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Role of DNA adducts in mutations and chemical carcinogenesis. The mutation induced by the DNA adduct of aristolochic acid I, an A:T>T:A transversion, is depicted as a prototype
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Hazardous chemicals in the environment and diet or their electrophilic metabolites can
form adducts with genomic DNA, which can lead to mutations and the initiation of
cancer. In addition, reactive intermediates can be generated in the body through
oxidative stress and damage the genome. The identification and measurement of DNA
adducts are require...
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Proteins contain many sites that are subject to modification by electrophiles. Detection and characterisation of these modifications can give insights into environmental agents and endogenous processes that may be contributing factors to chronic human diseases. An untargeted approach, utilising mass spectrometry to detect modified amino acids or pe...
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... These entities cause DNA miscoding during the replication process and mutations in oncogenes and tumor suppressor genes. Tobacco smoke also has free radicals which promote oxidation of lung tissue [9,10]. However, NSCLC is also reported in people who are never smokers, report from USA reveals that 12.5 % of the cases came from non-smokers [11]. ...
... For example, DNA adducts of aflatoxin B 1 (AFB B 1 ) and aristolochic acid I (AA-I) and their characteristic mutational signatures have been used to firmly establish their causative roles in liver and renal cancer, respectively. 6,7 DNA adducts can also serve as biomarkers to associate gene polymorphisms with susceptibility to cancer risk, 8,9 to measure levels of environmental exposures in humans 10,11 and marine species, 12 and to assess the efficacy of chemoprevention protocols and chemotherapeutic agents in precision medicine. 13 −15 Liquid chromatography−electrospray ionization tandem mass spectrometry (LC−ESI−MS 2 ) analysis has become the primary analytical tool for studying DNA adducts, and targeted methods have successfully measured different types of DNA adducts formed from a wide range of chemicals present in the environment, including tobacco smoke (e.g., 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK), 16 well-done cooked meats (e.g., 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine, PhIP), 17 and alcohol consumption (acetaldehyde), 18 or from endogenously produced electrophiles (e.g., malondial-dehyde). ...
... If DNA adduct is not entered much in the body , then it can be eliminated or repaired through using normal enzyme systems. When DNA adducts (chemicals bund to DNA) are not repaired then these chemicals generally induce cancer by inducing mutations in oncogenes like H-ras , K-ras and p53 tumour suppressor genes [14]. Tobacco used by persons cause a serious health problem by inducing cancers leading to millions of deaths annually. ...
... Toxic chemicals and their metabolites can bind to DNA (DNA adduct) causing mutations leading to cancer in human. Different methods like Immunoassays, Gas chromatography, Mass spectrometry and Liquid Chromatography/Mass spectrometry are used to measure DNA adducts [14]. DNA adducts may also bound to RNA and Protein besides DNA to cause many diseases in human (Figure 3 [17]. ...
... The damage in DNA caused by DNA adducts are generally repaired by enzymes normally, otherwise it can make disturbances in DNA replication and transcription causing single or multiple mutations. When DNA adduct is formed by some alkylating agents at the O⁶ position of the Guanine and O₂ (2 will be superscript) and O⁴ positions of the thymine then it will induce CG to AT, AT to GC and AT to TA multiple mutations [14]. It has also been found that the exposure of hazardous chemicals due to anthropogenic effect may also cause developmental and reproductive disorder in wild populations through covalent modifications of the genome, all these disorders in animals may abruptly affect their survival through loss of their populations in nature [18]. ...
With the advancement of-omic research in biological sciences , new vistas have opened in different disciplines of Genetics and health sciences. Again this revolution in these disciplines is possible with technological improvement of DNA sequencing technology. This modern technology is known as Next Generation Sequencing. Now-a-days biological analysis is done using multiple-omes such as Genome, Proteome, Transcriptome, Epigenome, Metabolome etc. Recently another Biological technique known as DNA Adductome is used to detect the cause of DNA damage done by many chemical agents, drugs, pollutants etc. Details of Next Generation Technology and Alignment technology have been discussed in the article. The application of Next Generation Sequence (NGS) technology has been applied for the improvement of crop plants. Another-omic technology is the study of DNA Adductomes. When DNA is bound to any chemical it is called DNA Adduct. The adduct formation is leading to DNA damage resulting into mutation. The origin of many human diseases like cancer and others have been found to be due to the formation of DNA adducts. The way of adduct formation in DNA has been discussed with special reference to human health. The measurement and identification of environmental pollutants can be monitored through the study of DNA Adduct. Thus this multiomic technology including DNA Adductomes may bring revolution in medicine and toxicological studies.
... If DNA adduct is not entered much in the body , then it can be eliminated or repaired through using normal enzyme systems. When DNA adducts (chemicals bund to DNA) are not repaired then these chemicals generally induce cancer by inducing mutations in oncogenes like H-ras , K-ras and p53 tumour suppressor genes [14]. Tobacco used by persons cause a serious health problem by inducing cancers leading to millions of deaths annually. ...
... Toxic chemicals and their metabolites can bind to DNA (DNA adduct) causing mutations leading to cancer in human. Different methods like Immunoassays, Gas chromatography, Mass spectrometry and Liquid Chromatography/Mass spectrometry are used to measure DNA adducts [14]. DNA adducts may also bound to RNA and Protein besides DNA to cause many diseases in human (Figure 3 [17]. ...
... The damage in DNA caused by DNA adducts are generally repaired by enzymes normally, otherwise it can make disturbances in DNA replication and transcription causing single or multiple mutations. When DNA adduct is formed by some alkylating agents at the O⁶ position of the Guanine and O₂ (2 will be superscript) and O⁴ positions of the thymine then it will induce CG to AT, AT to GC and AT to TA multiple mutations [14]. It has also been found that the exposure of hazardous chemicals due to anthropogenic effect may also cause developmental and reproductive disorder in wild populations through covalent modifications of the genome, all these disorders in animals may abruptly affect their survival through loss of their populations in nature [18]. ...
... Excessive ROS levels can cause initiation of malignant tumors leading to uncontrolled cell death in cancer cells. [29] DNA adduct formation may cause damage to DNA, affecting cell function and health, [30,31] while also impacting transcription accuracy and efficiency, thus regulating cell function. [32] Phagosomes participate in immune responses, [33] play an important role in epigenetic regulation, [34] and are involved in the formation and regulation of the tumor microenvironment. ...
Telomere dysfunction has been identified as a biological marker of cancer progression in several types of cancer, including Head and Neck Squamous Cell Carcinoma (HNSCC). This study aimed to characterize the telomere maintenance genes (TMG)-related signature in prognosis and treatment response in HNSCC. The transcriptome and clinical data of HNSCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases, respectively. Non-negative matrix factorization (NMF) was used to identify molecular subtypes derived from TMG. Gene set enrichment analysis (GSEA) was performed to analyze the differentially expressed pathways between subtypes, and a risk score model derived from TMG was established. Kaplan-Meier survival analysis was used to evaluate inter-group prognostic features, and the correlation between TMG-derived molecular subtypes and risk score model with immune infiltration, immunotherapy, and chemosensitivity was assessed. Two HNSCC subtypes were identified based on 59 TMG-related genes, which exhibit significant heterogeneity in prognosis, immune cell infiltration, and treatment response. Additionally, a TMG-derived risk signature containing 9 genes was developed to assess the prognosis of HNSCC patients. The signature had significant predictive ability for HNSCC prognosis and was significantly correlated with immune cell infiltration and immunotherapy response. A nomogram integrating the risk signature, N stage and radiotherapy was constructed to predict 1-, 3-, and 5-year overall survival (OS) of HNSCC patients, which had better performance than other prognostic models and included TMG-derived risk score, radiotherapy, and N stage. This study identified TMG-derived molecular subtypes in HNSCC and developed a novel prognostic score model, highlighting the potential value of TMG in HNSCC prognosis and immunotherapy.
... Preliminary steps in the optimization of HILIC for DNA adductomics have been undertaken [12], but HILIC has not been implemented for DNA adductome mapping in comparison to RPLC. Therefore, it was our aim to compare the DNA adductome mapping and modelling potential [13] and several useful DNA adduct isolation strategies have been examined and implemented successfully [8,[14][15][16][17]. The implementation of thermal acidic hydrolysis and SPE vs. enzymatic hydrolysis and fraction collection of DNA for DNA adductome mapping and modeling has however never been investigated previously. ...
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.
... HepG2 cells, when treated for 2 h with fenthion (50 to 200 µM) and terbufos, induced DNA damage and significant cell death in a concentration dependant manner [78]. OPs can alkylate DNA bases directly or indirectly via protein alkylation, leading to DNA disintegration [79]. MCP is a lot more reactive than other OP pesticides because of the existence of a methyl ester group. ...
... To understand the mutagenic significance of exposure and the causal role of a genotoxic chemical, as well as to monitor the disease, DNA adducts must be identified and measured. It also provides necessary information about adduct formation and aids in tracking sources contaminated with pesticides [79,104]. Thus, DNA adduct formation is an important biomarker for oxidative stress and genotoxicity. ...
Organophosphate pesticides (OPs) are widely used in agriculture, healthcare, and other industries due to their ability to kill pests. However, OPs can also have genotoxic effects on humans who are exposed to them. This review summarizes the research on DNA damage caused by OPs, the mechanisms behind this damage, and the resulting cellular effects. Even at low doses, OPs have been shown to damage DNA and cause cellular dysfunction. Common phenomena seen in cells that are exposed to OPs include the formation of DNA adducts and lesions, single-strand and double-strand DNA breaks, and DNA and protein inter and intra-cross-links. The present review will aid in comprehending the extent of genetic damage and the impact on DNA repair pathways caused by acute or chronic exposure to OPs. Additionally, understanding the mechanisms of the effects of OPs will aid in correlating them with various diseases, including cancer, Alzheimer’s, and Parkinson’s disease. Overall, knowledge of the potential adverse effects of different OPs will help in monitoring the health complications they may cause.
... In a study conducted by Hwa Yun et al. [43] in 2020, it was discovered that deoxyadenosine could be generated via modification reactions induced by ROS. Modified lipids can react with DNA directly or through bifunctional intermediates, leading to the formation of mutagenic etheno-DNA adducts. ...
Purpose: The highly competitive nature of tertiary education and the pressure to perform academically have increased psychological morbidity like emotional distress. Untargeted metabolomics was used to analyze serum samples of university students for biomarkers and perturbated metabolism due to stress, anxiety, and depression (SAD).Methods: Depression, Anxiety, Stress Scale 21 (DASS-21) was used to assess the severity of SAD in university students. The metabolite fingerprint of each subject was obtained using liquid chromatography-mass spectrometry quadrupole time-of-flight (LC/MS QTOF). The signature metabolites for each trait were determined by projections to latent structures discriminant analysis (PLS-DA) with variable importance for the projection (VIP) score > 1.0 (P<0.05) and subjected to analysis using the area under the receiver operating characteristic curve (AUROC). Potential biomarkers with an area under the curve (AUC) value exceeding 0.65 were identified.Results: Various groups of glycerophospholipids were upregulated in the studied traits. On the other hand, metabolites such as glycocholic acid was upregulated in depression, while hypoxanthine was upregulated in anxiety, and PE-Cer(d14:1(4E)/22:1(13Z)) was upregulated in stress.Conclusion: To our knowledge, this is the first study to assess the relationship of the differentially expressed metabolites in university students of different categories of SAD using the DASS-21 screening tool in Malaysia as we move forward with precision health.
... These mutated cells (cancer cells) do not have the growth control to perform cell cycle arrest. The addition of cancer cell mass will cause tumor development [32]. ...
Temulawak rhizome (Curcuma xanthorrhiza) contains curcumin and xanthorrhizol, which may be used as breast cancer drugs and hepatoprotection. This study aims to analyze the activity of alanine and aspartate transaminase enzymes and the histopathological picture of 7,12-Dimethylbenz(α)anthracene (DMBA)-induced rat liver due to the administration of temulawak extract. This study used 28 female white rats, divided into seven treatment groups, a control group (normal and DMBA) and a treatment group induced by temulawak extract orally with doses of 35, 70, 140, 210, and 280 mg/kg Body Weight (BW) during the 11-week study period. The results obtained were that the application of temulawak extract had a significant effect on alanine transaminase (ALT) levels but did not differ between groups. Aspartate transaminase (AST) levels differed at a 35 mg/kg BW dose. Temulawak extract at a dose of 140 mg/kg BW, the De Ritis ratio at normal values. The results of the histopathological analysis showed hepatocyte repair and sinusoidal dilatation were less than optimal at a dose of 140 mg/kg BW. This study concluded that the temulawak extract showed a significant but insignificant difference in the ALT value. The AST value significantly differed in administering temulawak extract at a dose of 35 mg/kg BW. The dose of 140 mg/kg BW controls the value of the De Ritis ratio to the normal value. Temulawak extract is expected to improve the healing of the liver damaged by carcinogenic substances.
... Similarly, the oxidation of lipids and proteins can generate intermediaries that could react with the DNA [23]. In the case of lipid decomposition, one of the final products of lipid peroxidation is the malondialdehyde (MDA), which forms the following adducts: Deoxyadenosine (M1dA), deoxycytidine (M1dC), and deoxyguanosine (M1dG) [24]. Meanwhile, as protein oxidation products, carbonyl groups, such as aldehydes and ketones, are generated [25]. ...
Human aging is a gradual and adaptive process characterized by a decrease in the homeostatic response, leading to biochemical and molecular changes that are driven by hallmarks of aging, such as oxidative stress (OxS), chronic inflammation , and telomere shortening. One of the diseases associated with the hallmarks of aging, which has a great impact on functionality and quality of life, is sarcopenia. However, the relationship between telomere length, sarcopenia, and age-related mortality has not been extensively studied. Moderate physical exercise has been shown to have a positive effect on sarcopenia, decreasing OxS and inflammation, and inducing protective effects on telomeric DNA. This results in decreased DNA strand breaks, reduced OxS and IA, and activation of repair pathways. Higher levels of physical activity are associated with an apparent increase in telomere length. This review aims to present the current state of the art of knowledge on the effect of physical exercise on telomeric maintenance and activation of repair mechanisms in sarcopenia.
