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Environmental Health and Preventive... May 2015Numerous experimental observations have been made on microorganisms and culture of the cells of mammals as well as the accounting of the chromosomal aberrations in the... (Comparative Study)
Comparative Study Review
Numerous experimental observations have been made on microorganisms and culture of the cells of mammals as well as the accounting of the chromosomal aberrations in the bone marrow cells of the mammals and of human cells displayed that the chromium and its compounds possess a pronounced mutagenic effect. Translocation test, induction record of DNA damage and repair systems in the mammalian and human cells with greater precision proves the presence of the mutagenic effect of the chromium and its compounds, which in turn is dependent on dose and time of this metal intoxication. Chromium and its compounds have pronounced mutagenic effect, on increased admission to organism of mammals and protozoa.
Topics: Animals; Bacteria; Carcinogens; Cell Survival; Chromium; Chromium Compounds; DNA; Humans; Invertebrates; Mutagens; Vertebrates
PubMed: 25877777
DOI: 10.1007/s12199-015-0458-2 -
Arhiv Za Higijenu Rada I Toksikologiju Sep 2016Knowing the mutagenic and carcinogenic properties of chemicals is very important for their hazard (and risk) assessment. One of the crucial events that trigger genotoxic... (Review)
Review
Knowing the mutagenic and carcinogenic properties of chemicals is very important for their hazard (and risk) assessment. One of the crucial events that trigger genotoxic and sometimes carcinogenic effects is the forming of adducts between chemical compounds and nucleic acids and histones. This review takes a look at the mechanisms related to specific functional groups (structural alerts or toxicophores) that may trigger genotoxic or epigenetic effects in the cells. We present up-to-date information about defined structural alerts with their mechanisms and the software based on this knowledge (QSAR models and classification schemes).
Topics: Carcinogens; Humans; Mutagens; Quantitative Structure-Activity Relationship; Risk Assessment
PubMed: 27749264
DOI: 10.1515/aiht-2016-67-2801 -
Environmental Science and Pollution... Sep 2022Despite the association between tobacco use and the harmful effects on general health as well as male fertility parameters, smoking remains globally prevalent. The main... (Review)
Review
Despite the association between tobacco use and the harmful effects on general health as well as male fertility parameters, smoking remains globally prevalent. The main content of tobacco smoke is nicotine and its metabolite cotinine. These compounds can pass the blood-testis barrier, which subsequently causes harm of diverse degree to the germ cells. Although controversial, smoking has been shown to cause not only a decrease in sperm motility, sperm concentration, and an increase in abnormal sperm morphology, but also genetic and epigenetic aberrations in spermatozoa. Both animal and human studies have highlighted the occurrence of sperm DNA-strand breaks (fragmentation), genome instability, genetic mutations, and the presence of aneuploids in the germline of animals and men exposed to tobacco smoke. The question to be asked at this point is, if smoking has the potential to cause all these genetic aberrations, what is the extent of damage? Hence, this review aimed to provide evidence that smoking has a mutagenic effect on sperm and how this subsequently affects male fertility. Additionally, the role of tobacco smoke as an aneugen will be explored. We furthermore aim to incorporate the epidemiological aspects of the aforementioned and provide a holistic approach to the topic.
Topics: Animals; Fertility; Humans; Male; Mutagens; Seeds; Smoke; Sperm Motility; Spermatozoa; Nicotiana; Tobacco Smoke Pollution
PubMed: 34536221
DOI: 10.1007/s11356-021-16331-x -
Genes Feb 2022The identification of mutants through forward genetic screens is the backbone of genetics research, yet many mutants identified through these screens have yet to be...
The identification of mutants through forward genetic screens is the backbone of genetics research, yet many mutants identified through these screens have yet to be mapped to the genome. This is especially true of mutants that have been identified as mutagen-sensitive (), but have not yet been mapped to their associated molecular locus. Our study addressed the need for additional gene identification by determining the locus and exploring the function of the -linked mutagen-sensitive gene using three available mutant alleles: , , and . After first confirming that all three alleles were sensitive to methyl methanesulfonate (MMS) using complementation analysis, we used deletion mapping to narrow the candidate genes for Through DNA sequencing, we were able to determine that is the uncharacterized gene which encodes the ortholog of the highly conserved DNA2 protein that is important for DNA replication and repair. We further used the sequence and structure of DNA2 to predict the impact of the allele mutations on the final gene product. Together, these results provide a tool for researchers to further investigate the role of DNA2 in DNA repair processes in
Topics: Animals; DNA Repair; Drosophila; Drosophila melanogaster; Methyl Methanesulfonate; Mutagens
PubMed: 35205357
DOI: 10.3390/genes13020312 -
Food and Chemical Toxicology : An... Jan 20193-NOP (3-nitroxy-propanol) is a new development compound which reduces methane emission from ruminating animals. For registration purposes with emphasis on EU and North...
3-NOP (3-nitroxy-propanol) is a new development compound which reduces methane emission from ruminating animals. For registration purposes with emphasis on EU and North America data requirements, mutagenic and genotoxic potential was assessed following OECD protocols and respective guidance documents. 3-NOP mutagenicity and genotoxicity testing raised no flags with regard to these endpoints. In silico assessment of 3-NOP and its major plasma metabolite NOPA (3-nitroxy-propionic acid) were predicted negative with regard to the bacterial reverse mutation (Ames) test. Ames test, mouse lymphoma assay, in vitro micronucleus test, and the oral in vivo micronucleus test using rat bone marrow were all negative. Exposure of the rat bone marrow was verified by the presence of 3-NOP and its metabolites NOPA and HPA (3-hydroxy-propionic acid) a naturally occurring substance in mammals) in plasma following oral dosing. It is therefore concluded that 3-NOP and its metabolites pose no mutagenic and genotoxic potential.
Topics: 1-Propanol; Animals; Bacteria; Cell Line; DNA Damage; Mice; Micronucleus Tests; Mutagenicity Tests; Mutagens
PubMed: 30408540
DOI: 10.1016/j.fct.2018.11.010 -
International Journal of Environmental... Jan 2020There are presently more than 18 known aflatoxins most of which have been insufficiently studied for their incidence, health-risk, and mechanisms of toxicity to allow... (Review)
Review
There are presently more than 18 known aflatoxins most of which have been insufficiently studied for their incidence, health-risk, and mechanisms of toxicity to allow effective intervention and control means that would significantly and sustainably reduce their incidence and adverse effects on health and economy. Among these, aflatoxin B1 (AFB1) has been by far the most studied; yet, many aspects of the range and mechanisms of the diseases it causes remain to be elucidated. Its mutagenicity, tumorigenicity, and carcinogenicity-which are the best known-still suffer from limitations regarding the relative contribution of the oxidative stress and the reactive epoxide derivative (Aflatoxin-exo 8,9-epoxide) in the induction of the diseases, as well as its metabolic and synthesis pathways. Additionally, despite the well-established additive effects for carcinogenicity between AFB1 and other risk factors, e.g., hepatitis viruses B and C, and the hepatotoxic algal microcystins, the mechanisms of this synergy remain unclear. This study reviews the most recent advances in the field of the mechanisms of toxicity of aflatoxins and the adverse health effects that they cause in humans and animals.
Topics: Aflatoxins; Animals; Chronic Disease; Humans; Immune System; Mutagens; Neoplasms; Teratogens
PubMed: 31936320
DOI: 10.3390/ijerph17020423 -
Basic & Clinical Pharmacology &... Sep 2017Mutation spectra in cancer genomes provide information on the disease aetiology and the causality underlying the evolution and progression of cancer. Genome-wide... (Review)
Review
Mutation spectra in cancer genomes provide information on the disease aetiology and the causality underlying the evolution and progression of cancer. Genome-wide mutation patterns reflect the effects of mutagenic insults and can thus reveal past carcinogen-specific exposures and inform hypotheses on the causative factors for specific cancer types. To identify mutation profiles in human cancers, single-gene studies were first employed, focusing mainly on the tumour suppressor gene TP53. Furthermore, experimental studies had been developed in model organisms. They allowed the characterization of the mutation patterns specific to known human carcinogens, such as polycyclic aromatic hydrocarbons or ultraviolet light. With the advent of massively parallel sequencing, mutation landscapes become revealed on a large scale, in human primary tumours and in experimental models, enabling deeper investigations of the functional and structural impact of mutations on the genome, including exposure-specific base-change fingerprints known as mutational signatures. These studies can now accelerate the identification of aetiological factors, contribute to carcinogen evaluation and classification and ultimately inform cancer prevention measures.
Topics: Animals; Carcinogens; Disease Models, Animal; Environmental Exposure; Genes, Reporter; Genetic Engineering; High-Throughput Nucleotide Sequencing; Humans; Models, Genetic; Mutagenicity Tests; Mutagens; Mutation; Neoplasms; Sequence Analysis, DNA
PubMed: 27754614
DOI: 10.1111/bcpt.12690 -
Basic & Clinical Pharmacology &... Sep 2017DNA-protein cross-links (DPCs) are unusually bulky DNA adducts that form in cells as a result of exposure to endogenous and exogenous agents including reactive oxygen... (Review)
Review
DNA-protein cross-links (DPCs) are unusually bulky DNA adducts that form in cells as a result of exposure to endogenous and exogenous agents including reactive oxygen species, ultraviolet light, ionizing radiation, environmental agents (e.g. transition metals, formaldehyde, 1,2-dibromoethane, 1,3-butadiene) and common chemotherapeutic agents. Covalent DPCs are cytotoxic and mutagenic due to their ability to interfere with faithful DNA replication and to prevent accurate gene expression. Key to our understanding of the biological significance of DPC formation is identifying the proteins most susceptible to forming these unusually bulky and complex lesions and quantifying the extent of DNA-protein cross-linking in cells and tissues. Recent advances in bottom-up mass spectrometry-based proteomics have allowed for an unbiased assessment of the whole protein DPC adductome after in vitro and in vivo exposures to cross-linking agents. This MiniReview summarizes current and emerging methods for DPC isolation and analysis by mass spectrometry-based proteomics. We also highlight several examples of successful applications of these novel methodologies to studies of DPC lesions induced by bis-electrophiles such as formaldehyde, 1,2,3,4-diepoxybutane, nitrogen mustards and cisplatin.
Topics: Cisplatin; Cross-Linking Reagents; DNA; DNA Adducts; DNA Damage; Environmental Exposure; Epoxy Compounds; Formaldehyde; Mass Spectrometry; Mutagenicity Tests; Mutagens; Nitrogen Mustard Compounds; Proteins; Proteomics
PubMed: 28032943
DOI: 10.1111/bcpt.12751 -
Nature Chemical Biology Feb 2023The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin's biological effects remains...
The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin's biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis.
Topics: Humans; Mutagens; Escherichia coli; Gastrointestinal Microbiome; Polyketides; Peptide Hydrolases
PubMed: 36253549
DOI: 10.1038/s41589-022-01147-8 -
Environment International Feb 2019The genotoxic, mutagenic and carcinogenic effects of polar polycyclic aromatic hydrocarbons (polar PAHs) are believed to surpass those of their parent PAHs; however,... (Review)
Review
The genotoxic, mutagenic and carcinogenic effects of polar polycyclic aromatic hydrocarbons (polar PAHs) are believed to surpass those of their parent PAHs; however, their environmental and human health implications have been largely unexplored. Oxygenated PAHs (oxy-PAHs) is a critical class of polar PAHs associated with carcinogenic effects without enzymatic activation. They also cause an upsurge in reactive oxygen species (ROS) in living cells. This results in oxidative stress and other consequences, such as abnormal gene expressions, altered protein activities, mutagenesis, and carcinogenesis. Similarly, some nitrated PAHs (N-PAHs) are probable human carcinogens as classified by the International Agency for Research on Cancer (IARC). Heterocyclic PAHs (polar PAHs containing nitrogen, sulphur and oxygen atoms within the aromatic rings) have been shown to be potent endocrine disruptors, primarily through their estrogenic activities. Despite the high toxicity and enhanced environmental mobility of many polar PAHs, they have attracted only a little attention in risk assessment of contaminated sites. This may lead to underestimation of potential risks, and remediation end points. In this review, the toxicity of polar PAHs and their associated mechanisms of action, including their role in mutagenic, carcinogenic, developmental and teratogenic effects are critically discussed. This review suggests that polar PAHs could have serious toxicological effects on human health and should be considered during risk assessment of PAH-contaminated sites. The implications of not doing so were argued and critical knowledge gaps and future research requirements discussed.
Topics: Biodegradation, Environmental; Biological Availability; Carcinogenesis; Carcinogens; DNA Damage; Environmental Health; Humans; Mutagens; Oxidative Stress; Polycyclic Aromatic Hydrocarbons
PubMed: 30622079
DOI: 10.1016/j.envint.2018.12.051