [Accepted: 10/08/2021] [Indexed: 11/08/2022]
Abstract
Approximately 8% of the world population and 35-45% of East Asians are carriers of the hereditary disorder aldehyde dehydrogenase 2 (ALDH2) deficiency. ALDH2 plays a central role in the liver to metabolize ethanol. With the common E487K variant, there is a deficiency of ALDH2 function; when ethanol is consumed, there is a systemic accumulation of acetaldehyde, an intermediate product in ethanol metabolism. In ALDH2-deficient individuals, ethanol consumption acutely causes the "Alcohol Flushing Syndrome" with facial flushing, tachycardia, nausea, and headaches. With chronic alcohol consumption, ALDH2 deficiency is associated with a variety of disorders, including a remarkably high risk for aerodigestive tract cancers. Acetaldehyde is a known carcinogen. The epidemiologic data relating to the association of ALDH2 deficiency and cancer risk are striking: ALDH2 homozygotes who are moderate-to-heavy consumers of ethanol have a 7-12-fold increased risk for esophageal cancer, making ALDH2 deficiency the most common hereditary disorder associated with an increased cancer risk. In this review, we summarize the genetics and biochemistry of ALDH2, the epidemiology of cancer risk associated with ALDH2 deficiency, the metabolic consequences of ethanol consumption associated with ALDH2 deficiency, and gene therapy strategies to correct ALDH2 deficiency and its associated cancer risk. With the goal of reducing the risk of aerodigestive tract cancers, in the context that ALDH2 is a hereditary disorder and ALDH2 functions primarily in the liver, ALDH2 deficiency is an ideal target for the application of adeno-associated virus-mediated liver-directed gene therapy to prevent cancer.
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17
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Vijayraghavan S, Porcher L, Mieczkowski PA, Saini N. Acetaldehyde makes a distinct mutation signature in single-stranded DNA. Nucleic Acids Res 2022; 50:7451-7464. [PMID: 35776120 PMCID: PMC9303387 DOI: 10.1093/nar/gkac570] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/09/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability to react with various biological molecules including DNA and proteins, which can greatly impede key processes such as replication and transcription and lead to DNA damage. As such AA is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous in vitro studies have shown that AA generates bulky adducts on DNA, with signature guanine-centered (GG→TT) mutations. However, due to its weak mutagenicity, short chemical half-life, and the absence of powerful genetic assays, there is considerable variability in reporting the mutagenic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA treatment is highly mutagenic to cells and leads to strand-biased mutations on guanines (G→T) at a high frequency on single stranded DNA (ssDNA). We further demonstrate that AA-derived mutations occur through lesion bypass on ssDNA by the translesion polymerase Polζ. Finally, we describe a unique mutation signature for AA, which we then identify in several whole-genome and -exome sequenced cancers, particularly those associated with alcohol consumption. Our study proposes a key mechanism underlying carcinogenesis by acetaldehyde—mutagenesis of single-stranded DNA.
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Affiliation(s)
- Sriram Vijayraghavan
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Latarsha Porcher
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Piotr A Mieczkowski
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Natalie Saini
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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18
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Zhong L, Chen W, Wang T, Zeng Q, Lai L, Lai J, Lin J, Tang S. Alcohol and Health Outcomes: An Umbrella Review of Meta-Analyses Base on Prospective Cohort Studies. Front Public Health 2022; 10:859947. [PMID: 35602135 PMCID: PMC9115901 DOI: 10.3389/fpubh.2022.859947] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/06/2022] [Indexed: 12/18/2022] Open
Abstract
An umbrella review of meta-analyses was performed to summarize the evidence of associations between alcohol consumption and health outcomes and to assess its credibility. Meta-analyses of prospective cohort studies reporting the associations of alcohol consumption with health outcomes were identified. We recalculated the random-effects summary effect size and 95% confidence interval, heterogeneity, and small-study effect for each meta-analysis and graded the evidence. Fifty-nine publications reporting 224 meta-analyses of prospective cohort studies with 140 unique health outcomes were included, in which there were 49 beneficial associations and 25 harmful associations with nominally statistically significant summary results. But quality of evidence was rated high only for seven beneficial associations (renal cell carcinoma risk, dementia risk, colorectal cancer mortality, and all-cause mortality in patients with hypertension for low alcohol consumption; renal cell carcinoma risk, cardiovascular disease (CVD) risk in patients with hypertension and all-cause mortality in patients with hypertension for moderate consumption) and four harmful associations (cutaneous basal cell carcinoma risk for low alcohol consumption; cutaneous basal cell carcinoma risk and cutaneous squamous cell carcinoma risk for moderate alcohol consumption; hemorrhagic stroke risk for high alcohol consumption). In this umbrella review, only 11 health outcomes (5 in low alcohol consumption, 5 in moderate alcohol consumption and 1 in high alcohol consumption) with statistically significant showed high quality of epidemiologic evidence. More robust and larger prospective studies are needed to verify our results.
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Affiliation(s)
- Lixian Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Weiwei Chen
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
- Department of Gastroenterology, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, China
| | - Tonghua Wang
- Department of Gastroenterology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Qiuting Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Leizhen Lai
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Junlong Lai
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Junqin Lin
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Shaohui Tang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China
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19
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Wang M, Dingler FA, Patel KJ. Genotoxic aldehydes in the hematopoietic system. Blood 2022; 139:2119-2129. [PMID: 35148375 DOI: 10.1182/blood.2019004316] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/24/2022] [Indexed: 11/20/2022] Open
Abstract
Reactive aldehydes are potent genotoxins that threaten the integrity of hematopoietic stem cells and blood production. To protect against aldehydes, mammals have evolved a family of enzymes to detoxify aldehydes, and the Fanconi anemia DNA repair pathway to process aldehyde-induced DNA damage. Loss of either protection mechanisms in humans results in defective hematopoiesis and predisposition to leukemia. This review will focus on the impact of genotoxic aldehydes on hematopoiesis, the sources of endogenous aldehydes, and potential novel protective pathways.
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Affiliation(s)
- Meng Wang
- Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
- Department of Haematology and
- Wellcome-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom; and
| | - Felix A Dingler
- Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - K J Patel
- Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
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20
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Muresanu C, Khalchitsky S. Updated Understanding of the Causes of Cancer, and a New Theoretical Perspective of Combinational Cancer Therapies, a Hypothesis. DNA Cell Biol 2022; 41:342-355. [PMID: 35262416 DOI: 10.1089/dna.2021.1118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We present an integrative understanding of cancer as a metabolic multifactorial, multistage disease. We focus on underlying genetics-environmental interactions, evidenced by telomere changes. A range of genetic and epigenetic factors, including physical agents and predisposing factors such as diet and lifestyle are included. We present a structured model of the causes of cancer, methods of investigations, approaches to cancer prevention, and polypharmaceutical multidisciplinary complex treatment within a framework of personalized medicine. We searched PubMed, National Cancer Institute online, and other databases for publications regarding causes of cancer, reports of novel mitochondrial reprogramming, epigenetic, and telomerase therapies and state-of-the-art investigations. We focused on multistep treatment protocols to enhance early detection of cancer, and elimination or neutralization of the causes and factors associated with cancer formation and progression.Our aim is to suggest a model therapeutic protocol that incorporates the patient's genome, metabolism, and immune system status; stage of tumor development; and comorbidity(ies), if any. Investigation and treatment of cancer is a challenge that requires further holistic studies that improve the quality of life and survival rates, but are most likely to aid prevention.
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Affiliation(s)
- Cristian Muresanu
- Research Center for Applied Biotechnology in Diagnosis and Molecular Therapies, Cluj-Napoca, Romania.,Department of Ecology, Taxonomy and Nature Conservation, Institute of Biology, Romanian Academy, Bucharest, Romania
| | - Sergei Khalchitsky
- H. Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery of the Ministry of Health of the Russian Federation, Saint-Petersburg, Russia
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21
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Saha J, Bae J, Wang SY, Lu H, Chappell LJ, Gopal P, Davis AJ. Ablating putative Ku70 phosphorylation sites results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma. Nucleic Acids Res 2021; 49:9836-9850. [PMID: 34428289 PMCID: PMC8464062 DOI: 10.1093/nar/gkab743] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/31/2022] Open
Abstract
Multiple pathways mediate the repair of DNA double-strand breaks (DSBs), with numerous mechanisms responsible for driving choice between the pathways. Previously, we reported that mutating five putative phosphorylation sites on the non-homologous end joining (NHEJ) factor, Ku70, results in sustained retention of human Ku70/80 at DSB ends and attenuation of DSB repair via homologous recombination (HR). In this study, we generated a knock-in mouse, in which the three conserved putative phosphorylation sites of Ku70 were mutated to alanine to ablate potential phosphorylation (Ku703A/3A), in order to examine if disrupting DSB repair pathway choice by modulating Ku70/80 dynamics at DSB ends results in enhanced genomic instability and tumorigenesis. The Ku703A/3A mice developed spontaneous and have accelerated chemical-induced hepatocellular carcinoma (HCC) compared to wild-type (Ku70+/+) littermates. The HCC tumors from the Ku703A/3A mice have increased γH2AX and 8-oxo-G staining, suggesting decreased DNA repair. Spontaneous transformed cell lines from Ku703A/3A mice are more radiosensitive, have a significant decrease in DNA end resection, and are more sensitive to the DNA cross-linking agent mitomycin C compared to cells from Ku70+/+ littermates. Collectively, these findings demonstrate that mutating the putative Ku70 phosphorylation sites results in defective DNA damage repair and disruption of this process drives genomic instability and accelerated development of HCC.
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Affiliation(s)
- Janapriya Saha
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Jinsung Bae
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Shih-Ya Wang
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Huiming Lu
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Purva Gopal
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Anthony J Davis
- Division of Molecular Radiation Biology, Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA
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22
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Sonohara Y, Takatsuka R, Masutani C, Iwai S, Kuraoka I. Acetaldehyde induces NER repairable mutagenic DNA lesions. Carcinogenesis 2021; 43:52-59. [PMID: 34546339 DOI: 10.1093/carcin/bgab087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 09/14/2021] [Accepted: 09/17/2021] [Indexed: 11/13/2022] Open
Abstract
Nucleotide excision repair (NER) is a repair mechanism that removes DNA lesions induced by UV radiation, environmental mutagens, and carcinogens. There exists sufficient evidence against acetaldehyde suggesting it to cause a variety of DNA lesions and be carcinogenic to humans. Previously, we found that acetaldehyde induces reversible intra-strand GG crosslinks in DNA similar to those induced by cis-diammineplatinum(II) that is subsequently repaired by NER. In this study, we analysed the repairability by NER mechanism and the mutagenesis of acetaldehyde. In an in vitro reaction setup with NER-proficient and NER-deficient xeroderma pigmentosum group A (XPA) cell extracts, NER reactions were observed in the presence of XPA recombinant proteins in acetaldehyde-treated plasmids. Using an in vivo assay with living XPA cells and XPA-correcting XPA cells, the repair reactions were also observed. Additionally, it was observed that DNA polymerase eta inserted dATP opposite guanine in acetaldehyde-treated oligonucleotides, suggesting that acetaldehyde induced GG to TT transversions. These findings show that acetaldehyde induces NER repairable mutagenic DNA lesions.
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Affiliation(s)
- Yuina Sonohara
- Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
| | - Reine Takatsuka
- Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
| | - Chikahide Masutani
- Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
| | - Shigenori Iwai
- Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
| | - Isao Kuraoka
- Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.,Department of Chemistry, Faculty of Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
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23
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Rumgay H, Murphy N, Ferrari P, Soerjomataram I. Alcohol and Cancer: Epidemiology and Biological Mechanisms. Nutrients 2021; 13:3173. [PMID: 34579050 PMCID: PMC8470184 DOI: 10.3390/nu13093173] [Citation(s) in RCA: 174] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/03/2021] [Accepted: 09/09/2021] [Indexed: 12/16/2022] Open
Abstract
Approximately 4% of cancers worldwide are caused by alcohol consumption. Drinking alcohol increases the risk of several cancer types, including cancers of the upper aerodigestive tract, liver, colorectum, and breast. In this review, we summarise the epidemiological evidence on alcohol and cancer risk and the mechanistic evidence of alcohol-mediated carcinogenesis. There are several mechanistic pathways by which the consumption of alcohol, as ethanol, is known to cause cancer, though some are still not fully understood. Ethanol's metabolite acetaldehyde can cause DNA damage and block DNA synthesis and repair, whilst both ethanol and acetaldehyde can disrupt DNA methylation. Ethanol can also induce inflammation and oxidative stress leading to lipid peroxidation and further DNA damage. One-carbon metabolism and folate levels are also impaired by ethanol. Other known mechanisms are discussed. Further understanding of the carcinogenic properties of alcohol and its metabolites will inform future research, but there is already a need for comprehensive alcohol control and cancer prevention strategies to reduce the burden of cancer attributable to alcohol.
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Affiliation(s)
- Harriet Rumgay
- Cancer Surveillance Branch, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France;
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France; (N.M.); (P.F.)
| | - Pietro Ferrari
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France; (N.M.); (P.F.)
| | - Isabelle Soerjomataram
- Cancer Surveillance Branch, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France;
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24
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Radaic A, Ganther S, Kamarajan P, Grandis J, Yom SS, Kapila YL. Paradigm shift in the pathogenesis and treatment of oral cancer and other cancers focused on the oralome and antimicrobial-based therapeutics. Periodontol 2000 2021; 87:76-93. [PMID: 34463982 PMCID: PMC8415008 DOI: 10.1111/prd.12388] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The oral microbiome is a community of microorganisms, comprised of bacteria, fungi, viruses, archaea, and protozoa, that form a complex ecosystem within the oral cavity. Although minor perturbations in the environment are frequent and compensable, major shifts in the oral microbiome can promote an unbalanced state, known as dysbiosis. Dysbiosis can promote oral diseases, including periodontitis. In addition, oral dysbiosis has been associated with other systemic diseases, including cancer. The objective of this review is to evaluate the epidemiologic evidence linking periodontitis to oral, gastrointestinal, lung, breast, prostate, and uterine cancers, as well as describe new evidence and insights into the role of oral dysbiosis in the etiology and pathogenesis of the cancer types discussed. Finally, we discuss how antimicrobials, antimicrobial peptides, and probiotics may be promising tools to prevent and treat these cancers, targeting both the microbes and associated carcinogenesis processes. These findings represent a novel paradigm in the pathogenesis and treatment of cancer focused on the oral microbiome and antimicrobial‐based therapies.
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Affiliation(s)
- Allan Radaic
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, USA
| | - Sean Ganther
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, USA
| | - Pachiyappan Kamarajan
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, USA
| | - Jennifer Grandis
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA
| | - Sue S Yom
- Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA
| | - Yvonne L Kapila
- Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, USA
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Hoes L, Dok R, Verstrepen KJ, Nuyts S. Ethanol-Induced Cell Damage Can Result in the Development of Oral Tumors. Cancers (Basel) 2021; 13:cancers13153846. [PMID: 34359747 PMCID: PMC8345464 DOI: 10.3390/cancers13153846] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Alcohol consumption is linked to 26.4% of all lip and oral cavity cancer cases worldwide. Despite this clear causal relationship, the exact molecular mechanisms by which ethanol damages cells are still under investigation. It is well-established that the metabolism of ethanol plays an important role. Ethanol metabolism yields reactive metabolites that can directly damage the DNA. If the damage is repaired incorrectly, mutations can be fixed in the DNA sequence. Whenever mutations affect key regulatory genes, for instance cell cycle regulating genes, uncontrolled cell growth can be the consequence. Recently, global patterns of mutations have been identified. These so-called mutational signatures represent a fingerprint of the different mutational processes over time. Interestingly, there were ethanol-related signatures discovered that did not associate with ethanol metabolism. This finding highlights there might be other molecular effects of ethanol that are yet to be discovered. Abstract Alcohol consumption is an underestimated risk factor for the development of precancerous lesions in the oral cavity. Although alcohol is a well-accepted recreational drug, 26.4% of all lip and oral cavity cancers worldwide are related to heavy drinking. Molecular mechanisms underlying this carcinogenic effect of ethanol are still under investigation. An important damaging effect comes from the first metabolite of ethanol, being acetaldehyde. Concentrations of acetaldehyde detected in the oral cavity are relatively high due to the metabolization of ethanol by oral microbes. Acetaldehyde can directly damage the DNA by the formation of mutagenic DNA adducts and interstrand crosslinks. Additionally, ethanol is known to affect epigenetic methylation and acetylation patterns, which are important regulators of gene expression. Ethanol-induced hypomethylation can activate the expression of oncogenes which subsequently can result in malignant transformation. The recent identification of ethanol-related mutational signatures emphasizes the role of acetaldehyde in alcohol-associated carcinogenesis. However, not all signatures associated with alcohol intake also relate to acetaldehyde. This finding highlights that there might be other effects of ethanol yet to be discovered.
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Affiliation(s)
- Lore Hoes
- Laboratory for Systems Biology, VIB-KU Leuven Center for Microbiology, 3000 Leuven, Belgium; (L.H.); (K.J.V.)
- Laboratory of Genetics and Genomics, Centre for Microbial and Plant Genetics, KU Leuven, 3000 Leuven, Belgium
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium;
| | - Rüveyda Dok
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium;
| | - Kevin J. Verstrepen
- Laboratory for Systems Biology, VIB-KU Leuven Center for Microbiology, 3000 Leuven, Belgium; (L.H.); (K.J.V.)
- Laboratory of Genetics and Genomics, Centre for Microbial and Plant Genetics, KU Leuven, 3000 Leuven, Belgium
| | - Sandra Nuyts
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium;
- Department of Radiation Oncology, Leuven Cancer Institute, University Hospital Leuven, 3000 Leuven, Belgium
- Correspondence: ; Tel.: +32-1634-7600; Fax: +32-1634-7623
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Jung H, Kim S, Yoo K, Lee J. Changes in acetaldehyde and formaldehyde contents in foods depending on the typical home cooking methods. JOURNAL OF HAZARDOUS MATERIALS 2021; 414:125475. [PMID: 33647618 DOI: 10.1016/j.jhazmat.2021.125475] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 02/16/2021] [Accepted: 02/18/2021] [Indexed: 06/12/2023]
Abstract
Analytical methods were validated for the evaluation of acetaldehyde and formaldehyde, which are harmful chemicals, using solid-phase microextraction-gas chromatography/mass spectrometry in four different matrices. Typical home-cooking methods including boiling, pan-frying, and stir-frying, were applied to beef, rapeseed oil, canned pork ham, egg, and rice wine. In addition, monosaccharides, disaccharides, alanine, and glycine were heated for the formation of both aldehydes. All validation parameters, including accuracy, precision, limit of detection, limit of quantification, and uncertainty, for four different matrices were within recommended ranges, confirming the validity of the current method. Acetaldehyde contents ranged from undetectable to 17.92 μg/g and formaldehyde contents ranged from undetectable to 0.27 μg/g. Generally, boiling decreased both aldehydes except acetaldehyde in egg. Pan- and stir-frying increased both aldehyde content substantially in rapeseed oil whereas pan-frying increased acetaldehyde content in canned pork ham and egg. Fructose and sucrose produced higher content of both aldehydes than maltose and glucose when heated. Depending on food type, the cooking process had slightly different effects on the contents of acetaldehyde and formaldehyde.
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Affiliation(s)
- HyunJeong Jung
- Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - SeHyeok Kim
- Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - KeunCheol Yoo
- Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea
| | - JaeHwan Lee
- Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.
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27
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Hyun J, Han J, Lee C, Yoon M, Jung Y. Pathophysiological Aspects of Alcohol Metabolism in the Liver. Int J Mol Sci 2021; 22:5717. [PMID: 34071962 PMCID: PMC8197869 DOI: 10.3390/ijms22115717] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The liver is the major organ that metabolizes alcohol; therefore, it is particularly sensitive to alcohol intake. Metabolites and byproducts generated during alcohol metabolism cause liver damage, leading to ALD via several mechanisms, such as impairing lipid metabolism, intensifying inflammatory reactions, and inducing fibrosis. Despite the severity of ALD, the development of novel treatments has been hampered by the lack of animal models that fully mimic human ALD. To overcome the current limitations of ALD studies and therapy development, it is necessary to understand the molecular mechanisms underlying alcohol-induced liver injury. Hence, to provide insights into the progression of ALD, this review examines previous studies conducted on alcohol metabolism in the liver. There is a particular focus on the occurrence of ALD caused by hepatotoxicity originating from alcohol metabolism.
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Affiliation(s)
- Jeongeun Hyun
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea;
- Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea
- Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan 31116, Korea
| | - Jinsol Han
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
| | - Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
| | - Myunghee Yoon
- Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Biomedical Research Institute, Pusan National University, Pusan 46241, Korea;
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea; (J.H.); (C.L.)
- Department of Biological Sciences, Pusan National University, Pusan 46241, Korea
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Kasai H, Kawai K. New Plausible Mechanism for Gastric and Colorectal Carcinogenesis: Free Radical-Mediated Acetaldehyde Generation in a Heme/Myoglobin-Linoleate-Ethanol Mixture. ACS OMEGA 2021; 6:12014-12021. [PMID: 34056355 PMCID: PMC8153976 DOI: 10.1021/acsomega.1c00614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/16/2021] [Indexed: 05/04/2023]
Abstract
Epidemiological studies have revealed that alcohol, red meat, and cooking oil (or linoleate) are risk factors for both gastric and colon cancers. A survey of the mutation spectra of the p53 tumor suppressor gene in these cancers suggested that the types of mutations and the hot spots are similar to those induced by acetaldehyde (AcAld) in an in vitro p53 mutation analysis system. Accordingly, various combinations of possible factors, components, or model compounds were reacted in an emulsion and tested for the generation of AcAld. Efficient AcAld formation was only observed with combinations of three factors, red meat homogenate (or heme/myoglobin), methyl linoleate, and ethanol, but not by any combination of the two. The generated AcAld levels (ca. 500 μM) far exceeded the minimum mutagenic concentration (40-100 μM) obtained using concentrations of meat homogenate (or heme/Mb), linoleate, and ethanol comparable to those in the stomach after an ordinary meal. A mutagenic level of AcAld (75 μM) was also generated with a physiological concentration of ethanol, heme, and linoleate in the colon. As a mechanism, linoleate hydroperoxide formation and its decomposition in the presence of myoglobin (or heme) to generate the OH radical seem to be involved in the ethanol-to-AcAld conversion.
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Abstract
DNA interstrand cross-links (ICLs) covalently connect the two strands of the double helix and are extremely cytotoxic. Defective ICL repair causes the bone marrow failure and cancer predisposition syndrome, Fanconi anemia, and upregulation of repair causes chemotherapy resistance in cancer. The central event in ICL repair involves resolving the cross-link (unhooking). In this review, we discuss the chemical diversity of ICLs generated by exogenous and endogenous agents. We then describe how proliferating and nonproliferating vertebrate cells unhook ICLs. We emphasize fundamentally new unhooking strategies, dramatic progress in the structural analysis of the Fanconi anemia pathway, and insights into how cells govern the choice between different ICL repair pathways. Throughout, we highlight the many gaps that remain in our knowledge of these fascinating DNA repair pathways.
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Affiliation(s)
- Daniel R Semlow
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; .,Current affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Johannes C Walter
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA; .,Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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Lu X, Li R, Han B, Ma H, Hou X, Kang Y, Zhang Y, Wang JJ. Fluorescence Sensing of Formaldehyde and Acetaldehyde Based on Responsive Inverse Opal Photonic Crystals: A Multiple-Application Detection Platform. ACS APPLIED MATERIALS & INTERFACES 2021; 13:13792-13801. [PMID: 33705107 DOI: 10.1021/acsami.0c22105] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Formaldehyde (FA) and acetaldehyde (AcH) used as common chemicals in many fields are carcinogenic. The presently reported detection methods usually need expensive instruments, professional technicians, and time-consuming processes, and the detection sensitivity still needs further improvement. Herein, we report a highly effective fluorescence (FL) sensing film for FA and AcH based on naphthalimide derivative-infiltrated responsive SiO2 inverse opal photonic crystals (PCs), establishing a practically multiple-application detection platform for FA and AcH in air, aquatic products, and living cells. Nucleophilic addition products between the amine group of the naphthalimide derivative and aldehydes emit strong FL at ∼550 nm, realizing selective FL detection for FA and AcH. The emitted FL can be enhanced remarkably because of the slow photon effect of PCs, in which the FL wavelength is located at the stopband edge of PCs. A highly sensitive detection for FA and AcH with limits of detection of 10.6 and 7.3 nM, respectively, is achieved, increasing 3 orders of magnitude compared with that in the solution system. Additionally, the interconnected three-dimensional microporous inverse opal structure endows the sensor with a rapid response within 1 min. Furthermore, the as-prepared PC sensor can be reused by simple washing in an acidic aqueous solution. The sensing system can be used as a FL multi-detection platform for FA and AcH in air, aqueous solution, and living cells. This FL sensing approach based on small organic molecule-functionalized PCs is universally available to develop various sensors for target analytes by designing new functional organic compounds.
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Affiliation(s)
- Xiaokang Lu
- Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an, Shaanxi 716000, PR China
| | - Ran Li
- Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an, Shaanxi 716000, PR China
| | - Bo Han
- Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an, Shaanxi 716000, PR China
| | - Haojie Ma
- Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an, Shaanxi 716000, PR China
| | - Xueyan Hou
- Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an, Shaanxi 716000, PR China
| | - Yulong Kang
- Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an, Shaanxi 716000, PR China
| | - Yuqi Zhang
- Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an, Shaanxi 716000, PR China
| | - Ji-Jiang Wang
- Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan'an University, Yan'an, Shaanxi 716000, PR China
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31
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Peterson LA, Oram MK, Flavin M, Seabloom D, Smith WE, O’Sullivan MG, Vevang KR, Upadhyaya P, Stornetta A, Floeder AC, Ho YY, Zhang L, Hecht SS, Balbo S, Wiedmann TS. Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung. Chem Res Toxicol 2021; 34:723-732. [PMID: 33629582 PMCID: PMC10901071 DOI: 10.1021/acs.chemrestox.0c00350] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Tobacco smoke is a complex mixture of chemicals, many of which are toxic and carcinogenic. Hazard assessments of tobacco smoke exposure have predominantly focused on either single chemical exposures or the more complex mixtures of tobacco smoke or its fractions. There are fewer studies exploring interactions between specific tobacco smoke chemicals. Aldehydes such as formaldehyde and acetaldehyde were hypothesized to enhance the carcinogenic properties of the human carcinogen, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) through a variety of mechanisms. This hypothesis was tested in the established NNK-induced A/J mouse lung tumor model. A/J mice were exposed to NNK (intraperitoneal injection, 0, 2.5, or 7.5 μmol in saline) in the presence or absence of acetaldehyde (0 or 360 ppmv) or formaldehyde (0 or 17 ppmv) for 3 h in a nose-only inhalation chamber, and lung tumors were counted 16 weeks later. Neither aldehyde by itself induced lung tumors. However, mice receiving both NNK and acetaldehyde or formaldehyde had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that aldehydes may increase the severity of NNK-induced lung adenomas. The aldehyde coexposure did not affect the levels of NNK-derived DNA adduct levels. Similar studies tested the ability of a 3 h nose-only carbon dioxide (0, 5, 10, or 15%) coexposure to influence lung adenoma formation by NNK. While carbon dioxide alone was not carcinogenic, it significantly increased the number of NNK-derived lung adenomas without affecting NNK-derived DNA damage. These studies indicate that the chemicals in tobacco smoke work together to form a potent lung carcinogenic mixture.
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Affiliation(s)
- Lisa A. Peterson
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Marissa K. Oram
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Monica Flavin
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Donna Seabloom
- AeroCore Testing Service, Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota, USA
| | - William E. Smith
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - M. Gerard O’Sullivan
- College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108, USA
- Comparative Pathology Shared Resource, Masonic Cancer Center, University of Minnesota, St. Paul, Minnesota, USA
| | - Karin R. Vevang
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Pramod Upadhyaya
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Alessia Stornetta
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Andrew C. Floeder
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Yen-Yi Ho
- Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Lin Zhang
- Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Stephen S. Hecht
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Silvia Balbo
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Timothy S. Wiedmann
- Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA
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Identification of New Markers of Alcohol-Derived DNA Damage in Humans. Biomolecules 2021; 11:biom11030366. [PMID: 33673538 PMCID: PMC7997542 DOI: 10.3390/biom11030366] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/16/2021] [Accepted: 02/21/2021] [Indexed: 12/13/2022] Open
Abstract
Alcohol consumption is a risk factor for the development of several cancers, including those of the head and neck and the esophagus. The underlying mechanisms of alcohol-induced carcinogenesis remain unclear; however, at these sites, alcohol-derived acetaldehyde seems to play a major role. By reacting with DNA, acetaldehyde generates covalent modifications (adducts) that can lead to mutations. Previous studies have shown a dose dependence between levels of a major acetaldehyde-derived DNA adduct and alcohol exposure in oral-cell DNA. The goal of this study was to optimize a mass spectrometry (MS)-based DNA adductomic approach to screen for all acetaldehyde-derived DNA adducts to more comprehensively characterize the genotoxic effects of acetaldehyde in humans. A high-resolution/-accurate-mass data-dependent constant-neutral-loss-MS3 methodology was developed to profile acetaldehyde-DNA adducts in purified DNA. This resulted in the identification of 22 DNA adducts. In addition to the expected N2-ethyldeoxyguanosine (after NaBH3CN reduction), two previously unreported adducts showed prominent signals in the mass spectra. MSn fragmentation spectra and accurate mass were used to hypothesize the structure of the two new adducts, which were then identified as N6-ethyldeoxyadenosine and N4-ethyldeoxycytidine by comparison with synthesized standards. These adducts were quantified in DNA isolated from oral cells collected from volunteers exposed to alcohol, revealing a significant increase after the exposure. In addition, 17 of the adducts identified in vitro were detected in these samples confirming our ability to more comprehensively characterize the DNA damage deriving from alcohol exposures.
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Housh K, Jha JS, Haldar T, Amin SBM, Islam T, Wallace A, Gomina A, Guo X, Nel C, Wyatt JW, Gates KS. Formation and repair of unavoidable, endogenous interstrand cross-links in cellular DNA. DNA Repair (Amst) 2021; 98:103029. [PMID: 33385969 PMCID: PMC8882318 DOI: 10.1016/j.dnarep.2020.103029] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023]
Abstract
Genome integrity is essential for life and, as a result, DNA repair systems evolved to remove unavoidable DNA lesions from cellular DNA. Many forms of life possess the capacity to remove interstrand DNA cross-links (ICLs) from their genome but the identity of the naturally-occurring, endogenous substrates that drove the evolution and retention of these DNA repair systems across a wide range of life forms remains uncertain. In this review, we describe more than a dozen chemical processes by which endogenous ICLs plausibly can be introduced into cellular DNA. The majority involve DNA degradation processes that introduce aldehyde residues into the double helix or reactions of DNA with endogenous low molecular weight aldehyde metabolites. A smaller number of the cross-linking processes involve reactions of DNA radicals generated by oxidation.
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Affiliation(s)
- Kurt Housh
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Jay S Jha
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Tuhin Haldar
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Saosan Binth Md Amin
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Tanhaul Islam
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Amanda Wallace
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Anuoluwapo Gomina
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Xu Guo
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Christopher Nel
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Jesse W Wyatt
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States
| | - Kent S Gates
- University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States; University of Missouri, Department of Biochemistry, Columbia, MO 65211, United States.
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Liu CW, Hsiao YC, Hoffman G, Lu K. LC-MS/MS Analysis of the Formation and Loss of DNA Adducts in Rats Exposed to Vinyl Acetate Monomer through Inhalation. Chem Res Toxicol 2021; 34:793-803. [PMID: 33486946 DOI: 10.1021/acs.chemrestox.0c00404] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Formation of DNA adducts is a key event during carcinogenesis. DNA adducts, if not repaired properly, can lead to mutations and cancer. DNA adducts have been frequently used as biomarkers to evaluate chemical exposure. Vinyl acetate monomer (VAM) is widely used in the manufacture of various industrial polymers. Previous studies have documented that VAM induced nasal tumors in rodents exposed to high exposure levels of VAM. VAM is metabolized by carboxylesterase to acetaldehyde (AA), which subsequently results in DNA adducts. However, AA is also an endogenous metabolite in living cells, which impedes accurate assessment of the contribution of VAM exposure under the substantial endogenous background. To address this challenge, we exposed rats to stable isotope labeled [13C2]-VAM at 50, 200, and 400 ppm through inhalation for 6 h, followed by DNA adduct analysis in nasal respiratory and olfactory epithelia with highly sensitive mass spectrometry. Our results show that exogenous N2-ethyl-dG adducts were present in all rats exposed to [13C2]-VAM, with over 2-fold higher DNA adducts in nasal respiratory epithelium than olfactory epithelium. Our data also show that N2-ethyl-dG is a more sensitive biomarker to assess VAM exposure than 1,N2-propano-dG adducts. Moreover, a very low amount of exogenous N2-ethyl-dG adducts were detected in peripheral blood mononuclear cell samples of exposed rats, suggesting that only an extremely small percentage of [13C2]-VAM or its metabolite may enter into systemic circulation to potentially damage tissues beyond nasal epithelium. Furthermore, exogenous N2-ethyl-dG DNA adducts undergo rapid repair or spontaneous loss in nasal epithelium of exposed rats. Taken together, the results presented herein provide novel quantitative data and lay the foundation for future studies to improve risk assessment of VAM.
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Affiliation(s)
- Chih-Wei Liu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Yun-Chung Hsiao
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Gary Hoffman
- Covance CRS, LLC, 100 Mettlers Road, Somerset, New Jersey 08873, United States
| | - Kun Lu
- Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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Bhoge BA, Mala P, Kurian JS, Srinivasan V, Saraogi I. Selective functionalization at N 2-position of guanine in oligonucleotides via reductive amination. Chem Commun (Camb) 2020; 56:13832-13835. [PMID: 33084637 DOI: 10.1039/d0cc05492e] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chemo- and site-specific modifications in oligonucleotides have wide applicability as mechanistic probes in chemical biology. However, methods that label specific sites in nucleic acids are scarce, especially for labeling DNA/RNA from biological or enzymatic sources rather than synthetic ones. Here we have employed a classical reaction, reductive amination, to selectively functionalize the N2-amine of guanosine and 2'-deoxyguanosine monophosphate (GMP/dGMP). This method specifically modifies guanine in DNA and RNA oligonucleotides, while leaving the other nucleobases unaffected. Using this approach, we have successfully incorporated a reactive handle chemoselectively into nucleic acids for further functionalization and downstream applications.
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Affiliation(s)
- Bapurao A Bhoge
- Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal 462066, MP, India.
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Alamil H, Galanti L, Heutte N, Van Der Schueren M, Dagher Z, Lechevrel M. Genotoxicity of aldehyde mixtures: profile of exocyclic DNA-adducts as a biomarker of exposure to tobacco smoke. Toxicol Lett 2020; 331:57-64. [PMID: 32442718 DOI: 10.1016/j.toxlet.2020.05.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/06/2020] [Accepted: 05/11/2020] [Indexed: 01/14/2023]
Abstract
Electrophilic compounds present in humans, originating from endogenous processes or pollutant exposures, pose a risk to health though their reaction with nucleophilic sites in protein and DNA. Among this chemical class, aldehydes are mainly present in indoor air and they can also be produced by endogenous lipid peroxidation arising from oxidative stress. Known to be very reactive, aldehydes have the ability to form exocyclic adducts to DNA that, for the most if not repaired correctly, are mutagenic and by consequence potential agents involved in carcinogenesis. The aim of this work was to establish profiles of exocyclic DNA adducts induced by aldehyde mixtures, which could ultimately be considered as a genotoxic marker of endogenous and environmental aldehyde exposure. Adducts were quantified by an accurate, sensitive and validated ultra high performance liquid chromatography-electrospray ionization analytical method coupled to mass spectrometry in the tandem mode (UHPLC-ESI-MS/MS). We simultaneously measured nine exocyclic DNA adducts generated during the exposure in vitro of calf thymus DNA to different concentrations of each aldehyde along, as well as, to an equimolar mixture of these aldehydes. This approach has enabled us to establish dose-response relationships that allowed displaying the specific reactivity of aldehydes towards corresponding adducts formation. Profiles of these adducts determined in DNA of current smokers and non-smokers blood samples supported these findings. These first results are encouraging to explore genotoxicity induced by aldehyde mixtures and can furthermore be used as future reference for adductomic approaches.
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Affiliation(s)
- Héléna Alamil
- Normandie University, UNICAEN, ABTE EA4651, Caen, France; CCC François Baclesse, UNICANCER, Caen, France; L2GE, Microbiology-Tox/Ecotox Team, Faculty of Sciences, Lebanese University, Fanar, Lebanon.
| | | | - Natacha Heutte
- CCC François Baclesse, UNICANCER, Caen, France; Normandie University, UNIROUEN, CETAPS EA3832, Mont Saint Aignan, Cedex, France
| | | | - Zeina Dagher
- L2GE, Microbiology-Tox/Ecotox Team, Faculty of Sciences, Lebanese University, Fanar, Lebanon
| | - Mathilde Lechevrel
- Normandie University, UNICAEN, ABTE EA4651, Caen, France; CCC François Baclesse, UNICANCER, Caen, France.
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Hirohashi K, Ohashi S, Amanuma Y, Nakai Y, Ida T, Baba K, Mitani Y, Mizumoto A, Yamamoto Y, Kikuchi O, Matsubara J, Yamada A, Miyamoto S, Seno H, Matsuda T, Muto M. Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice. Carcinogenesis 2020; 41:194-202. [PMID: 31074772 PMCID: PMC7175241 DOI: 10.1093/carcin/bgz091] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 04/15/2019] [Accepted: 05/09/2019] [Indexed: 12/15/2022] Open
Abstract
Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2′-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.
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Affiliation(s)
- Kenshiro Hirohashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Shinya Ohashi
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Yusuke Amanuma
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Yukie Nakai
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Tomomi Ida
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Kiichiro Baba
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Yosuke Mitani
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Ayaka Mizumoto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Yoshihiro Yamamoto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Osamu Kikuchi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Junichi Matsubara
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Atsushi Yamada
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Shin’ichi Miyamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
| | - Tomonari Matsuda
- Research Center for Environmental Quality Management, Kyoto University, Yumihama, Otsu, Japan
| | - Manabu Muto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan
- To whom correspondence should be addressed. Tel: +81 75 751 4592; Fax:+81 75 751 4594;
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Rageul J, Kim H. Fanconi anemia and the underlying causes of genomic instability. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2020; 61:693-708. [PMID: 31983075 PMCID: PMC7778457 DOI: 10.1002/em.22358] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 01/03/2020] [Accepted: 01/21/2020] [Indexed: 05/02/2023]
Abstract
Fanconi anemia (FA) is a rare genetic disorder, characterized by birth defects, progressive bone marrow failure, and a predisposition to cancer. This devastating disease is caused by germline mutations in any one of the 22 known FA genes, where the gene products are primarily responsible for the resolution of DNA interstrand cross-links (ICLs), a type of DNA damage generally formed by cytotoxic chemotherapeutic agents. However, the identity of endogenous mutagens that generate DNA ICLs remains largely elusive. In addition, whether DNA ICLs are indeed the primary cause behind FA phenotypes is still a matter of debate. Recent genetic studies suggest that naturally occurring reactive aldehydes are a primary source of DNA damage in hematopoietic stem cells, implicating that they could play a role in genome instability and FA. Emerging lines of evidence indicate that the FA pathway constitutes a general surveillance mechanism for the genome by protecting against a variety of DNA replication stresses. Therefore, understanding the DNA repair signaling that is regulated by the FA pathway, and the types of DNA lesions underlying the FA pathophysiology is crucial for the treatment of FA and FA-associated cancers. Here, we review recent advances in our understanding of the relationship between reactive aldehydes, bone marrow dysfunction, and FA biology in the context of signaling pathways triggered during FA-mediated DNA repair and maintenance of the genomic integrity. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc.
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Affiliation(s)
- Julie Rageul
- Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794, USA
| | - Hyungjin Kim
- Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794, USA
- Stony Brook Cancer Center, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York 11794, USA
- Correspondence to: Hyungjin Kim, Ph.D., Department of Pharmacological Sciences, Renaissance School of Medicine at Stony Brook University, Basic Sciences Tower 8-125, 100 Nicolls Rd., Stony Brook, NY 11794, Phone: 631-444-3134, FAX: 631-444-3218,
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39
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Face recognition system with PCA-GA algorithm for smart home door security using Rasberry Pi. JURNAL TEKNOLOGI DAN SISTEM KOMPUTER 2020. [DOI: 10.14710/jtsiskom.2020.13590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Genetic algorithm (GA) can improve the classification of the face recognition process in the principal component analysis (PCA). However, the accuracy of this algorithm for the smart home security system has not been further analyzed. This paper presents the accuracy of face recognition using PCA-GA for the smart home security system on Raspberry Pi. PCA was used as the face recognition algorithm, while GA to improve the classification performance of face image search. The PCA-GA algorithm was implemented on the Raspberry Pi. If an authorized person accesses the door of the house, the relay circuit will unlock the door. The accuracy of the system was compared to other face recognition algorithms, namely LBPH-GA and PCA. The results show that PCA-GA face recognition has an accuracy of 90 %, while PCA and LBPH-GA have 80 % and 90 %, respectively.
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40
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Interplay between Cellular Metabolism and the DNA Damage Response in Cancer. Cancers (Basel) 2020; 12:cancers12082051. [PMID: 32722390 PMCID: PMC7463900 DOI: 10.3390/cancers12082051] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/20/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022] Open
Abstract
Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.
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41
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Ethanol exposure increases mutation rate through error-prone polymerases. Nat Commun 2020; 11:3664. [PMID: 32694532 PMCID: PMC7374746 DOI: 10.1038/s41467-020-17447-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 06/30/2020] [Indexed: 12/19/2022] Open
Abstract
Ethanol is a ubiquitous environmental stressor that is toxic to all lifeforms. Here, we use the model eukaryote Saccharomyces cerevisiae to show that exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate. Specifically, we find that ethanol slows down replication and affects localization of Mrc1, a conserved protein that helps stabilize the replisome. In addition, ethanol exposure also results in the recruitment of error-prone DNA polymerases to the replication fork. Interestingly, preventing this recruitment through mutagenesis of the PCNA/Pol30 polymerase clamp or deleting specific error-prone polymerases abolishes the mutagenic effect of ethanol. Taken together, this suggests that the mutagenic effect depends on a complex mechanism, where dysfunctional replication forks lead to recruitment of error-prone polymerases. Apart from providing a general mechanistic framework for the mutagenic effect of ethanol, our findings may also provide a route to better understand and prevent ethanol-associated carcinogenesis in higher eukaryotes. Whereas the toxic effects of ethanol are well-documented, the underlying mechanism is obscure. This study uses the eukaryotic model S. cerevisiae to reveal how exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate.
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42
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Wine Consumption and Oral Cavity Cancer: Friend or Foe, Two Faces of Janus. Molecules 2020; 25:molecules25112569. [PMID: 32486484 PMCID: PMC7321235 DOI: 10.3390/molecules25112569] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/21/2020] [Accepted: 05/28/2020] [Indexed: 12/29/2022] Open
Abstract
The health benefits of moderate wine consumption have been extensively studied during the last few decades. Some studies have demonstrated protective associations between moderate drinking and several diseases including oral cavity cancer (OCC). However, due to the various adverse effects related to ethanol content, the recommendation of moderate wine consumption has been controversial. The polyphenolic components of wine contribute to its beneficial effects with different biological pathways, including antioxidant, lipid regulating and anti-inflammatory effects. On the other hand, in the oral cavity, ethanol is oxidized to form acetaldehyde, a metabolite with genotoxic properties. This review is a critical compilation of both the beneficial and the detrimental effects of wine consumption on OCC.
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Kaminen-Ahola N. Fetal alcohol spectrum disorders: Genetic and epigenetic mechanisms. Prenat Diagn 2020; 40:1185-1192. [PMID: 32386259 DOI: 10.1002/pd.5731] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 03/26/2020] [Accepted: 05/03/2020] [Indexed: 12/11/2022]
Abstract
Fetal alcohol spectrum disorders (FASD) are a consequence of prenatal alcohol exposure (PAE). The etiology of the complex FASD phenotype with growth deficit, birth defects, and neurodevelopmental impairments is under extensive research. Both genetic and environmental factors contribute to the wide phenotype: chromosomal rearrangements, risk and protective alleles, environmental-induced epigenetic alterations as well as gene-environment interactions are all involved. Understanding the molecular mechanisms of PAE can provide tools for prevention or intervention of the alcohol-induced developmental disorders in the future. By revealing the alcohol-induced genetic and epigenetic alterations which associate with the variable FASD phenotypes, it is possible to identify biomarkers for the disorder. This would enable early diagnoses and personalized support for development of the affected child.
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Affiliation(s)
- Nina Kaminen-Ahola
- Environmental Epigenetics Laboratory, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
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44
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Suzuki A, Katoh H, Komura D, Kakiuchi M, Tagashira A, Yamamoto S, Tatsuno K, Ueda H, Nagae G, Fukuda S, Umeda T, Totoki Y, Abe H, Ushiku T, Matsuura T, Sakai E, Ohshima T, Nomura S, Seto Y, Shibata T, Rino Y, Nakajima A, Fukayama M, Ishikawa S, Aburatani H. Defined lifestyle and germline factors predispose Asian populations to gastric cancer. SCIENCE ADVANCES 2020; 6:eaav9778. [PMID: 32426482 PMCID: PMC7202881 DOI: 10.1126/sciadv.aav9778] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 02/03/2020] [Indexed: 05/11/2023]
Abstract
Germline and environmental effects on the development of gastric cancers (GC) and their ethnic differences have been poorly understood. Here, we performed genomic-scale trans-ethnic analysis of 531 GCs (319 Asian and 212 non-Asians). There was one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, almost all of which were attributable to alcohol intake behavior, smoking habit, and Asian-specific defective ALDH2 allele. Alcohol-related GCs have low mutation burden and characteristic immunological profiles. In addition, we found frequent (7.4%) germline CDH1 variants among Japanese GCs, most of which were attributed to a few recurrent single-nucleotide variants shared by Japanese and Koreans, suggesting the existence of common ancestral events among East Asians. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective ALDH2 allele or to CDH1 variants. These results revealed uncharacterized impacts of germline variants and lifestyles in the high incidence areas.
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Affiliation(s)
- Akihiro Suzuki
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Hiroto Katoh
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Daisuke Komura
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Miwako Kakiuchi
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
| | - Amane Tagashira
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shogo Yamamoto
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
| | - Kenji Tatsuno
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
| | - Hiroki Ueda
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
| | - Genta Nagae
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
| | - Shiro Fukuda
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
| | - Takayoshi Umeda
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
| | - Yasushi Totoki
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroyuki Abe
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuya Matsuura
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Eiji Sakai
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Takashi Ohshima
- Department of Surgery, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
- Laboratory of Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yasushi Rino
- Department of Surgery, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shumpei Ishikawa
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
- Corresponding author. (H.A.); (S.I.)
| | - Hiroyuki Aburatani
- Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo, Japan
- Corresponding author. (H.A.); (S.I.)
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Sobh A, Loguinov A, Stornetta A, Balbo S, Tagmount A, Zhang L, Vulpe CD. Genome-Wide CRISPR Screening Identifies the Tumor Suppressor Candidate OVCA2 As a Determinant of Tolerance to Acetaldehyde. Toxicol Sci 2020; 169:235-245. [PMID: 31059574 DOI: 10.1093/toxsci/kfz037] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Acetaldehyde, a metabolite of ethanol, is a cellular toxicant and a human carcinogen. A genome-wide CRISPR-based loss-of-function screen in erythroleukemic K562 cells revealed candidate genetic contributors affecting acetaldehyde cytotoxicity. Secondary screening exposing cells to a lower acetaldehyde dose simultaneously validated multiple candidate genes whose loss results in increased sensitivity to acetaldehyde. Disruption of genes encoding components of various DNA repair pathways increased cellular sensitivity to acetaldehyde. Unexpectedly, the tumor suppressor gene OVCA2, whose function is unknown, was identified in our screen as a determinant of acetaldehyde tolerance. Disruption of the OVCA2 gene resulted in increased acetaldehyde sensitivity and higher accumulation of the acetaldehyde-derived DNA adduct N2-ethylidene-dG. Together these results are consistent with a role for OVCA2 in adduct removal and/or DNA repair.
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Affiliation(s)
- Amin Sobh
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida.,Department of Nutritional Sciences & Toxicology, Comparative Biochemistry Program, University of California, Berkeley, California
| | - Alex Loguinov
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Alessia Stornetta
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Silvia Balbo
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.,Division of Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota
| | - Abderrahmane Tagmount
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California
| | - Chris D Vulpe
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
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46
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47
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Kahila H, Marjonen H, Auvinen P, Avela K, Riikonen R, Kaminen‐Ahola N. 18q12.3-q21.1 microdeletion detected in the prenatally alcohol-exposed dizygotic twin with discordant fetal alcohol syndrome phenotype. Mol Genet Genomic Med 2020; 8:e1192. [PMID: 32096599 PMCID: PMC7196488 DOI: 10.1002/mgg3.1192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 11/21/2019] [Accepted: 12/10/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND A pair of dizygotic twins discordantly affected by heavy prenatal alcohol exposure (PAE) was reported previously by Riikonen, suggesting the role of genetic risk or protective factors in the etiology of alcohol-induced developmental disorders. Now, we have re-examined these 25-year-old twins and explored genetic origin of the phenotypic discordancy reminiscent with fetal alcohol syndrome (FAS). Furthermore, we explored alterations in DNA methylation profile of imprinting control region at growth-related insulin-like growth factor 2 (IGF2)/H19 locus in twins' white blood cells (WBC), which have been associated earlier with alcohol-induced genotype-specific changes in placental tissue. METHODS Microarray-based comparative genomic hybridization (aCGH) was used to detect potential submicroscopic chromosomal abnormalities, and developmental as well as phenotypic information about twins were collected. Traditional bisulfite sequencing was used for DNA methylation analysis. RESULTS Microarray-based comparative genomic hybridization revealed a microdeletion 18q12.3-q21.1. in affected twin, residing in a known 18q deletion syndrome region. This syndrome has been associated with growth restriction, developmental delay or intellectual deficiency, and abnormal facial features in previous studies, and thus likely explains the phenotypic discordancy between the twins. We did not observe association between WBCs' DNA methylation profile and PAE, but interestingly, a trend of decreased DNA methylation at the imprinting control region was seen in the twin with prenatal growth retardation at birth. CONCLUSIONS The microdeletion emphasizes the importance of adequate chromosomal testing in examining the etiology of complex alcohol-induced developmental disorders. Furthermore, the genotype-specific decreased DNA methylation at the IGF2/H19 locus cannot be considered as a biological mark for PAE in adult WBCs.
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Affiliation(s)
- Hanna Kahila
- Department of Obstetrics and GynecologyHelsinki University Hospital and University of HelsinkiHelsinkiFinland
| | - Heidi Marjonen
- Department of Medical and Clinical GeneticsMedicumUniversity of HelsinkiHelsinkiFinland
| | - Pauliina Auvinen
- Department of Medical and Clinical GeneticsMedicumUniversity of HelsinkiHelsinkiFinland
| | - Kristiina Avela
- Department of Clinical GeneticsHelsinki University HospitalHUSLABHelsinkiFinland
| | - Raili Riikonen
- Children's HospitalKuopio University HospitalUniversity of Eastern FinlandKuopioFinland
| | - Nina Kaminen‐Ahola
- Department of Medical and Clinical GeneticsMedicumUniversity of HelsinkiHelsinkiFinland
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Gooderham NJ, Cohen SM, Eisenbrand G, Fukushima S, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Bastaki M, Linman MJ, Taylor SV. The safety evaluation of food flavoring substances: the role of genotoxicity studies. Crit Rev Toxicol 2020; 50:1-27. [PMID: 32162576 DOI: 10.1080/10408444.2020.1712589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The Flavor and Extract Manufacturers Association (FEMA) Expert Panel relies on the weight of evidence from all available data in the safety evaluation of flavoring substances. This process includes data from genotoxicity studies designed to assess the potential of a chemical agent to react with DNA or otherwise cause changes to DNA, either in vitro or in vivo. The Panel has reviewed a large number of in vitro and in vivo genotoxicity studies during the course of its ongoing safety evaluations of flavorings. The adherence of genotoxicity studies to standardized protocols and guidelines, the biological relevance of the results from those studies, and the human relevance of these studies are all important considerations in assessing whether the results raise specific concerns for genotoxic potential. The Panel evaluates genotoxicity studies not only for evidence of genotoxicity hazard, but also for the probability of risk to the consumer in the context of exposure from their use as flavoring substances. The majority of flavoring substances have given no indication of genotoxic potential in studies evaluated by the FEMA Expert Panel. Examples illustrating the assessment of genotoxicity data for flavoring substances and the consideration of the factors noted above are provided. The weight of evidence approach adopted by the FEMA Expert Panel leads to a rational assessment of risk associated with consumer intake of flavoring substances under the conditions of use.
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Affiliation(s)
| | - Samuel M Cohen
- Havlik-Wall Professor of Oncology, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Gerhard Eisenbrand
- Food Chemistry & Toxicology, University of Kaiserslautern (retired), Heidelberg, Germany
| | | | - F Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Stephen S Hecht
- Masonic Cancer Center and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | | | - Thomas J Rosol
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Maria Bastaki
- Flavor and Extract Manufacturers Association, Washington, DC, USA
| | - Matthew J Linman
- Flavor and Extract Manufacturers Association, Washington, DC, USA
| | - Sean V Taylor
- Flavor and Extract Manufacturers Association, Washington, DC, USA
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49
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Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms. Nature 2020; 579:603-608. [PMID: 32132710 DOI: 10.1038/s41586-020-2059-5] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 01/31/2020] [Indexed: 11/08/2022]
Abstract
Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5-7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision-analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions-instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.
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Hernandez-Castillo C, Termini J, Shuck S. DNA Adducts as Biomarkers To Predict, Prevent, and Diagnose Disease-Application of Analytical Chemistry to Clinical Investigations. Chem Res Toxicol 2020; 33:286-307. [PMID: 31638384 DOI: 10.1021/acs.chemrestox.9b00295] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Characterization of the chemistry, structure, formation, and metabolism of DNA adducts has been one of the most significant contributions to the field of chemical toxicology. This work provides the foundation to develop analytical methods to measure DNA adducts, define their relationship to disease, and establish clinical tests. Monitoring exposure to environmental and endogenous toxicants can predict, diagnose, and track disease as well as guide therapeutic treatment. DNA adducts are one of the most promising biomarkers of toxicant exposure owing to their stability, appearance in numerous biological matrices, and characteristic analytical properties. In addition, DNA adducts can induce mutations to drive disease onset and progression and can serve as surrogate markers of chemical exposure. In this perspective, we highlight significant advances made within the past decade regarding DNA adduct quantitation using mass spectrometry. We hope to expose a broader audience to this field and encourage analytical chemistry laboratories to explore how specific adducts may be related to various pathologies. One of the limiting factors in developing clinical tests to measure DNA adducts is cohort size; ideally, the cohort would allow for model development and then testing of the model to the remaining cohort. The goals of this perspective article are to (1) provide a summary of analyte levels measured using state-of-the-art analytical methods, (2) foster collaboration, and (3) highlight areas in need of further investigation.
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Affiliation(s)
- Carlos Hernandez-Castillo
- Department of Molecular Medicine , Beckman Research Institute at City of Hope Duarte , California 91010 , United States
| | - John Termini
- Department of Molecular Medicine , Beckman Research Institute at City of Hope Duarte , California 91010 , United States
| | - Sarah Shuck
- Department of Molecular Medicine , Beckman Research Institute at City of Hope Duarte , California 91010 , United States
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