RESUMO
Tobacco usage is linked to multiple cancer types and accounts for a quarter of all cancer-related deaths. Tobacco smoke contains various carcinogenic compounds, including polycyclic aromatic hydrocarbons (PAH), though the mutagenic potential of many tobacco-related chemicals remains largely unexplored. In particular, the highly carcinogenic tobacco-specific nitrosamines NNN and NNK form pre-mutagenic pyridyloxobutyl (POB) DNA adducts. In the study presented here, we identified genome-scale POB-induced mutational signatures in cell lines and rat tumors, while also investigating their role in human cancer. These signatures are characterized by T>N and C>T mutations forming from specific POB adducts damaging dT and dC residues. Analysis of 2,780 cancer genomes uncovered POB signatures in â¼180 tumors; from cancer types distinct from the ones linked to smoking-related signatures SBS4 and SBS92. This suggests that, unlike PAH compounds, the POB pathway may contribute uniquely to the mutational landscapes of certain hematological malignancies and cancers of the kidney, breast, prostate and pancreas.
RESUMO
The widespread contamination of the environment by polyhalogenated carbazoles (PHCZs) has been increasingly observed during the past decade. Among numerous PHCZ congeners, 3,6-dichlorocarbazole (36-CCZ) is often among the most frequently detected at higher concentrations. Although the environmental level of the legacy pesticide p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) has been declining, it continues to be ubiquitously detected. These two compounds were found to interfere with each other during analyses using gas chromatography (GC) coupled with single- or triple-quadrupole low-resolution mass spectrometry (MS or MS/MS). The base peak in the mass spectra was that of m/z 235 for both compounds. In MS/MS with multiple reaction monitoring (MRM), the same transitions (235 â 200 and 235 â 165) were often used. Under the same GC operating conditions, the SH-I-5MS capillary column used in this work did not resolve the two compounds at baseline. Pre-treatment using cleanup column chromatography can fractionate the sample extract, with the two compounds separated in different fractions before instrumental analyses. Reversed-phase HPLC columns also work for resolving 36-CCZ and p,p'-DDT. Possible overlaps in GC retention and similarity in MS spectra might have caused data inaccuracy for 36-CCZ as well as p,p'-DDT in some studies published to date, and steps to avoid the interference should be taken into quality control protocols in future research and environmental monitoring.
Assuntos
DDT , Espectrometria de Massas em Tandem , Cromatografia Gasosa-Espectrometria de Massas , Monitoramento Ambiental , CarbazóisRESUMO
The alternative flame retardants, novel brominated flame retardants (NBFRs) and organophosphate flame retardants (OPFRs) are ubiquitous in the environment and biota and may induce endocrine disruption effects. Associations between traditional endocrine-disrupting chemicals and type 2 diabetes have been extensively reported in epidemiological studies. However, the effects of NBFRs and OPFRs in humans have not been reported to date. This paper reports a case-control study of 344 participants aged 25-80 years from Shandong Province, East China, where potential associations between serum NBFR and OPFR concentrations and type 2 diabetes are assessed for the first time. After adjusting for covariates (i.e., age, sex, body mass index, smoking status, alcohol consumption, triglycerides, and total cholesterol), serum concentrations of pentabromotoluene, 2,3-dibromopropyl 2,4,6-tribromophenyl ether, tri-n-propyl phosphate, triphenyl phosphate, and tris (2-ethylhexyl) phosphate were significantly positively associated with type 2 diabetes. In the control group, decabromodiphenyl ethane and triphenyl phosphate were significantly positively associated with fasting plasma glucose, triglycerides, and high-density lipoprotein cholesterol. In the quantile g-computation model, significant positive mixture effect was found between the flame retardants mixtures and high-density lipoprotein cholesterol levels, and decabromodiphenyl ethane contributed the largest positive weights to the mixture effect. Overall, these findings suggest that exposure to NBFRs and OPFRs may promote type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Retardadores de Chama , Humanos , Monitoramento Ambiental , Retardadores de Chama/análise , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Éteres Difenil Halogenados/análise , Organofosfatos , China/epidemiologia , Fosfatos , Lipoproteínas HDL , ColesterolRESUMO
We developed a liquid chromatography-nanoelectrospray ionization-high-resolution tandem mass spectrometry (LC-NSI-HRMS/MS) method for simultaneous quantitative analysis of 5 oral cell DNA adducts associated with cigarette smoking: (8R/S)-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dGuo, 1) from acrolein; (6S,8S and 6R,8R)-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)-one [(6S,8S)γ-OH-Cro-dGuo, 2; and (6R,8R)γ-OH-Cro-dGuo, 3] from crotonaldehyde; 1,N6-etheno-dAdo (4) from acrylonitrile, vinyl chloride, lipid peroxidation, and inflammation; and 8-oxo-dGuo (5) from oxidative damage. Oral cell DNA was isolated in the presence of glutathione to prevent artifact formation. Clear LC-NSI-HRMS/MS chromatograms were obtained allowing quantitation of each adduct using the appropriately labeled internal standards. The accuracy and precision of the method were validated, and the assay limit of quantitation was 5 fmol/µmol dGuo for adducts 1-4 and 20 fmol/µmol for adduct 5. The assay was applied to 80 buccal cell samples selected from those collected in the Shanghai Cohort Study: 40 from current smokers and 40 from never smokers. Significant differences were found in all adduct levels between smokers and nonsmokers. Levels of 8-oxo-dGuo (5) were at least 3000 times greater than those of the other adducts in both smokers and nonsmokers, and the difference between amounts of this adduct in smokers versus nonsmokers, while significant (P = 0.013), was not as great as the differences of the other DNA adducts between smokers and nonsmokers (P-values all less than 0.001). No significant relationship of adduct levels to risk of lung cancer incidence was found. This study provides a new LC-NSI-HRMS/MS methodology for the quantitation of diverse DNA adducts resulting from exposure to the α,ß-unsaturated aldehydes acrolein and crotonaldehyde, inflammation, and oxidative damage which are all associated with carcinogenesis. We anticipate application of this assay in ongoing studies of the molecular epidemiology of cancers of the lung and oral cavity related to cigarette smoking.
Assuntos
Fumar Cigarros , Adutos de DNA , Humanos , Espectrometria de Massas em Tandem , Acroleína/química , 8-Hidroxi-2'-Desoxiguanosina , Estudos de Coortes , Espectrometria de Massas por Ionização por Electrospray/métodos , China , Cromatografia Líquida , Purinas , Inflamação , Cromatografia Líquida de Alta Pressão/métodosRESUMO
The use of electronic cigarettes (e-cigarettes) has increased rapidly in the United States, especially among high school students. e-Cigarettes contain some recognized carcinogens and may induce DNA damage in oral cells. The aim of this review is to summarize studies reporting DNA adducts or other types of DNA damage in oral cells in vitro or in vivo upon exposure to e-cigarette vapor and to evaluate the possible connections between e-cigarette exposure and oral cancer. Three databases including PubMed, Scopus, and EMBASE and gray literature were searched for articles published up to April 24, 2022. After screening 321 articles, we extracted 27 for further investigation. Based on the inclusion criteria, 22 articles were eligible for this review. The in vitro studies demonstrate that e-cigarette liquid or vapor can induce DNA damage, oxidative stress, DNA double-stranded breaks, apoptosis, cytotoxicity, and genotoxicity in different types of oral cells. The clinical studies showed that e-cigarette users have significantly higher levels of N'-nitrosonornicotine, acrolein DNA adducts, metanuclear anomalies, gene regulation, and lactate dehydrogenase enzyme expression and significantly lower levels of apurinic/apyrimidinic sites than non-users. Comparison of micronuclei levels between e-cigarette users and non-users gave inconsistent results. e-Cigarettes are implicated in DNA damage to oral cells, but publications to date present limited evidence. Future studies with larger sample sizes are required to investigate the long-term consequences of e-cigarette use.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Produtos do Tabaco , Humanos , Estados Unidos , Adutos de DNA , Dano ao DNARESUMO
DNA adducts are central in the mechanism of carcinogenesis by genotoxic agents. We compared levels of a DNA adduct of acrolein, a genotoxic carcinogen found in e-cigarette vapor, in oral cell DNA of e-cigarette users and non-users of any tobacco or nicotine product. e-Cigarette users and non-users visited our clinic once monthly for 6 months, and oral brushings and urine samples were collected. For this study, we analyzed oral cell DNA adducts from three monthly visits in e-cigarette users and non-users as confirmed by urinary cyanoethyl mercapturic acid and total nicotine equivalents. DNA was isolated from the oral brushings and analyzed by a validated liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method for the acrolein DNA adduct 8R/S-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10-(3H)-one (γ-OH-Acr-dGuo). The median value of this DNA adduct in the e-cigarette users was 179 fmol/µmol dGuo (range 5.0 - 793 fmol/µmol dGuo) while that for non-users was 21.0 fmol/µmol dGuo (range 5.0 - 539 fmol/µmol dGuo), P = 0.001. These results demonstrate for the first time that e-cigarette users have elevated levels of a carcinogen-DNA adduct in their oral cells.
Assuntos
Adutos de DNA , Sistemas Eletrônicos de Liberação de Nicotina , Acroleína/química , Acroleína/toxicidade , Carcinógenos/análise , Carcinógenos/toxicidade , Cromatografia Líquida de Alta Pressão , DNA , Nicotina , Espectrometria de Massas por Ionização por Electrospray/métodosRESUMO
Cigarette smoking is an established risk factor for oral cancer. The health effects of e-cigarettes are still under investigation but may disturb oral cavity homeostasis and cause lung and cardiovascular diseases. Carcinogens and toxicants in tobacco products and e-cigarettes may damage DNA, resulting in the formation of apurinic/apyrimidinic (AP) sites and initiation of the carcinogenic process. In this study, we optimized a liquid chromatography-nanoelectrospray ionization-high-resolution tandem mass spectrometry method to analyze AP sites in buccal cell DNA of 35 nonsmokers, 30 smokers, and 30 e-cigarette users. AP sites in e-cigarette users (median 3.3 per 107 nts) were significantly lower than in smokers (median 5.7 per 107 nts) and nonsmokers (median 6.0 per 107 nts). AP sites in smokers were not significantly different from nonsmokers (p > 0.05). The e-cigarette vaporizing solvents propylene glycol and glycerin were tested and did not protect against AP site formation in in vitro control and carcinogen exposed rat liver homogenates. However, propylene glycol may inhibit bacteria in oral cells, resulting in reduced inflammation and related effects, and reduced AP site levels in e-cigarette user DNA. This is the first study to examine AP site formation in e-cigarette users and to evaluate AP sites in human oral cell DNA.
Assuntos
Fumar Cigarros , DNA/análise , Sistemas Eletrônicos de Liberação de Nicotina , Mucosa Bucal/química , não Fumantes , Animais , Cromatografia Líquida , Humanos , Estrutura Molecular , Mucosa Bucal/citologia , Controle de Qualidade , Ratos , Espectrometria de Massas em TandemRESUMO
Metabolic activation of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) results in formation of reactive electrophiles that modify DNA to produce a variety of products including methyl, 4-(3-pyridyl)-4-oxobutyl (POB)-, and 4-(3-pyridyl)-4-hydroxybutyl adducts. Among these are adducts such as 7-POB-deoxyguanosine (N7POBdG) which can lead to apurinic/apyrimidinic (AP) sites by facile hydrolysis of the base-deoxyribonucleoside bond. In this study, we used a recently developed highly sensitive mass spectrometric method to quantitate AP sites by derivatization with O-(pyridin-3-yl-methyl)hydroxylamine (PMOA) (detection limit, 2 AP sites per 108 nucleotides). AP sites were quantified in DNA isolated from tissues of rats treated with NNN and NNK and from human lung tissue and leukocytes of cigarette smokers and nonsmokers. Rats treated with 5 or 21 mg/kg bw NNK for 4 days by s.c. injection had 2-6 and 2-17 times more AP sites than controls in liver and lung DNA (p < 0.05). Increases in AP sites were also found in liver DNA of rats exposed for 10 and 30 weeks (p < 0.05) but not for 50 and 70 weeks to 5 ppm of NNK in their drinking water. Levels of N7POBG were significantly correlated with AP sites in rats treated with NNK. In rats treated with 14 ppm (S)-NNN in their drinking water for 10 weeks, increased AP site formation compared to controls was observed in oral and nasal respiratory mucosa DNA (p < 0.05). No significant increase in AP sites was found in human lung and leukocyte DNA of cigarette smokers compared to nonsmokers, although AP sites in leukocyte DNA were significantly correlated with urinary levels of the NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). This is the first study to use mass spectrometry based methods to examine AP site formation by carcinogenic tobacco-specific nitrosamines in laboratory animals and to evaluate AP sites in DNA of smokers and nonsmokers.