Analysis of 7‐methylguanine using isotope dilution and gas chromatography/electron‐capture negative chemical ionization mass spectrometry

Chiang, Su‐Yin; Huang, Tai Hung; Uang, Shi Nian; Wu, Hanwei; Wei, Yi Chiech; Lin, Hui Yi; Swenberg, James A.; Wu, Kaung-Hsiung

doi:10.1002/rcm.2003

Cited by 7 publications

(2 citation statements)

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“…There is, however, little information on the formation of methylated DNA damage induced by arsenic exposure. Arsenic-treated mice have an arsenic-related increase in hepatic N 7 -methylguanine (N 7 -MeG), a marker of methylated DNA damage that reflects the overall rate of DNA methylation [19], [20], but this finding has not been confirmed in humans.…”

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confidence: 99%

Maternal Arsenic Exposure and DNA Damage Biomarkers, and the Associations with Birth Outcomes in a General Population from Taiwan

et al. 2014

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Inorganic arsenic (iAs) is an established transplacental agent known to affect fetal development in animal studies. However, iAs has not been adequately studied in the general population with respect to iAs exposure during pregnancy and its impact on the health status of newborns. The aims of this study were to 1) elucidate the association between arsenic exposure and oxidative/methylated DNA damage in pregnant women, and 2) determine the association with birth outcomes. A birth cohort study of 299 pregnant mother-newborn pairs was recruited during 2001–2002 in Taiwan. We collected maternal urine samples during the 3rd trimester for measuring iAs and its metabolites. We used high-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC-ICP-MS) for quantifications of the arsenic species. Liquid chromatography/tandem mass spectrometer (LC-MS/MS) was used to measure the 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and N7-methylguanosine (N7-MeG) DNA damage biomarkers. Birth outcomes were collected to assess the associations with maternal arsenic exposure and the DNA damage biomarkers. Multiple regression analyses showed that maternal urinary iAs had positive associations with the methylated N7-MeG (beta = 0.35, p<0.001) and oxidative 8-oxodG (beta = 0.24, p<0.001) DNA damage biomarkers, and a decreased one-minute (1-min) Apgar score (beta = -0.23, p = 0.041). Maternal N7-MeG was also associated with a decreased 1-min Apgar score (beta = −0.25, p = 0.042). Mutual adjustment for iAs and N7-MeG showed an independent and significant prediction for a decreased 1-min Apgar score of iAs (beta = −0.28, p = 0.036). Maternal iAs exposure was associated with both maternal DNA damage and adverse newborn health. Maternal N7-MeG levels might be a novel biomarker for monitoring fetal health related to iAs.

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confidence: 99%

Maternal Arsenic Exposure and DNA Damage Biomarkers, and the Associations with Birth Outcomes in a General Population from Taiwan

et al. 2014

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“…5 Upon metabolic activation TSNA can form DNA adducts of which N 7 -methylguanine (m 7 Gua) is by far the most abundant, representing 70-90% of methylation products. [6][7][8][9][10] Whereas m 7 Gua is innocuous in DNA, the levels increase dose-dependently in DNA upon administration of methylating agents, correlating with pro-mutagenic and carcinogenic methyl-adducts, such as O 6 -methylguanine and methyladenine, [11][12][13] and may thus serve as biomarker of exposure to methylating agents. Indeed, a physiologically based pharmacokinetic model for interspecies dose extrapolation of dimethyl sulphate has been based on m 7 Gua adducts in the nasal cavity.…”

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Prospective study of urinary excretion of 7‐methylguanine and the risk of lung cancer: Effect modification by mu class glutathione‐S‐transferases

Loft

Svoboda

Kasai

et al. 2007

Intl Journal of Cancer

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Nitrosamines are mainly mutagenic through methylation of DNA. 7-Methylguanine (m 7 Gua) is a product of base excision repair and spontaneous depurination of such lesions in DNA and a metabolite from RNA. Associations between urinary excretion of m 7 Gua and risk of lung cancer were examined in a population-based cohort of 25,717 men and 27,972 women aged 50-64 years. During 3-7 years follow-up 260 cases with lung cancer were identified and a subcohort of 263 individuals matched on sex, age and smoking duration was selected for comparison. Urine collected at entry was analyzed for m 7 Gua by HPLC. Effect modification by glutathione-S-transferases GSTM1, GSTM3, GSTT1 and GSTP1 was investigated. We found higher excretion of m 7 Gua among current smokers than among former smokers. The IRR (incidence rate ratio) of lung cancer was 1.20 (95% CI: 1.00-1.43) per doubling of m 7 Gua excretion in unadjusted analysis and 1.12 (95% CI: 0.93-1.35) after adjustment for smoking status, intensity and duration at entry. This association was mainly present among current smokers. Comparing the highest with the lowest tertile of m 7 Gua excretion the IRR of lung cancer was 1.75 (95% CI: 1.04-2.95) irrespective of genotype and 2.75 (95% CI: 1.33-5.81) in subjects with GSTM1 null genotype. If not caused by residual confounding by smoking a possible association between m 7 Gua excretion and lung cancer supports the importance of methylation of guanine. The finding of an association between m 7 Gua excretion and lung cancer risk mainly among current smokers and subjects with GSTM1 null genotype supports causality in this respect. ' 2007 Wiley-Liss, Inc.Key words: lung cancer; smoking; cohort study; biomarkers; 7-methylguanine; glutathione-S-transferasesThe causal factors of lung cancer include active smoking, environmental tobacco smoke, various occupational exposures and probably ambient air pollution. 1-4 Tobacco smoke contain more than 50 known carcinogens including polycyclic aromatic hydrocarbons, aromatic amines and tobacco-specific nitrosamines (TSNA), such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). TSNA are formed by nitrosation of nicotine and secondary amines during curing and smoking of tobacco. 5 Upon metabolic activation TSNA can form DNA adducts of which N 7 -methylguanine (m 7 Gua) is by far the most abundant, representing 70-90% of methylation products. 6-10 Whereas m 7 Gua is innocuous in DNA, the levels increase dose-dependently in DNA upon administration of methylating agents, correlating with pro-mutagenic and carcinogenic methyl-adducts, such as O 6 -methylguanine and methyladenine, 11-13 and may thus serve as biomarker of exposure to methylating agents. Indeed, a physiologically based pharmacokinetic model for interspecies dose extrapolation of dimethyl sulphate has been based on m 7 Gua adducts in the nasal cavity. 14 Glutathione-S-transferases (GST) are a superfamily of genetically polymorphic enzymes detoxifying carcinogens, including many of those from tobacco smoke. The mu class of GSTs include...

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Voltammetric Behaviour of 7‐Methylguanine Using Screen‐printed Graphite Electrodes: towards a Guanine Methylation Electrochemical Sensor

et al. 2015

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1IntroductionEpigenetic modificationsi nD NA result in chemical alterations of the nucleic bases withouta ny change in the DNAs equence [1].T he best knowne pigenetic modification is cytosine methylation,w hose role is not fully understood yet, although it is well-accepted that methylation functions controls the gene expression and the protection of the host organism against expression of undesired sequences [2] Carcinogens comprise ad iverse group of chemicals which are able to react with nucleophilic sites (electron rich, S, Na nd Oa toms), in DNAa nd proteins.I ti s known that DNAa dduct formation occurs at nucleophilic sites in DNA, and the N7-position of guanine (G) is the most reactive of these nucleophilic sites [7].N 7-guanine adductsa re chemically unstable and the N7-position does not participatei nW atson Crick base pairing, so N7-guanine adducts are classified as non-promutagenic with minimal biological relevance [8].E ven thought hese adducts are innocuous,t he development of analytical methods for detecting 7mG has great biological importance since as the levels of methylation of guanine increase due to the presence of methylating agents,this increment can be correlated to pro-mutagenic and carcinogenic, such as O6-methylguaninea nd methyladenine [9].T herefore,7 mG can servea sb iomarker of internal exposure to methylating agents, [ 10].M oreover, it has been also reported that the presenceo f7 mG in excretion increasedi nl aboratory animals after exposure to methylating agents [11] and also was highera mong smokers than among nonsmokers [12].C onsequentlyi ti si mportant to improve the analytical methodologiesf or the 7mG determination,s ince it could be used as acancer biomarker.Differentt echnologies have been usedf or analysis of N7-guanine adducts,s uch as,c hromatography [13],h igh pressure liquid chromatography (HPLC) [14],3 2P-postlabelingm ethods [15],g as chromatography [16] or liquid chromatography tandem mass spectrometry [17].H owever, althought hesem ethods are sensitive enough, they are time-consuming and theirc osts made them economically unfeasible for routine implementation. Fort hat reason electrochemical methods are very promising tools for DNAs tudies since they are easy to implement,y et providing rapid and accurate results while beinge conomically viable to be routinely implemented.H owever, these electrochemical methodss till require improvements in terms of reproducibility and repeatability.Very few examplesc an be found in the literature regarding the electrochemicald etermination of this alkylatAbstract:T he determination of 7-methylguanine (7mG) is an interesting analyticalt arget since its quantification can be correlated with the methylation of cytosine which is one of the most relevant epigenetic modificationo f DNA. In this work, screen-printedg raphite electrodes were used to study the electrochemicalc haracterization of 7mG by cyclic and square wave voltammetry.7 mG concentration and pH were examined, as well as the repeatability of the measurements.T he electroche...

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Analysis of 7‐methylguanine using isotope dilution and gas chromatography/electron‐capture negative chemical ionization mass spectrometry

Cited by 7 publications

References 19 publications

Maternal Arsenic Exposure and DNA Damage Biomarkers, and the Associations with Birth Outcomes in a General Population from Taiwan

Maternal Arsenic Exposure and DNA Damage Biomarkers, and the Associations with Birth Outcomes in a General Population from Taiwan

Prospective study of urinary excretion of 7‐methylguanine and the risk of lung cancer: Effect modification by mu class glutathione‐S‐transferases

Voltammetric Behaviour of 7‐Methylguanine Using Screen‐printed Graphite Electrodes: towards a Guanine Methylation Electrochemical Sensor

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