Acetaldehyde induces NER repairable mutagenic DNA lesions

Sonohara, Yuina; Takatsuka, Reine; Masutani, Chikahide; Iwai, Shigenori; Kuraoka, Isao

doi:10.1093/carcin/bgab087

Cited by 5 publications

(2 citation statements)

References 29 publications

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“…96 Moreover, ethanol and its metabolites in colon epithelial cells contribute to the formation of ROS, reactive nitrogen species and mucosal inflammatory response, 97 98 which may indirectly lead to DNA damage and initiate malignant transformation. 99 100 As a very reactive and toxic intermediate metabolite of ethanol, acetaldehyde causes various DNA modifications, including mutagenic DNA lesions and chromosomal instability, 100 101 single-strand or double-strand breaks, reacting with deoxyguanosine to form N2-ethylidenedeoxyguanosine, a Schiff base adduct 102 and formation of adducts with DNA or proteins, 103 which has been shown to correlate with hyperproliferation of colon crypt cells and CRC development. 100 104 In addition to the carcinogenic roles, recent evidence suggests that ethanol and its metabolites can directly function on a variety of molecular pathways in CRC.…”

Section: Alcohol-associated Colon Cancermentioning

confidence: 99%

Alcohol-associated bowel disease: new insights into pathogenesis

Maccioni,

Fu,

Horsmans

et al. 2023

egastro

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Excessive alcohol drinking can cause pathological changes including carcinogenesis in the digestive tract from mouth to large intestine, but the underlying mechanisms are not fully understood. In this review, we discuss the effects of alcohol on small and large intestinal functions, such as leaky gut, dysbiosis and alterations of intestinal epithelium and gut immune dysfunctions, commonly referred to as alcohol-associated bowel disease (ABD). To date, detailed mechanistic insights into ABD are lacking. Accumulating evidence suggests a pathogenic role of ethanol metabolism in dysfunctions of the intestinal tract. Ethanol metabolism generates acetaldehyde and acetate, which could potentially promote functional disruptions of microbial and host components of the intestinal barrier along the gastrointestinal tract. The potential involvement of acetaldehyde and acetate in the pathogenesis of the underlying ABD, including cancer, is discussed. We also highlight some gaps in knowledge existing in the field of ABD. Finally, we discuss future directions in exploring the role of acetaldehyde and acetate generated during chronic alcohol intake in various pathologies affecting different sites of the intestinal tract.

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Section: Alcohol-associated Colon Cancermentioning

confidence: 99%

Alcohol-associated bowel disease: new insights into pathogenesis

Maccioni,

Fu,

Horsmans

et al. 2023

egastro

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“…The Fanconi anemia pathway was also found to be responsible for repair of DNA intra-strand crosslinks created in vitro on plasmids [25]. Cell extracts deficient in xeroderma pigmentosum group A (XPA) proteins or human cell lines with XPA defects were unable to repair acetaldehyde-induced DNA damage on plasmid DNA, indicating a role of NER in repair of acetaldehyde DNA damage [26]. Additionally, in Schizosaccharomyces pombe, defects in homologous recombination, aldehyde clearance pathways, nucleotide excision repair, fork protection complex and checkpoint response pathways were found to sensitize cells to exogenous acetaldehyde [27].…”

Section: Introductionmentioning

confidence: 99%

Multiple DNA repair pathways prevent acetaldehyde-induced mutagenesis in yeast

Porcher,

Vijayraghavan,

McCollum

et al. 2024

Preprint

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Acetaldehyde is the primary metabolite of alcohol and is present in many environmental sources including tobacco smoke. Acetaldehyde is genotoxic, whereby it can form DNA adducts and lead to mutagenesis. Individuals with defects in acetaldehyde clearance pathways have increased susceptibility to alcohol-associated cancers. Moreover, a mutation signature specific to acetaldehyde exposure is widespread in alcohol and smoking-associated cancers. However, the pathways that repair acetaldehyde-induced DNA damage and thus prevent mutagenesis are vaguely understood. Here, we used Saccharomycescerevisiae to systematically delete genes in each of the major DNA repair pathways to identify those that alter acetaldehyde-induced mutagenesis. We found that deletion of the nucleotide excision repair (NER) genes, RAD1 or RAD14, led to an increase in mutagenesis upon acetaldehyde exposure. Acetaldehyde-induced mutations were dependent on translesion synthesis as well as DNA inter-strand crosslink (ICL) repair in Drad1 strains. Moreover, whole genome sequencing of the mutated isolates demonstrated an increase in C?A changes coupled with an enrichment of gCn?A changes in the acetaldehyde-treated Drad1 isolates. The gCn?A mutation signature has been shown to be diagnostic of acetaldehyde exposure in yeast and in human cancers. We also demonstrated that the deletion of the two DNA-protein crosslink (DPC) repair proteases, WSS1 and DDI1, also led to increased acetaldehyde-induced mutagenesis. Defects in base excision repair (BER) led to a mild increase in mutagenesis, while defects in mismatch repair (MMR), homologous recombination repair (HR) and post replicative repair pathways did not impact mutagenesis upon acetaldehyde exposure. Our results in yeast were further corroborated upon analysis of whole exome sequenced liver cancers, wherein, tumors with defects in ERCC1 and ERCC4 (NER), FANCD2 (ICL repair) or SPRTN (DPC repair) carried a higher gCn?A mutation load than tumors with no deleterious mutations in these genes. Our findings demonstrate that multiple DNA repair pathways protect against acetaldehyde-induced mutagenesis.

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Acetaldehyde as a Food Flavoring Substance: Aspects of Risk Assessment

Cartus,

Lachenmeier,

Guth

et al. 2023

Molecular Nutrition Food Res

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The Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) has reviewed the currently available data in order to assess the health risks associated with the use of acetaldehyde as a flavoring substance in foods. Acetaldehyde is genotoxic in vitro. Following oral intake of ethanol or inhalation exposure to acetaldehyde, systemic genotoxic effects of acetaldehyde in vivo cannot be ruled out (induction of DNA adducts and micronuclei). At present, the key question of whether acetaldehyde is genotoxic and mutagenic in vivo after oral exposure cannot be answered conclusively. There is also insufficient data on human exposure. Consequently, it is currently not possible to reliably assess the health risk associated with the use of acetaldehyde as a flavoring substance. However, considering the genotoxic potential of acetaldehyde as well as numerous data gaps that need to be filled to allow a comprehensive risk assessment, the SKLM considers that the use of acetaldehyde as a flavoring may pose a safety concern. For reasons of precautionary consumer protection, the SKLM recommends that the scientific base for approval of the intentional addition of acetaldehyde to foods as a flavoring substance should be reassessed.

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Acetaldehyde induces NER repairable mutagenic DNA lesions

Cited by 5 publications

References 29 publications

Alcohol-associated bowel disease: new insights into pathogenesis

Alcohol-associated bowel disease: new insights into pathogenesis

Multiple DNA repair pathways prevent acetaldehyde-induced mutagenesis in yeast

Acetaldehyde as a Food Flavoring Substance: Aspects of Risk Assessment

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