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Nutrients Jan 2024The PHYTOME study investigated the effect of consuming processed meat products on outcomes related to colorectal cancer risk without testing the impact of genetic...
Genetic Variability Impacts Genotoxic and Transcriptome Responses in the Human Colon after the Consumption of Processed Red Meat Products and Those with Added Phytochemical Extracts.
The PHYTOME study investigated the effect of consuming processed meat products on outcomes related to colorectal cancer risk without testing the impact of genetic variability on these responses. This research aims to elucidate the genetic impact on apparent total N-nitroso compound (ATNC) excretion, colonic DNA adduct formation, ex vivo-induced DNA damage, and gene expression changes in colon biopsies of healthy participants. Through a systematic literature review, candidate polymorphisms were selected and then detected using TaqMan and PCR analysis. The effect of genotype on study outcomes was determined via a linear mixed model and analysis of variance. Machine learning was used to evaluate relative allele importance concerning genotoxic responses, which established a ranking of the most protective alleles and a combination of genotypes (gene scores). Participants were grouped by GSTM1 genotype and differentially expressed genes (DEGs), and overrepresented biological pathways were compared between groups. Stratifying participants by ten relevant genes revealed significant variations in outcome responses. After consumption of processed red meat, variations in NQO1 and COMT impacted responses in ATNC levels (µmol/L) (+9.56 for wildtype vs. heterozygous) and DNA adduct levels (pg/µg DNA) (+1.26 for variant vs. wildtype and +0.43 for variant vs. heterozygous), respectively. After phytochemicals were added to the meat, GSTM1 variation impacted changes in DNA adduct levels (-6.12 for deletion vs. wildtype). The gene scores correlated with these responses and DEGs were identified by GSTM1 genotype. The altered pathways specific to the GSTM1 wildtype group included 'metabolism', 'cell cycle', 'vitamin D receptor', and 'metabolism of water-soluble vitamins and co-factors'. Genotype impacted both the potential genotoxicity of processed red meat and the efficacy of protective phytochemical extracts.
Topics: Humans; Meat Products; DNA Adducts; Transcriptome; DNA Damage; Meat; Red Meat; Nitroso Compounds; Colon
PubMed: 38337709
DOI: 10.3390/nu16030425 -
Journal of Applied Toxicology : JAT Jan 2024The International Agency for Research on Cancer has classified N-nitrosodiethylamine (NDEA) as a possible carcinogen and mutagenic substances, placing it in category 2A... (Review)
Review
The International Agency for Research on Cancer has classified N-nitrosodiethylamine (NDEA) as a possible carcinogen and mutagenic substances, placing it in category 2A of compounds that are probably harmful to humans. It is found in nature and tobacco smoke, along with its precursors, and is also synthesized endogenously in the human body. The oral or parenteral administration of a minimal quantity of NDEA results in severe liver and kidney organ damage. The NDEA required bioactivation by CYP450 enzyme to form DNA adduct in the alkylation mechanism. Thus, this bioactivation directs oxidative stress and injury to cells due to the higher formation of reactive oxygen species and alters antioxidant system in tissues, whereas free radical scavengers guard the membranes from NDEA-directed injury in many enzymes. This might be one of the reasons in the etiology of cancer that is not limited to a certain target organ but can affect various organs and organ systems. Although there are various possible approaches for the treatment of NDEA-induced cancer, their therapeutic outcomes are still very dismal. However, several precautions were considered to be taken during handling or working with NDEA, as it considered being the best way to lower down the occurrence of NDEA-directed cancers. The present review was designed to enlighten the general guidelines for working with NDEA, possible mechanism, to alter the antioxidant line to cause malignancy in different parts of animal body along with its protective agents. Thus, revelation to constant, unpredictable stress situations even in common life may remarkably augment the toxic potential through the rise in the oxidative stress and damage of DNA.
PubMed: 38212177
DOI: 10.1002/jat.4574 -
Balkan Journal of Medical Genetics :... May 2023The term "aristolochic acid nephropathy" (AAN) is used to include any form of toxic interstitial nephropathy that is caused either by ingestion of plants containing...
Molecular Characterization of Microrna Interference and Aristolochic Acid Intoxication Found in Upper Tract Urothelial Carcinoma in Patients with Balkan Endemic Nephropathy: A Systematic Review of the Current Literature.
The term "aristolochic acid nephropathy" (AAN) is used to include any form of toxic interstitial nephropathy that is caused either by ingestion of plants containing aristolochic acids (AA) or by the environmental contaminants in food such as in Balkan endemic nephropathy (BEN). Aristolochic acid (AA) intoxication is strongly associated with the development of upper tract urothelial carcinoma (UTUC); however, the underlying molecular mechanism remains to be defined. MicroRNAs (miRNA) regulate several biological processes, including cell proliferation, differentiation, and metabolism, acting as oncogenes or tumor suppressors. A unique miRNA expression profile suggested that miRNAs could function as regulators in UTUC developmental processes. This review aimed to summarize data available in the literature about underlying molecular mechanisms leading to the expression of miRNAs in AA-UTUC patients with BEN. Strong correlation in AA-UTUC has a distinctive gene alteration pattern, AL-DNA adducts, and a unique tumor protein (TP53) mutational spectrum AAG to TAG (A: T→T: A) transversion in codon 139 (Lys → Stop) of exon 5 activates the p53 tumor suppressor protein. Further, p53 protein is responsible not only for the expression of miRNAs but also acts as a target molecule for miRNAs and plays a crucial function in the AA-UTUC pathogenicity through activation of cyclin-dependent kinase (CyclinD1) and cyclin protein kinase 6(CDK6) to support cell cycle arrest. This study, proposed a molecular mechanism that represented a possible unique relationship between AA intoxication, miRNAs expression, and the progression of UTUC in patients with BEN.
PubMed: 37265966
DOI: 10.2478/bjmg-2022-0027 -
International Journal of Molecular... Nov 2022Aldehydes, particularly acetaldehyde, are carcinogenic molecules and their concentrations in foodstuffs should be controlled to avoid upper aerodigestive tract (UADT)... (Review)
Review
Aldehydes, particularly acetaldehyde, are carcinogenic molecules and their concentrations in foodstuffs should be controlled to avoid upper aerodigestive tract (UADT) and liver cancers. Highly reactive, acetaldehyde forms DNA and protein adducts, impairing physiological functions and leading to the development of pathological conditions. The consumption of aged beer, outside of the ethanol metabolism, exposes habitual drinkers to this carcinogen, whose concentrations can be over-increased due to post-brewing chemical and biochemical reactions. Storage-related changes are a challenge faced by the brewing industry, impacting volatile compound formation and triggering flavor instability. Aldehydes are among the volatile compounds formed during beer aging, recognized as off-flavor compounds. To track and understand aldehyde formation through multiple pathways during beer storage, consequent changes in flavor but particularly quality losses and harmful compound formation, this systematic review reunited data on volatile compound profiles through gas chromatography analyses from 2011 to 2021. Conditions to avoid flavor instability and successful methods for reducing beer staling, and consequent acetaldehyde accumulation, were raised by exploring the dynamic conversion between free and bound-state aldehydes. Future research should focus on implementing sensory analyses to investigate whether adding aldehyde-binding agents, e.g., cysteine and bisulfite, would contribute to consumer acceptance, restore beer flavor, and minimize acetaldehyde-related health damage.
Topics: Humans; Aged; Acetaldehyde; Aldehydes; Beer; Carcinogens; Carcinogenesis
PubMed: 36430619
DOI: 10.3390/ijms232214147 -
Frontiers in Oncology 2022The ecteinascidins trabectedin and lurbinectedin are very interesting antineoplastic agents, with a favorable toxicity profile and peculiar mechanisms of action. These...
Trabectedin and lurbinectedin: Mechanisms of action, clinical impact, and future perspectives in uterine and soft tissue sarcoma, ovarian carcinoma, and endometrial carcinoma.
The ecteinascidins trabectedin and lurbinectedin are very interesting antineoplastic agents, with a favorable toxicity profile and peculiar mechanisms of action. These drugs form adducts in the minor groove of DNA, which produce single-strand breaks (SSBs) and double-strand breaks (DSBs) and trigger a series of events resulting in cell cycle arrest and apoptosis. Moreover, the ecteinascidins interact with the tumor microenvironment, reduce the number of tumor-associated macrophages, and inhibit the secretion of cytokines and chemokines. Trabectedin has been approved by the Federal Drug Administration (FDA) for patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-based regimen. Moreover, trabectedin in combination with pegylated liposomal doxorubicin (PLD) has been approved in the European Union for the treatment of platinum-sensitive recurrent ovarian cancer. Lurbinectedin has been approved by the FDA for patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. The review assesses and experimental studies on the antineoplastic effects of both ecteinascidins as well as the clinical trials on the activity of trabectedin in uterine sarcoma and ovarian carcinoma and of lurbinectedin in ovarian carcinoma and endometrial carcinoma.
PubMed: 36408147
DOI: 10.3389/fonc.2022.914342 -
World Journal of Urology Apr 2023The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of...
PURPOSE
The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of Aristolochia-based herbal medicines. Here we systematically review the molecular epidemiology, clinical presentation and biomarkers associated with AA-induced UTUC.
METHODS
This is a narrative review. Medline, Embase, and Web of Science were searched from inception to December 31, 2021. Studies evaluating the association, detection, and clinical characteristics of AA and UTUC were included.
RESULTS
A nationwide database revealed 39% of the Taiwanese population had been exposed to AA-containing herbs between 1997 and 2003. Epidemiological reports revealed AA posed a significantly higher hazard for renal failure and UTUC in herbalists and the general population who ingested AA-containing herbs. The presence of aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, located predominantly on the non-transcribed DNA strand, with a strong preference for deoxyadenosine in a consensus sequence (CAG), was observed in many UTUC patients. Clinically, AA-related UTUC patients were characterized by a younger age, female gender, impaired renal function and recurrence of contralateral UTUC. To date, there are no preventive measures, except prophylactic nephrectomy, for subjects at risk of AA nephropathy or AA-related UTUC.
CONCLUSION
AA exposure via Aristolochia-based herbal medicines is a problem throughout Taiwan, resulting in a high incidence of UTUC. Aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, can be used as biomarkers to identify AA-related UTUC. AA-related UTUC is associated with a high recurrence rate of contralateral UTUC.
Topics: Humans; Female; Carcinoma, Transitional Cell; DNA Adducts; Drugs, Chinese Herbal; Taiwan; Urinary Bladder Neoplasms; Carcinogens; Kidney Neoplasms; Aristolochic Acids; Ureteral Neoplasms; Urinary Tract
PubMed: 35867141
DOI: 10.1007/s00345-022-04100-5 -
International Journal of Trichology 2022Smoking and its role in Androgenetic Alopecia has long been debated. Smoking may lead to hair loss by vasoconstriction, by forming DNA adducts, free radical damage to... (Review)
Review
Smoking and its role in Androgenetic Alopecia has long been debated. Smoking may lead to hair loss by vasoconstriction, by forming DNA adducts, free radical damage to hair follicle, by enhancing senescence and hormonal effects. We have reviewed the available literature on AGA and smoking. Data available show that there is a significant association between smoking and AGA. However, studies demonstrating the benefit of avoidance of smoking in improving hair loss are lacking. Furthermore, large controlled studies with histological documentation are still unavailable to affirm the findings.
PubMed: 35531482
DOI: 10.4103/ijt.ijt_59_21 -
Chemosphere Mar 2022Breast cancer (BC) is the most frequently diagnosed cancer in women. However, only 58% of cases have been associated with known risk factors (reproductive, hormonal,... (Meta-Analysis)
Meta-Analysis
Breast cancer (BC) is the most frequently diagnosed cancer in women. However, only 58% of cases have been associated with known risk factors (reproductive, hormonal, lifestyles, and genetic), and the rest to unknown causes. Nevertheless, growing evidence suggests that exposure to environmental contaminants is an important risk factor for BC. Polycyclic aromatic hydrocarbons (PAHs) are formed during organic matter combustion, including smoking, grilled meat, and fuels, and are important carcinogenic constituents of environmental pollution. We examined the information generated by epidemiological studies evaluating the association between BC and PAHs exposure from multiple sources. Our work was conducted according to Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) guidelines. We searched PubMed, Web of Science, and Scopus from January 2000 to December 2019. A total of 124 records were identified, and only 23 articles met all inclusion criteria. Occupational and/or environmental exposure to PAHs was significantly associated with BC, irrespective of exposure being assessed by direct or indirect methods. CYP1A1 and CYP1B1 adverse polymorphisms, familial BC history and smoking status, significantly strengthened the association between PAHs exposure and BC, whereas high fruit and vegetable intake had antagonistic associations. The positive relationships obtained in the studies here reviewed indicated that PAHs exposure is a risk factor for BC. Research needs include the improvement of exposure assessment, particularly identification of specific PAHs, reconstruction of time-varying and distant past exposures and further studies on the interaction between known BC factors and modifiable diet and life-style factors allowing BC prevention and control.
Topics: Breast Neoplasms; Carcinogens; Environmental Exposure; Environmental Pollution; Female; Humans; Polycyclic Aromatic Hydrocarbons
PubMed: 34929281
DOI: 10.1016/j.chemosphere.2021.133237 -
Cancer Chemotherapy and Pharmacology Nov 2021Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand...
PURPOSE
Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response.
METHODS
A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria.
RESULTS
Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (CDKN1A, ERCC1, ERCC2, ERCC4, ERCC6, EXO1, MLH1, MNAT1, MUTYH, PARP4, PCNA, POLE, POLR1G, RAD23B, RFC1, RFC3, RPA1, RPA3, TREX1, UNG, XPC, XRCC1) and somatic expression (CDKN1A, PARP1, PCNA, MGMT, RECQL, RFC5) were associated with melphalan outcomes in ≥ 1 study.
CONCLUSION
It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.
Topics: Antineoplastic Agents, Alkylating; DNA Adducts; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Melphalan; Neoplasms; Pharmacogenomic Variants; Progression-Free Survival; Treatment Outcome
PubMed: 34347127
DOI: 10.1007/s00280-021-04340-z -
Mutation Research. Reviews in Mutation... Oct 2017Vinyl chloride (VC) is widely used in industry in the production of polyvinyl chloride (PVC), which is used to manufacture a large variety of materials. VC was... (Meta-Analysis)
Meta-Analysis Review
Vinyl chloride (VC) is widely used in industry in the production of polyvinyl chloride (PVC), which is used to manufacture a large variety of materials. VC was classified as a known (Group 1) human carcinogen by IARC on the basis of increased risk for liver angiosarcoma and hepatocellular cancer, and the carcinogenicity of VC was shown to be mediated by a genotoxic mechanism. Following inhalation, the compound is rapidly absorbed and metabolized in the liver to the electrophilic metabolites chloroethylene-oxide and chloroacetaldehyde, which form DNA adducts that can be processed into point mutations in cancer-related genes detected in humans and rats exposed to VC. A number of genotoxicity biomarkers were applied in workers exposed to VC to detect early biological responses associated with the carcinogenesis process. The present systematic review analyzed the published studies in which the cytokinesis-block micronucleus assay in peripheral lymphocytes (L-CBMN) was applied in VC-exposed subjects. Thirteen out of fifteen retrieved studies performed in China showed increased MN frequencies (FR 1.92-3.98) associated with increased cumulative exposure or employment time. Twofold and more than threefold increases were detected in PVC-exposed workers exposed to a mean of 50ppm of VC in the former Yugoslavia and in South India, respectively. The meta-analysis of MN frequency from six eligible studies confirmed this tendency (pooled MR 2.32 - 95% CI 1.64-3.27). The benchmark dose lower limit for 10% excess risk (BMDL 10) calculated from three studies resulted in an estimated exposure limit of 0.03-0.07mg/m. Overall the results of this review showed the need for further studies, especially because PVC products from China may contain high levels of uncoupled VCM that could represent a source of exposure to workers and consumers. Moreover, the results underline the importance of re-evaluating the recommended exposure limits using new biomonitoring methods in addition to MN.
Topics: Biomarkers; Cytokinesis; Environmental Monitoring; Humans; Lymphocytes; Micronucleus Tests; Occupational Exposure; Vinyl Chloride
PubMed: 29173494
DOI: 10.1016/j.mrrev.2017.07.003