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The International Journal of... Sep 2023Cisplatin, a widely prescribed chemotherapeutic agent for treating solid tumors, induces DNA adducts and activates cellular defense mechanisms, including DNA repair,...
Cisplatin, a widely prescribed chemotherapeutic agent for treating solid tumors, induces DNA adducts and activates cellular defense mechanisms, including DNA repair, cell cycle checkpoint control, and apoptosis. Considering the circadian rhythmicity displayed by most chemotherapeutic agents and their varying therapeutic efficacy based on treatment timing, our study aimed to investigate whether the circadian clock system influences the DNA damage responses triggered by cisplatin in synchronized cells. We examined the DNA damage responses in circadian-synchronized wild-type mouse embryonic fibroblasts (WT-MEF; clock-proficient cells), cryptochrome1 and 2 double knock-out MEF (CRY; clock-deficient cells), and mouse hepatocarcinoma Hepa1c1c7 cells. Varying the treatment time resulted in a significant difference in the rate of platinum-DNA adduct removal specifically in circadian-synchronized WT-MEF, while CRY did not exhibit such variation. Moreover, diurnal variation in other DNA damage responses, such as cell cycle checkpoint activity indicated by p53 phosphorylation status and apoptosis measured by DNA break frequency, was observed only in circadian-synchronized WT-MEF, not in CRY or mouse hepatocarcinoma Hepa1c1c7 cells. These findings highlight that the DNA damage responses triggered by cisplatin are indeed governed by circadian control exclusively in clock-proficient cells. This outcome bears potential implications for enhancing or devising chronotherapy approaches for cancer patients.
Topics: Animals; Mice; Cisplatin; DNA Adducts; DNA Damage; Fibroblasts; DNA Repair; Circadian Clocks; Neoplasms; Apoptosis
PubMed: 37574041
DOI: 10.1016/j.biocel.2023.106454 -
International Journal of Environmental... Jul 2011Polycyclic aromatic hydrocarbons (PAHs) are combustion products of organic materials, mixtures of which contain multiple known and probable human carcinogens. PAHs occur... (Review)
Review
Polycyclic aromatic hydrocarbons (PAHs) are combustion products of organic materials, mixtures of which contain multiple known and probable human carcinogens. PAHs occur in indoor and outdoor air, as well as in char-broiled meats and fish. Human exposure to PAHs occurs by inhalation, ingestion and topical absorption, and subsequently formed metabolites are either rendered hydrophilic and excreted, or bioactivated and bound to cellular macromolecules. The formation of PAH-DNA adducts (DNA binding products), considered a necessary step in PAH-initiated carcinogenesis, has been widely studied in experimental models and has been documented in human tissues. This review describes immunohistochemistry (IHC) studies, which reveal localization of PAH-DNA adducts in human tissues, and semi-quantify PAH-DNA adduct levels using the Automated Cellular Imaging System (ACIS). These studies have shown that PAH-DNA adducts concentrate in: basal and supra-basal epithelium of the esophagus, cervix and vulva; glandular epithelium of the prostate; and cytotrophoblast cells and syncitiotrophoblast knots of the placenta. The IHC photomicrographs reveal the ubiquitous nature of PAH-DNA adduct formation in human tissues as well as PAH-DNA adduct accumulation in specific, vulnerable, cell types. This semi-quantative method for PAH-DNA adduct measurement could potentially see widespread use in molecular epidemiology studies.
Topics: Carcinogens; DNA Adducts; Female; Humans; Immunohistochemistry; Male; Polycyclic Aromatic Hydrocarbons; Tissue Distribution
PubMed: 21845152
DOI: 10.3390/ijerph8072675 -
The Journal of Organic Chemistry Jan 2016N(2)-Furfuryl-deoxyguanosine (fdG) is carcinogenic DNA adduct that originates from furfuryl alcohol. It is also a stable structural mimic of the damage induced by the...
N(2)-Furfuryl-deoxyguanosine (fdG) is carcinogenic DNA adduct that originates from furfuryl alcohol. It is also a stable structural mimic of the damage induced by the nitrofurazone family of antibiotics. For the structural and functional studies of this model N(2)-dG adduct, reliable and rapid access to fdG-modified DNAs are warranted. Toward this end, here we report the synthesis of fdG-modified DNAs using phosphoramidite chemistry involving only three steps. The functional integrity of the modified DNA has been verified by primer extension studies with DNA polymerases I and IV from E. coli. Introduction of fdG into a DNA duplex decreases the Tm by ∼1.6 °C/modification. Molecular dynamics simulations of a DNA duplex bearing the fdG adduct revealed that though the overall B-DNA structure is maintained, this lesion can disrupt W-C H-bonding, stacking interactions, and minor groove hydrations to some extent at the modified site, and these effects lead to slight variations in the local base pair parameters. Overall, our studies show that fdG is tolerated at the minor groove of the DNA to a better extent compared with other bulky DNA damages, and this property will make it difficult for the DNA repair pathways to detect this adduct.
Topics: Base Pairing; DNA; DNA Adducts; DNA, B-Form; Deoxyguanosine; Escherichia coli; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation
PubMed: 26650891
DOI: 10.1021/acs.joc.5b02341 -
Medical Hypotheses Jun 2019DNA adducts are associated with a number of diseases, including cancer. Based on a recent report by our group, the aim of this study was to test the hypothesis that DNA...
DNA adducts are associated with a number of diseases, including cancer. Based on a recent report by our group, the aim of this study was to test the hypothesis that DNA adducts can be removed by means of one or more of the following three intervention programmes: intermittent whole-body hyperthermia; detoxification; and cell repair. The number of DNA adducts and total DNA adduct concentrations were measured in 104 patients who underwent one or more of the three intervention programmes. DNA adduct assessments were carried out on extracted genomic DNA by gas-liquid chromatography, with any DNA adducts found being localised using DNA microarrays. The baseline median number of DNA adducts was 2. The follow-up median number of adducts was highly significantly lower at 0 (p < 0.000000000000003). The mean total DNA adduct concentration at baseline was 9.308 ng/mL, and highly significantly lower at follow-up at 1.553 ng/mL (p < 0.000000000000006). Of the three intervention programmes, only the intermittent whole-body hyperthermia was associated with a significant reduction in DNA adducts. This study offers support for the hypothesis that DNA adducts can be removed by intermittent whole-body hyperthermia. The intermittent hyperthermia used involved infrared-A (wavelength 700-1400 nm, or, equivalently, a frequency of 215-430 THz) being preferentially delivered to the whole body, apart from the head, for up to one hour per session, with gradual core body temperature elevation usually occurring during the first 20-30 min. These results may offer an explanation at the molecular level for other reported clinical benefits of intermittent whole-body hyperthermia.
Topics: Administration, Intravenous; Chromatography, Gas; DNA Adducts; Fatty Acids; Female; Humans; Hyperthermia, Induced; Male; Middle Aged; Models, Biological; Neoplasms; Oligonucleotide Array Sequence Analysis; Parkinson Disease; Phospholipids; Reproducibility of Results
PubMed: 31088632
DOI: 10.1016/j.mehy.2019.03.031 -
Talanta Dec 2014DNA adducts represent an important category of biomarkers for detection and exposure surveillance of potential carcinogenic and genotoxic chemicals in the environment.... (Review)
Review
DNA adducts represent an important category of biomarkers for detection and exposure surveillance of potential carcinogenic and genotoxic chemicals in the environment. Sensitive and specific analytical methods are required to detect and differentiate low levels of adducts from native DNA from in vivo exposure. In addition to biomonitoring of environmental pollutants, analytical methods have been developed for structural identification of adducts which provides fundamental information for determining the toxic pathway of hazardous chemicals. In order to achieve the required sensitivity, mass spectrometry has been increasingly utilized to quantify adducts at low levels as well as to obtain structural information. Furthermore, separation techniques such as chromatography and capillary electrophoresis can be coupled to mass spectrometry to increase the selectivity. This review will provide an overview of advances in detection of adducted and modified DNA by mass spectrometry with a focus on the analysis of nucleosides since 2007. Instrument advances, sample and instrument considerations, and recent applications will be summarized in the context of hazard assessment. Finally, advances in biomonitoring applying mass spectrometry will be highlighted. Most importantly, the usefulness of DNA adducts measurement and detection will be comprehensively discussed as a tool for assessment of in vitro and in vivo exposure to environmental pollutants.
Topics: Carcinogens, Environmental; DNA Adducts; Environmental Monitoring; Environmental Pollutants; Humans; Mass Spectrometry; Safety Management
PubMed: 25159438
DOI: 10.1016/j.talanta.2014.06.050 -
Mutation Research May 2000The process of carcinogenesis is initiated by mutagenesis, which often involves replication past damaged DNA. One question - what exactly is a DNA polymerase seeing when... (Comparative Study)
Comparative Study Review
Toward an understanding of the role of DNA adduct conformation in defining mutagenic mechanism based on studies of the major adduct (formed at N(2)-dG) of the potent environmental carcinogen, benzo[a]pyrene.
The process of carcinogenesis is initiated by mutagenesis, which often involves replication past damaged DNA. One question - what exactly is a DNA polymerase seeing when it incorrectly copies a damaged DNA base (e.g., inserting dATP opposite a dG adduct)? - has not been answered in any case. Herein, we reflect on this question, principally by considering the mutagenicity of one activated form of benzo[a]pyrene, (+)-anti-B[a]PDE, and its major adduct [+ta]-B[a]P-N(2)-dG. In previous work, [+ta]-B[a]P-N(2)-dG was shown to be capable of inducing>95% G-->T mutations in one sequence context (5'-TGC), and approximately 95% G-->A mutations in another (5'-AGA). This raises the question - how can a single chemical entity induce different mutations depending upon DNA sequence context? Our current working hypothesis is that adduct conformational complexity causes adduct mutational complexity, where DNA sequence context can affect the former, thereby influencing the latter. Evidence supporting this hypothesis was discussed recently (Seo et al., Mutation Res. [in press]). Assuming this hypothesis is correct (at least in some cases), one goal is to consider what these mutagenic conformations might be. Based on molecular modeling studies, 16 possible conformations for [+ta]-B[a]P-N(2)-dG are proposed. A correlation between molecular modeling and mutagenesis work suggests a hypothesis (Hypothesis 3): a base displaced conformation with the dG moiety of the adduct in the major vs. minor groove gives G-->T vs. G-->A mutations, respectively. (Hypothesis 4, which is a generalized version of Hypothesis 3, is also proposed, and can potentially rationalize aspects of both [+ta]-B[a]P-N(2)-dG and AP-site mutagenesis, as well as the so-called "A-rule".) Finally, there is a discussion of how conformational complexity might explain some unusual mutagenesis results that suggest [+ta]-B[a]P-N(2)-dG can become trapped in different conformations, and why we think it makes sense to interpret adduct mutagenesis results by modeling ds-DNA (at least in some cases), even though the mutagenic event must occur at a ss/ds-DNA junction in the presence of a DNA polymerase.
Topics: Base Sequence; Benzo(a)pyrene; Binding Sites; Carcinogens, Environmental; DNA Adducts; Deoxyguanosine; Frameshift Mutation; Models, Genetic; Mutation; Nucleic Acid Conformation; Point Mutation; Thermodynamics
PubMed: 10838133
DOI: 10.1016/s0027-5107(00)00015-4 -
Chemical Research in Toxicology Jan 1998
Review
Topics: DNA; DNA Adducts; Epoxy Compounds; Glycols; Polycyclic Aromatic Hydrocarbons
PubMed: 9477220
DOI: 10.1021/tx970142f -
Food and Chemical Toxicology : An... May 2018The consumption of red meat has been linked to an increased colorectal cancer (CRC) risk. One of the major hypotheses states that heme iron (present in red meat)...
The consumption of red meat has been linked to an increased colorectal cancer (CRC) risk. One of the major hypotheses states that heme iron (present in red meat) stimulates the formation of genotoxic N-nitroso compounds (NOCs) and lipid peroxidation products (LPOs). By means of DNA adductomics, chemically induced DNA adduct formation can be mapped in relation to e.g. dietary exposures. In this study, this state-of-the-art methodology was used to investigate alkylation and (lipid per)oxidation induced DNA adduct formation in in vitro red vs. white meat digests. In doing so, 90 alkylation and (lipid per)oxidation induced DNA adduct types could be (tentatively) identified. Overall, 12 NOC- and/or LPO-related DNA adduct types, i.e. dimethyl-T (or ethyl-T), hydroxymethyl-T, tetramethyl-T, methylguanine (MeG), guanidinohydantoin, hydroxybutyl-C, hydroxymethylhydantoin, malondialdehyde-x3-C, O-carboxymethylguanine, hydroxyethyl-T, carboxyethyl-T and 3,N-etheno-C were singled out as potential heme-rich meat digestion markers. The retrieval of these DNA adduct markers is in support of the heme, NOC and LPO hypotheses, suggesting that DNA adduct formation may indeed contribute to red meat related CRC risk.
Topics: Adult; Aged; Animals; Cattle; Chickens; Chromatography, High Pressure Liquid; Colon; Colorectal Neoplasms; DNA Adducts; DNA Damage; Digestion; Female; Heme; Humans; Lipid Peroxidation; Male; Mass Spectrometry; Middle Aged; Nitroso Compounds; Oxidation-Reduction; Red Meat; Young Adult
PubMed: 29458163
DOI: 10.1016/j.fct.2018.02.032 -
Chemical Research in Toxicology Apr 2021The tobacco-specific nitrosamines '-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered to be two of the most important...
The tobacco-specific nitrosamines '-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered to be two of the most important carcinogens in unburned tobacco and its smoke. They readily cause tumors in laboratory animals and are classified as "carcinogenic to humans" by the International Agency for Research on Cancer. DNA adduct formation by these two carcinogens is believed to play a critical role in tobacco carcinogenesis. Among all the DNA adducts formed by NNN and NNK, 2'-deoxyadenosine (dAdo)-derived adducts have not been fully characterized. In the study reported here, we characterized the formation of -[4-(3-pyridyl)-4-oxo-1-butyl]-2'-deoxyadenosine (-POB-dAdo) and its reduced form -PHB-dAdo formed by NNN 2'-hydroxylation in rat liver and lung DNA. More importantly, we characterized a new dAdo adduct -[4-hydroxy-1-(pyridine-3-yl)butyl]-2'-deoxyadenosine (-HPB-dAdo) formed after NaBHCN or NaBH reduction both in calf thymus DNA reacted with 5'-acetoxy-'-nitrosonornicotine and in rat liver and lung upon treatment with NNN. This adduct was specifically formed by NNN 5'-hydroxylation. Chemical standards of -HPB-dAdo and the corresponding isotopically labeled internal standard [pyridine-]-HPB-dAdo were synthesized using a four-step method. Both NMR and high-resolution mass spectrometry data agreed well with the proposed structure of -HPB-dAdo. The new adduct coeluted with the synthesized internal standard under various LC conditions. Its product ion patterns of MS and MS transitions were also consistent with the proposed fragmentation patterns. Chromatographic resolution of the two diastereomers of -HPB-dAdo was successfully achieved. Quantitation suggested a dose-dependent response of the levels of this new adduct in the liver and lung of rats treated with NNN. However, its level was lower than that of 2-[2-(3-pyridyl)--pyrrolidinyl]-2'-deoxyinosine, a previously reported dGuo adduct that is also formed from NNN 5'-hydroxylation. The identification of -HPB-dAdo in this study leads to new insights pertinent to the mechanism of carcinogenesis by NNN and to the development of biomarkers of NNN metabolic activation.
Topics: Animals; DNA; DNA Adducts; Deoxyadenosines; Liver; Lung; Molecular Structure; Nitrosamines; Prohibitins; Rats
PubMed: 33705110
DOI: 10.1021/acs.chemrestox.1c00013 -
Chemical Research in Toxicology Sep 2020The formation and repair of -(-isosafrol-3'-yl)-2'-deoxyguanosine (S-3'--dG) DNA adduct derived from the spice and herbal alkenylbenzene constituent safrole were...
The formation and repair of -(-isosafrol-3'-yl)-2'-deoxyguanosine (S-3'--dG) DNA adduct derived from the spice and herbal alkenylbenzene constituent safrole were investigated. DNA adduct formation and repair were studied and using molecular dynamics (MD) simulations. DNA adduct formation was quantified using liquid chromatography-mass spectrometry (LCMS) in wild type and NER (nucleotide excision repair) deficient CHO cells and also in HepaRG cells and primary rat hepatocytes after different periods of repair following exposure to safrole or 1'-hydroxysafrole (1'-OH safrole). The slower repair of the DNA adducts found in NER deficient cells compared to that in CHO wild type cells indicates a role for NER in repair of S-3'--dG DNA adducts. However, DNA repair in liver cell models appeared to be limited, with over 90% of the adducts remaining even after 24 or 48 h recovery. In our further studies, MD simulations indicated that S-3'--dG adduct formation causes only subtle changes in the DNA structure, potentially explaining inefficient activation of NER. Inefficiency of NER mediated repair of S-3'--dG adducts points at persistence and potential bioaccumulation of safrole DNA adducts upon daily dietary exposure.
Topics: Animals; Cells, Cultured; DNA Adducts; DNA Repair; Humans; Molecular Dynamics Simulation; Rats; Safrole
PubMed: 32786539
DOI: 10.1021/acs.chemrestox.0c00097