Development and Validation of a New, Sensitive Immunochemical Assay for O6-Methylguanine in DNA and Its Application in a Population Study

Georgiadis, Panagiotis; Kaila, Stella; Makedonopoulou, Paraskevi; Fthenou, Eleni; Chatzi, Leda; Pletsa, Vasiliki; Kyrtopoulos, Soterios A.

doi:10.1158/1055-9965.epi-10-0788

Cited by 18 publications

(22 citation statements)

References 28 publications

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“…Levels of O 6 -meG were determined in DNA isolated from NOC-exposed Caco-2 cells using a newly developed ELISA method as recently described by Georgiadis et al (2011). DNA samples were analyzed in triplicate.…”

Section: Determination Of O 6 -Meg In Dna By Elisamentioning

confidence: 99%

Time-series analysis of gene expression profiles induced by nitrosamides and nitrosamines elucidates modes of action underlying their genotoxicity in human colon cells

et al. 2011

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N-nitroso compounds (NOCs) may represent a carcinogenic risk to humans following endogenous colonic nitrosation processes. We used the colon adenocarcinoma cell line Caco-2 to investigate transcriptomic changes at three time points (1, 6, 24 h) following exposure to genotoxic concentrations of six different NOCs (two nitrosamides, four nitrosamines) with the purpose of identifying biological processes that may play a part in the carcinogenicity of these compounds. This is especially important for nitrosamide exposure where, in light of their high reactivity, important gene expression modifications may take place early in the exposure. We also analyzed NOC-induced O(6)-methylguanine adducts in relation to transcriptomics since these adducts may influence the expression of genes pivotal in NOC-associated carcinogenicity. Many modified pathways appeared related to DNA damage, cell cycle, apoptosis, growth factor signaling and differentiation, which are linked with carcinogenicity. Nitrosamides showed the strongest response at 1h of exposure, while nitrosamines had the strongest effect at 6 and 24 h. Additionally, methylation was strongly associated with processes that may contribute to the carcinogenic risk. In summary, we have found that NOC-induced gene expression changes vary over time and that many of the modified pathways and processes indicate a carcinogenic risk associated with NOC exposure.

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Section: Determination Of O 6 -Meg In Dna By Elisamentioning

confidence: 99%

Time-series analysis of gene expression profiles induced by nitrosamides and nitrosamines elucidates modes of action underlying their genotoxicity in human colon cells

et al. 2011

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“…Georgiadis et al . published a second study of O 6 ‐MeG adducts in 120 pairs of maternal and cord blood DNA samples utilizing a new immunochemical assay that analyzed digested DNA using an antiss‐DNA antisera.…”

Section: Literature Reviewmentioning

confidence: 99%

“…Approximately 20% of the bases in human DNA are guanine . Therefore, the results of the second Georgiadis study can be normalized with the first by simply multiplying by 5 and then by 10 (to convert to a denominator of 10 9 ) to arrive at 32.5 O 6 ‐MeG/10 9 G. Therefore, the mean values of the second study are about 63% of those observed in the first study. This may be due, in part, from exclusion of smokers from the second study.…”

Section: Literature Reviewmentioning

confidence: 99%

Drinking Water as a Proportion of Total Human Exposure to Volatile N‐Nitrosamines

Hrudey

Bull²,

Cotruvo³

et al. 2013

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Some volatile N-nitrosamines, primarily N-nitrosodimethylamine (NDMA), are recognized as products of drinking water treatment at ng/L levels and as known carcinogens. The U.S. EPA has identified the N-nitrosamines as contaminants being considered for regulation as a group under the Safe Drinking Water Act. Nitrosamines are common dietary components, and a major database (over 18,000 drinking water samples) has recently been created under the Unregulated Contaminant Monitoring Rule. A Monte Carlo modeling analysis in 2007 found that drinking water contributed less than 2.8% of ingested NDMA and less than 0.02% of total NDMA exposure when estimated endogenous formation was considered. Our analysis, based upon human blood concentrations, indicates that endogenous NDMA production is larger than expected. The blood-based estimates are within the range that would be calculated from estimates based on daily urinary NDMA excretion and an estimate based on methylated guanine in DNA of lymphocytes from human volunteers. Our analysis of ingested NDMA from food and water based on Monte Carlo modeling with more complete data input shows that drinking water contributes a mean proportion of the lifetime average daily NDMA dose ranging from between 0.0002% and 0.001% for surface water systems using free chlorine or between 0.001% and 0.01% for surface water systems using chloramines. The proportions of average daily dose are higher for infants (zero to six months) than other age cohorts, with the highest mean up to 0.09% (upper 95th percentile of 0.3%).

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“…These analyses were carried out using ultrasensitive sandwich chemiluminescence immunoassays as previously described for O 6 -MedG (Georgiadis et al 2011) and PAH (polycyclic aromatic hydrocarbons)–DNA adducts (Georgiadis et al 2012). …”

Section: Methodsmentioning

confidence: 99%

Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression: The NewGeneris Cohort

Merlo

Agramunt

Anna

et al. 2014

Environ Health Perspect

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Background: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development.Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored.Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe.Results: Malondialdehyde DNA adducts (M1dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure–outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M1dG–DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/2 and CYP2E1 were associated with MNBN.Conclusion: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.Citation: Merlo DF, Agramunt S, Anna L, Besselink H, Botsivali M, Brady NJ, Ceppi M, Chatzi L, Chen B, Decordier I, Farmer PB, Fleming S, Fontana V, Försti A, Fthenou E, Gallo F, Georgiadis P, Gmuender H, Godschalk RW, Granum B, Hardie LJ, Hemminki K, Hochstenbach K, Knudsen LE, Kogevinas M, Kovács K, Kyrtopoulos SA, Løvik M, Nielsen JK, Nygaard UC, Pedersen M, Rydberg P, Schoket B, Segerbäck D, Singh R, Sunyer J, Törnqvist M, van Loveren H, van Schooten FJ, Vande Loock K, von Stedingk H, Wright J, Kleinjans JC, Kirsch-Volders M, van Delft JHM, NewGeneris Consortium. 2014. Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormona...

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Development and Validation of a New, Sensitive Immunochemical Assay for O6-Methylguanine in DNA and Its Application in a Population Study

Abstract: Background: Investigations of the presence of the precarcinogenic DNA adduct O

Cited by 18 publications

References 28 publications

Time-series analysis of gene expression profiles induced by nitrosamides and nitrosamines elucidates modes of action underlying their genotoxicity in human colon cells

Time-series analysis of gene expression profiles induced by nitrosamides and nitrosamines elucidates modes of action underlying their genotoxicity in human colon cells

Drinking Water as a Proportion of Total Human Exposure to Volatile N‐Nitrosamines

Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression: The NewGeneris Cohort

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