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  • 1
    Keywords: EXPRESSION ; IN-VITRO ; BLOOD ; CELL ; evaluation ; VITRO ; LUNG-CANCER ; COHORT ; EXPOSURE ; WORKERS ; ENZYMES ; GENE ; GENES ; METABOLISM ; DNA ; MARKER ; GENETIC POLYMORPHISMS ; INDUCTION ; ASSOCIATION ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; FREQUENCIES ; NO ; ASSAY ; CHROMOSOMAL-ABERRATIONS ; DNA-REPAIR ; REPAIR ; ABERRATIONS ; MARKERS ; PCR ; COMET ASSAY ; genotoxicity ; LYMPHOCYTES ; POLYCYCLIC AROMATIC-HYDROCARBONS ; GENOTYPES ; WILD-TYPE ; INDIVIDUALS ; PERIPHERAL-BLOOD ; SINGLE-STRAND BREAKS ; SISTER-CHROMATID EXCHANGES ; ASSOCIATIONS ; VARIANT ; OCCUPATIONAL-EXPOSURE ; CAPACITY ; ALLELE ; TOBACCO-SMOKE ; GSTM1 ; GSTT1 ; XPD ; HYDROCARBONS ; XRCC1 ; STYRENE ; DNA repair rates ; HUMAN SENSITIVITY ; individual susceptibility ; MICROSOMAL EPOXIDE HYDROLASE ; occupational exposure to xenobiotics
    Abstract: Workers employed in tire plants are exposed to a variety of xenobiotics, such as 1,3-butodiene (BD), soots containing polycyclic aromatic hydrocarbons, and other organic chemicals (e.g., styrene). In the present study, we investigated markers of genotoxicity [chromosomal aberrations (CAs) and single-strand breaks (SSBs)] in a cohort of 110 tire plant workers engaged in jobs with different levels of xenobiotic exposure in relation to various polymorphisms in genes coding for biotransformation enzymes (CYP1A1, CYP2E1, EPHX1, GSTM1, GSTP1, and GSTT1) and in genes involved in DNA repair (XPD exon 23, XPG exon 15, XPC exon 15, XRCC1 exon 10, and XRCC3 exon 7). In addition, the expression of CYP2E1, a gene playing a key role in BD metabolism, was determined by realtime PCR in peripheral blood lymphocytes, and the capacity of lymphocytes to repair gamma-ray-induced SSBs and to convert 8-oxoguanine in HeLa cell DNA into SSBs was assessed using in vitro assays. No positive associations were detected between the CA frequency or SSB induction and levels of workplace exposure; however, a nonsignificant twofold higher irradiation-specific DNA repair rate was found among highly exposed workers. In evaluations conducted with the markers of individual susceptibility, workers with low-EPHX1-activity genotypes exhibited a significantly higher CA frequency as compared to those with medium and high-EPHX1-activity genotypes (P = 0.050). CA frequencies were significantly lower in individuals homozygous for the XPD exon 23 variant allele in comparison to those with the wild-type CC genotype (P = 0.003). Interestingly, CAs were higher in individuals with higher CYP2E1 expression levels, but the association was nonsignificant (P = 0.097). The results from this study suggest the importance of evaluating markers of individual susceptibility, since they may modulate genotoxic effects induced by occupational exposure to xenobiotics. (C) 2004 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15470755
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  • 2
    Keywords: DNA adducts ; TUMORS ; ACTIVATION ; DNA ; PATTERNS ; METABOLIC-ACTIVATION ; aristolochic acid ; BALKAN ENDEMIC NEPHROPATHY ; CHINESE HERBS NEPHROPATHY ; DT-DIAPHORASE ; P-32 POSTLABELING ANALYSIS ; ACETYLTRANSFERASE ; urothelial cancer ; sulfotransferase ; molecular modeling ; reductive activation ; NAD(P)H-QUINONE OXIDOREDUCTASE ; CYTOCHROMES P450 1A1 ; NAD(P)H:quinone oxidoreductase ; HUMAN CANCER HAZARD
    Abstract: Ingestion of aristolochic acid (AA) is associated with development of urothelial tumors linked with AA nephropathy and is implicated in the development of Balkan endemic nephropathy-associated urothelial tumors. We investigated the efficiency of human NAD(P)H:quinone oxidoreductase (NQO1) to activate aristolochic acid I (AAI) and used in silico docking, using soft-soft (flexible) docking procedure, to study the interactions of AAI with the active site of human NQO1. AAI binds to the active site of NQO1 indicating that the binding orientation allows for direct hydride transfer (i.e., two electron reductions) to the nitro group of AAI. NQO1 activated AAI, generating DNA adduct patterns reproducing those found in urothelial tissues from humans exposed to AA. Because reduced aromatic nitro-compounds are often further activated by sulfotransferases (SULTs) or N,O-acetlytransferases (NATs), their roles in AAI activation were investigated. Our results indicate that phase II reactions do not play a major role in AAI bioactivation; neither native enzymes present in human hepatic or renal cytosols nor human SULT1A1, -1A2, -1A3, -1E, or -2A nor NAT1 or NAT2 further enhanced DNA adduct formation by AAI. Instead under the in vitro conditions used, DNA adducts arise by enzymatic reduction of AAI through the formation of a cyclic hydroxamic acid (N-hydroxyaristolactam I) favored by the carboxy group in peri position to the nitro group without additional conjugation. These results emphasize the major importance of NQO1 in the metabolic activation of AAI and provide the first evidence that initial nitroreduction is the rate limiting step in AAI activation.
    Type of Publication: Journal article published
    PubMed ID: 21370283
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  • 3
    Keywords: brain ; CANCER ; LUNG ; MODEL ; MODELS ; SUPPORT ; DISEASE ; DISEASES ; DNA adducts ; EXPOSURE ; liver ; NEW-YORK ; RISK ; TISSUE ; HEART ; MICE ; DNA ; animals ; TISSUES ; CONTRAST ; INTERVENTION ; MOUSE ; PLASMA ; DECREASE ; smoking ; MODULATION ; DAMAGE ; NUCLEOTIDES ; DNA-DAMAGE ; ADDUCTS ; APOLIPOPROTEIN-E ; ATHEROSCLEROSIS ; benzo[alpha]pyrene,DNA adduct,plasma lipids,apolipoprotein E,chronic degenerative diseases ; CARCINOGENS ; cholesterol ; DIET ; DIETARY ; FAT ; LDL ; lipids ; LIPOPROTEIN ; LOW-DENSITY-LIPOPROTEIN ; NETHERLANDS ; STOMACH
    Abstract: The role of plasma lipids in the uptake, transportation, and distribution of lipophilic carcinogens like benzo[a]pyrene (B[a]P) remains unclear. Therefore, we studied the effects of dietary-modulated plasma lipids on B[a]P-induced DNA damage in several organs of two hyperlipidemic mouse models. Male apolipoprotein E (ApoE)*3-Leiden (n = 22) and ApoE knockout (ApoE-KO) mice (n = 20) were fed a high-fat cholesterol (HFC) diet or low-fat cholesterol (LFC; standard mouse chow) diet for 3 weeks, after which the animals were exposed to a single oral dose of 5 mg/kg bw B[a]P or vehicle and killed 4 days later. Plasma lipids were determined and DNA adducts were measured in aorta, heart, lung, liver, brain, and stomach. Total cholesterol and low-density lipoprotein (LDL) cholesterol were increased in all animals on a HFC diet, whereas a decrease of triglycerides was seen only in the ApoE-KO mice. In ApoE-KO mice on a normal diet, DNA-adduct levels were highest in aorta (10.8 +/- 1.4 adducts/10(8) nucleotides), followed by brain (7.8 +/- 1.3), lung (3.3 +/- 0.7), heart (3.1 +/- 0.6), liver (1.5 +/- 0.2) and stomach (1.2 +/- 0.2). In the ApoE*3-Leiden mice, adduct levels were equally high in aorta, heart, and lung (4.6 +/- 0.7, 5.0 +/- 0.5 and 4.6 +/- 0.4, respectively), followed by stomach (2.7 +/- 0.4), brain (2.3 +/- 0.2), and liver (1.7 +/- 0.2). In the ApoE-KO mice, the HFC diet intervention resulted in lower adduct levels in lung (2.1 +/- 0.2), heart (1.9 +/- 0.2), and brain (2.9 +/- 0.5), as compared with the LFC group. In contrast, a nonsignificant increase of adducts was found in aorta (13.1 +/- 1.5). A similar but nonsignificant trend was observed in the ApoE*3-Leiden mice. Multiple regression analysis showed that in aorta, DNA adducts were inversely related to plasma triglycerides (P = 0.004) and were also modulated by the ApoE genotype (P 〈 0.001). The results of the present study support further investigation into the role of dietary modulation of plasma lipids, ApoE, and polycyclic aromatic hydrocarbon exposure on the formation of DNA adducts in chronic degenerative diseases. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
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  • 4
    Keywords: CELLS ; CELL ; human ; IN-VIVO ; PATHWAY ; PATHWAYS ; GENE ; GENES ; TIME ; DNA ; IMPACT ; recombination ; BASE ; polymorphism ; POLYMORPHISMS ; NO ; score ; ASSAY ; REPAIR ; genetics ; smoking ; SWEDEN ; COMET ASSAY ; DAMAGE ; LYMPHOCYTES ; DNA-DAMAGE ; MAMMALIAN-CELLS ; SAFETY ; INDIVIDUALS ; HEALTHY ; NUCLEOTIDE EXCISION-REPAIR ; heredity ; DNA repair ; EXCISION-REPAIR ; HOMOLOGOUS RECOMBINATION ; SINGLE-STRAND BREAKS ; HUMAN-LYMPHOCYTES ; VARIANT ; XPD ; XRCC1 ; ALLELES ; DNA damage ; USA ; LUNG-CANCER RISK ; base excision repair ; VARIANT ALLELES ; XRCC3 ; RATIO ; GENE POLYMORPHISMS ; alkaline comet assay ; GENE POLYMORPHISM ; NUCLEOTIDE ; CRUCIAL ROLE ; APEX1 ; methylmethane sulphonate ; POLYMERASE-BETA
    Abstract: We have applied the alkaline comet assay to study the functional impact of gene polymorphisms in base excision repair (APEX1 Asp148Glu, XRCC1 Arg194Trp, XRCC1 Arg399Gln) and homologous recombination repair (XRCC3 Thr-241Met, NBS1 Glu185Gln), two pathways that play crucial roles in the repair of DNA damage induced by methylmethane sulphonate (MMS). We also examined the effect of polymorphisms in mismatch repair (MLH1 -93 A/G) and nucleotide excision repair (XPD Lys751Gln) as putative negative controls based on the limited roles of these pathways in MMS-induced repair. Phyto-hemagglutinin-stimulated peripheral lymphocytes from 52 healthy individuals were treated with MMS and allowed to repair for 0, 15, 40, or 120 min after a 6-min washing step. DNA damage was measured as a pseudo-percentage score (comparable to % tail DNA) converted from a total visual score calculated from the distribution of cells with different degrees of damage (normal, mild, moderate and severe). The repair was faster at the beginning of the observation period than towards the end, and was not complete after 2 hr. Presence of the APEX1 148ASp, XRCC3 241Met or NBS1 185Gln alleles were significantly associated with a high pseudo-percentage score (above median) at early time points, with the APEX1 effect being most prolonged (up to 40 min after washing, odds ratio 5.6, 95% confidence interval 2.0-15.5). No significant effects were seen with the XRCC1 Arg194Trp, XRCC1 Arg399Gln, MLH1 -93A/G and XPD LyS751 Gln polymorphisms. Our results provide evidence for the functional nature of the variant alleles studied in the APEX1, XRCC3, and NBS1 genes. Environ. Mal. Mutagen. 49:669-675, 2008. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18627000
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  • 5
    Keywords: EXPOSURE ; POLYMORPHISMS ; BLADDER-CANCER ; METHYLATION ; SKIN-CANCER ; UROTHELIAL CARCINOMA ; GENOTYPE ; PROFILE ; HUNGARY ; SLOVAKIA
    Abstract: Exposure to inorganic arsenic increases the risk of basal cell carcinoma (BCC). Arsenic metabolism is a susceptibility factor for arsenic toxicity, and specific haplotypes in arsenic (+3 oxidation state) methyltransferase (AS3MT) have been associated with increased urinary fractions of the most toxic arsenic metabolite, methylarsonic acid (MMA). The aim of this study is to elucidate the association of AS3MT haplotypes with arsenic metabolism and the risk of BCC. Four AS3MT polymorphisms were genotyped in BCC cases (N=529) and controls (N=533) from Eastern Europe with low to moderate arsenic exposure (lifetime average drinking water concentration: 1.3 mu g/L, range 0.01-167 mu g/L). Urinary metabolites [inorganic arsenic (iAs), MMA, dimethylarsinic acid (DMA)] were analyzed by HPLC-ICPMS. Five AS3MT haplotypes (based on rs3740400 A/C, rs3740393 G/C, rs11191439 T/C and rs1046778 T/C) had frequencies 〉5%. Individuals with the CCTC haplotype had lower %iAs (P=0.032) and %MMA (P=0.020) in urine, and higher %DMA (P=0.033); individuals with the CGCT haplotype had higher %MMA (P〈0.001) and lower %DMA (P〈0.001). All haplotypes showed increased risk of BCC with increasing arsenic exposure through drinking water (ORs 1.1-1.4, P values from 〈0.001 to 0.082), except for the CCTC haplotype (OR 1.0, CI 0.9-1.2, P value 0.85). The results suggest that carriage of AS3MT haplotypes associated with less-efficient arsenic methylation, or lack of AS3MT haplotypes associated with a more-efficient arsenic methylation, results in higher risk of arsenic-related BCC. The fact that AS3MT haplotype status modified arsenic metabolism, and in turn the arsenic-related BCC risk, supports a causal relationship between low-level arsenic exposure and BCC. Environ. Mol. Mutagen. 56:60-69, 2015.
    Type of Publication: Journal article published
    PubMed ID: 25156000
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  • 6
    Abstract: Benzo[a]pyrene (BaP) is a human carcinogen that covalently binds to DNA after metabolic activation by cytochrome P450 (CYP) enzymes. In this study human recombinant CYPs (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, and 3A5) were expressed in Supersomes together with their reductases, NADPH:CYP oxidoreductase, epoxide hydrolase and cytochrome b5 , to investigate BaP metabolism. Human CYPs produced up to eight BaP metabolites. Among these, BaP-7,8-dihydrodiol and BaP-9-ol, which are intermediates in BaP-derived DNA adduct formation, were mainly formed by CYP1A1 and 1B1, and to a lesser extent by CYP2C19 and 3A4. BaP-3-ol, a metabolite that is a 'detoxified' product of BaP, was formed by most human CYPs tested, although CYP1A1 and 1B1 produced it the most efficiently. Based on the amounts of the individual BaP metabolites formed by these CYPs and their expression levels in human liver, we determined their contributions to BaP metabolite formation in this organ. Our results indicate that hepatic CYP1A1 and CYP2C19 are most important in the activation of BaP to BaP-7,8-dihydrodiol, whereas CYP2C19, 3A4, and 1A1 are the major enzymes contributing to the formation of BaP-9-ol. BaP-3-ol is predominantly formed by hepatic CYP3A4, while CYP1A1 and 2C19 are less active. Environ. Mol. Mutagen. 57:229-235, 2016. (c) 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 26919089
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  • 7
  • 8
    Keywords: EXPRESSION ; radiotherapy ; DNA ; IMPACT ; GENE ; GENE-EXPRESSION ; gene expression ; genetics ; REPAIR ; DNA-REPAIR ; heredity ; DNA repair ; side effects ; USA ; TOXICOLOGY ; PREDICT ; LEVEL ; mutagen
    Type of Publication: Meeting abstract published
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  • 9
    Keywords: DNA ; GENES ; GENE ; DAMAGE ; DNA-DAMAGE ; ASSAY ; DNA-REPAIR ; REPAIR ; genetics ; POLYMORPHISMS ; polymorphism ; DNA repair ; heredity ; USA ; TOXICOLOGY ; mutagen
    Type of Publication: Meeting abstract published
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  • 10
    Keywords: IN-VITRO ; human ; IN-VIVO ; LUNG ; VITRO ; VIVO ; DNA adducts ; liver ; NEW-YORK ; GENE ; TISSUE ; MICE ; ACTIVATION ; DNA ; kidney ; 3-nitrobenzanthrone ; DIESEL EXHAUST ; HETEROCYCLIC AMINES ; INDUCTION ; RAT ; BODY-WEIGHT ; CONTAMINANT 3-NITROBENZANTHRONE ; RATS ; TISSUES ; BINDING ; SEQUENCE ; treatment ; FREQUENCY ; METABOLITES ; MOUSE ; MUTANT ; TRANSGENIC MICE ; PATTERNS ; ASSAY ; MUTATION ; BLADDER ; DNA-BINDING ; NUCLEOTIDES ; POLLUTANT 3-NITROBENZANTHRONE ; MUTATIONS ; ADDUCTS ; TESTIS ; PERFORMANCE LIQUID-CHROMATOGRAPHY ; 3-nitrobenzanthrone,Muta Mouse,mutation spectra,cll,DNA adducts,P-32-post-labeling,diesel exhaust,ai ; CII GENE ; DEOXYADENOSINE ; DNA-ADDUCTS ; LAMBDA/LACZ TRANSGENIC MICE ; micronuclei ; POTENT ; SURFACE SOIL ; V79 CELLS
    Abstract: 3-nitrobenzanthrone (3-NBA) is an extremely potent mutagen in the Salmonella reversion assay and a suspected human carcinogen identified in diesel exhaust and in ambient airborne particulate matter. To evaluate the in vivo mutagenicity of 3-NBA, we analyzed the mutant frequency (MF) in the cll gene of various organs (lung, liver, kidney, bladder, colon, spleen, and testis) in lambda/lacZ transgenic mice (Muta Mouse) after intraperitoneal treatment with 3-NBA (25 mg/kg body weight injected once a week for 4 weeks). Increases in MF were found in colon, liver, and bladder, with 7.0-, 4.8-, and 4.1-fold increases above the control value, respectively, whereas no increase in MF was found in lung, kidney, spleen, and testis. Simultaneously, induction of micronuclei in peripheral blood reticulocytes was observed. The sequence alterations in the cll gene recovered from 41 liver mutants from 3-NBA-treated mice were compared with 32 spontaneous mutants from untreated mice. Base substitution mutations predominated for both the 3-NBA-treated (80%) and the untreated (81%) groups. However, the proportion of G:C--〉T:A transversions in the mutants from 3-NBA-treated mice was higher (49% vs. 6%) and the proportion of G:C--〉A:T transitions was lower than those from untreated mice (10% vs. 66%). The increase in MF in the liver was associated with strong DNA binding by 3-NBA, whereas in lung, in which there was no increase in MF, a low level of DNA binding was observed (268.0-282.7 vs. 8.8-15.9 adducts per 10(8) nucleotides). DNA adduct patterns with multiple adduct spots, qualitatively similar to those formed in vitro after activation of 3-NBA with nitroreductases and in vivo in rats, were observed in all tissues examined. Using high-pressure liquid cochromatographic analysis, we confirmed that all major 3-NBA-DNA adducts produced in vivo in mice are derived from reductive metabolites bound to purine bases (70-80% with deoxyguanosine and 20-30% with deoxyadenosine in liver). These results suggest that G:C--〉T:A transversions induced by 3-NBA are caused by misreplication of adducted guanine residues through incorporation of adenine opposite the adduct (A-rule)
    Type of Publication: Journal article published
    PubMed ID: 15065206
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