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Chemosphere Feb 20202,4-dichlorophenoxyacetic acid (2,4-D) is a herbicide that is used worldwide in agricultural and urban activities to control pests, reaching natural environments... (Review)
Review
2,4-dichlorophenoxyacetic acid (2,4-D) is a herbicide that is used worldwide in agricultural and urban activities to control pests, reaching natural environments directly or indirectly. The research on 2,4-D toxicology and mutagenicity has advanced rapidly, and for this reason, this review summarizes the available data in Web of Science (WoS) to provide insights into the specific characteristics of 2,4-D toxicity and mutagenicity. Contrary to traditional reviews, this study uses a new method to quantitatively visualize and summarize information about the development of this field. Among all countries, the USA was the most active contributor with the largest publication and centrality, followed by Canada and China. The WoS categories 'Toxicology' and 'Biochemical and Molecular Biology' were the areas of greatest influence. 2,4-D research was strongly related to the keywords glyphosate, atrazine, water and gene expression. The studies trended to be focused on occupational risk, neurotoxicity, resistance or tolerance to herbicides, and to non-target species (especially aquatic ones) and molecular imprinting. In general, the authors have worked collaboratively, with concentrated efforts, allowing important advances in this field. Future research on 2,4-D toxicology and mutagenicity should probably focus on molecular biology, especially gene expression, assessment of exposure in human or other vertebrate bioindicators, and pesticide degradation studies. In summary, this scientometric analysis allowed us to make inferences about global trends in 2,4-D toxicology and mutagenicity, in order to identify tendencies and gaps and thus contribute to future research efforts.
Topics: 2,4-Dichlorophenoxyacetic Acid; Atrazine; Environmental Pollution; Gene Expression; Glycine; Herbicides; Humans; Mutagens; Glyphosate
PubMed: 31683446
DOI: 10.1016/j.chemosphere.2019.125016 -
Acta Neuropathologica Communications Feb 2024
Topics: Humans; Mutagens; Guam; Methylazoxymethanol Acetate; Mutagenesis; Amyotrophic Lateral Sclerosis
PubMed: 38383591
DOI: 10.1186/s40478-024-01725-y -
Molekuliarnaia Biologiia 2022Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against... (Review)
Review
Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against viruses, the introduction of point mutations into DNA during somatic hypermutation, and antibody isotype switching. Since these deaminases, especially AID, are potent mutagens, their expression, activity, and specificity are regulated by several intra-cellular mechanisms. In this review, we discuss the mechanisms of impaired expression and activation of AID/APOBEC proteins in human tumors and their role in carcinogenesis and tumor progression. Also, the diagnostic and potential therapeutic value of increased expression of AID/APOBEC in different types of tumors is analyzed. We assume that in the case of solid tumors, increased expression of endogenous deaminases can serve as a marker of response to immunotherapy since multiple point mutations in host DNA could lead to amino acid substitutions in tumor proteins and thereby increase the frequency of neoepitopes.
Topics: APOBEC Deaminases; Antiviral Restriction Factors; Carcinogenesis; Cytidine Deaminase; Humans; Mutagens
PubMed: 35082258
DOI: 10.31857/S0026898422010086 -
Cell Reports Jun 2021Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins...
Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on T cells-the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATM-p38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and T cell senescence.
Topics: Cellular Senescence; DNA Damage; Humans; Mutagens; T-Lymphocytes
PubMed: 34107253
DOI: 10.1016/j.celrep.2021.109220 -
Cancer Cell Mar 2024Co-culture of intestinal organoids with a colibactin-producing pksE. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). E. coli...
Co-culture of intestinal organoids with a colibactin-producing pksE. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). E. coli Nissle 1917 (EcN) remains a commonly used probiotic, despite harboring the pks operon and inducing double strand DNA breaks. We determine the mutagenicity of EcN and three CRC-derived pksE. coli strains with an analytical framework based on sequence characteristic of colibactin-induced mutations. All strains, including EcN, display varying levels of mutagenic activity. Furthermore, a machine learning approach attributing individual mutations to colibactin reveals that patients with colibactin-induced mutations are diagnosed at a younger age and that colibactin can induce a specific APC mutation. These approaches allow the sensitive detection of colibactin-induced mutations in ∼12% of CRC genomes and even in whole exome sequencing data, representing a crucial step toward pinpointing the mutagenic activity of distinct pksE. coli strains.
Topics: Humans; Escherichia coli; Mutation; DNA Damage; Mutagens; Colorectal Neoplasms; Organoids; Peptides; Polyketides
PubMed: 38471458
DOI: 10.1016/j.ccell.2024.02.009 -
Nature Genetics Jan 2024The chemotherapeutic agent CX-5461, or pidnarulex, has been fast-tracked by the United States Food and Drug Administration for early-stage clinical studies of BRCA1-,...
The chemotherapeutic agent CX-5461, or pidnarulex, has been fast-tracked by the United States Food and Drug Administration for early-stage clinical studies of BRCA1-, BRCA2- and PALB2-mutated cancers. It is under investigation in phase I and II trials. Here, we find that, although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, nonselective, collateral mutagenesis in all three cell lines tested, to magnitudes that exceed known environmental carcinogens.
Topics: Humans; Mutagens; BRCA1 Protein; BRCA2 Protein; Benzothiazoles; Naphthyridines; Neoplasms
PubMed: 38036782
DOI: 10.1038/s41588-023-01602-9 -
International Journal of Environmental... Jan 2023Cancer is one of the longest-known human diseases, yet only in recent times have we begun to perceive that the percentage of neoplasms caused by environmental factors,... (Review)
Review
Cancer is one of the longest-known human diseases, yet only in recent times have we begun to perceive that the percentage of neoplasms caused by environmental factors, lifestyle and chemicals, is likely underestimated. The first medical reports associating cancer with pollutants like tars appeared by the early 20th century, but despite initial evidence relating oncogenesis and chromosomal alterations, only after the structure of DNA had been elucidated in the 1950s have genetic disorders been fully perceived as cause. This led to a growing interest in genotoxic and mutagenic pollutants. Even though we are now familiar with a range of environmental carcinogens spanning between aromatic hydrocarbons and asbestos to radionuclides and forms of carbon nanomaterials, establishing causal networks between pollutants and cancer remains cumbersome. In most part, this is due to the complexity of toxicant matrices, unknown modes-of-action of chemicals or their mixtures, the widening array of novel pollutants plus difficulties in subtracting background effects from true aetiology of disease. Recent advances in analytical chemistry, high-throughput toxicology, next-generation sequencing, computational biology and databases that allocate whole normal and cancer genomes, all indicate that we are on the verge of a new age of research into mechanistic 'oncotoxicology', but how can it impact risk assessment and prevention?
Topics: Humans; Carcinogens; Mutagens; Neoplasms; Environmental Pollutants; Carcinogens, Environmental; Causality
PubMed: 36673796
DOI: 10.3390/ijerph20021040 -
Viruses Apr 2022In RNA viruses, a small increase in their mutation rates can be sufficient to exceed their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on... (Review)
Review
In RNA viruses, a small increase in their mutation rates can be sufficient to exceed their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on the use of mutagens, driving viral populations to extinction. Extinction catastrophe can be experimentally induced by promutagenic nucleosides in cell culture models. The loss of HIV infectivity has been observed after passage in 5-hydroxydeoxycytidine or 5,6-dihydro-5-aza-2'-deoxycytidine while producing a two-fold increase in the viral mutation frequency. Among approved nucleoside analogs, experiments with polioviruses and other RNA viruses suggested that ribavirin can be mutagenic, although its mechanism of action is not clear. Favipiravir and molnupiravir exert an antiviral effect through lethal mutagenesis. Both drugs are broad-spectrum antiviral agents active against RNA viruses. Favipiravir incorporates into viral RNA, affecting the G→A and C→U transition rates. Molnupiravir (a prodrug of β-d-N-hydroxycytidine) has been recently approved for the treatment of SARS-CoV-2 infection. Its triphosphate derivative can be incorporated into viral RNA and extended by the coronavirus RNA polymerase. Incorrect base pairing and inefficient extension by the polymerase promote mutagenesis by increasing the G→A and C→U transition frequencies. Despite having remarkable antiviral action and resilience to drug resistance, carcinogenic risks and genotoxicity are important concerns limiting their extended use in antiviral therapy.
Topics: Antiviral Agents; COVID-19; Humans; Mutagenesis; Mutagens; Nucleosides; RNA Viruses; RNA, Viral; SARS-CoV-2
PubMed: 35458571
DOI: 10.3390/v14040841 -
Molecules (Basel, Switzerland) Dec 2021Aflatoxins are mycotoxins produced as secondary fungal metabolites. Among them, aflatoxin B1 (AFB1) stands out due to its genotoxic and mutagenic potential, being a... (Review)
Review
Aflatoxins are mycotoxins produced as secondary fungal metabolites. Among them, aflatoxin B1 (AFB1) stands out due to its genotoxic and mutagenic potential, being a potent initiator of carcinogenesis. In this review, the outcomes from the published literature in the past 10 years on the effects of AFB1 pathophysiological mechanisms on embryological and fetal development are discussed. In several animal species, including humans, AFB1 has a teratogenic effect resulting in bone malformations, visceral anomalies, lesions in several organs, and behavioral and reproductive changes, in addition to low birth weight. The mutagenic capacity of AFB1 in prenatal life is greater than in adults, indicating that when exposure occurs in the womb, the risk of the development of neoplasms is higher. Studies conducted in humans indicate that the exposure to this mycotoxin during pregnancy is associated with low birth weight, decreased head circumference, and DNA hypermethylation. However, as the actual impacts on humans are still unclear, the importance of this issue cannot be overemphasized and studies on the matter are essential.
Topics: Aflatoxin B1; Animals; DNA Methylation; Female; Humans; Mutagens; Neoplasms; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 34885894
DOI: 10.3390/molecules26237312 -
Molecular Aspects of Medicine Oct 2019The somatic mutation spectrum imprinted in the genome of a tumor represents the mutational processes that have been active in that tumor. Large sequencing efforts in... (Review)
Review
The somatic mutation spectrum imprinted in the genome of a tumor represents the mutational processes that have been active in that tumor. Large sequencing efforts in various cancer types have resulted in the identification of multiple mutational signatures, of which several have been linked to specific biological mechanisms. Several pan-cancer mutational signatures have been identified, while other signatures are only found in specific tissue types. Research on tumors from individuals with specific DNA repair defects has led to links between specific mutational signatures and mutational processes. Studying mutational signatures in cancers that are likely the result of a genetic predisposition may represent an interesting strategy to identify constitutional DNA repair defects, including those underlying polyposis and colorectal cancer.
Topics: Adenomatous Polyposis Coli; Aging; Colorectal Neoplasms; DNA Repair; Genetic Association Studies; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Mutagens; Mutation; Organ Specificity
PubMed: 31108140
DOI: 10.1016/j.mam.2019.05.002