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Mutagenic
Terms modified by Mutagenic Selected AbstractsMutagenic and antimutagenic potential of the medicinal plants M. laevigata and C. xanthocarpaPHYTOTHERAPY RESEARCH, Issue 3 2003J. B. F. Fernandes Abstract Aqueous extracts of medicinal plants (Mikania laevigata and Campomanesia xanthocarpa) were screened for the presence of mutagenic activity in the Salmonella/microsome assay. The extracts of Campomanesia xanthocarpa showed frameshift (TA97a strain) signs of mutagenic activity without exogenous metabolism (S9 fraction). The infusions of Mikania laevigata, negative for mutagenic activity, showed high percentages of inhibition of mutagenesis induced by mutagens 2AF (2-amino,uorene), in the presence of exogenous metabolism (S9 fraction), for frameshift (TA98) and base pair substitution (TA100) lesions. In addition, these inhibitions were observed against mutagen SAZ (sodium azide) in assays with the TA100 strain, without exogenous metabolism (S9 fraction). A synergistic effect was also observed in frameshift mutagenic events, with direct action in the presence of 4NQO (4-oxide-1-nitroquinoline) and a tendency to a low percentage of action enhancement, in the presence of the 2AF mutagen. The variable responses observed in the extract assays show the potentials for interaction of the different active principles in genetic material. Copyright © 2003 John Wiley & Sons, Ltd. [source] Hydrophobic derivatives of 5-(hydroxymethyl)isophthalic acid that selectively induce apoptosis in leukemia cells but not in fibroblasts,,DRUG DEVELOPMENT RESEARCH, Issue 4 2008Anna Galkin Abstract New apoptosis modulating agents are widely sought, because failure in regulation of apoptosis is associated with many diseases. In this study, we have evaluated apoptosis inducing the potential of ten new hydrophobic derivatives of 5-(hydroxymethyl)isophthalic acid. Cancerous leukemia cells (HL-60) and non-malignant fibroblasts (Swiss 3T3) were incubated with test compounds for 24,h and morphologically evaluated. The changes in mitochondrial membrane potential (,,m) and caspase-3 activity were used to confirm the results and to study early induction of apoptosis. Cytotoxicity was determined using the lactate dehydrogenase (LDH) assay and mutagenicity with miniaturized Ames-test. The most potent selective apoptosis inducers were compounds 1c and 1,h having IC50 values of 41 and 23,µM, respectively, in leukemia cells (HL-60) while effects in fibroblasts (Swiss 3T3) were insignificant. Reduction of ,,m and increase in caspase-3 activity were observed already during the first 2,hr in the HL-60 cells treated with compounds 1,c and 1,h. Neither of the compounds was cytotoxic or mutagenic. The results indicate that compounds 1,c and 1,h are selective apoptosis inducers and should be studied further for possible use in cancer therapy. Drug Dev. Res. 69: 185,195, 2008. © 2008 Wiley-Liss, Inc. [source] Simultaneous Determination of Quinoline and Pyridine Compounds in Gasoline and Diesel by Differential Pulse VoltammetryELECTROANALYSIS, Issue 6 2007Leonardo Abstract The presence of trace basic organonitrogen compounds such as quinoline and pyridine in derivative petroleum fuels plays an important role in maintaining the engines of vehicles. However, these substances can contaminate the environment and so must be controlled because most of them are potentially carcinogenic and mutagenic. For these reasons, a reliable and sensitive method was developed for the determination of basic nitrogen compounds in fuel samples such as gasoline and diesel. This method utilizes preconcentration on an ion,exchange resin (Amberlyte IR,120,H) followed by differential pulse voltammetry (DPV) on a glassy carbon electrode. The electrochemical behavior of quinoline and pyridine as studied by cyclic voltammetry (CV) suggests that their reduction occurs via a reversible electron transfer followed by an irreversible chemical reaction. Very well resolved diffusion-controlled voltammetric peaks were obtained in dimethylformamide (DMF) with tetrabutylammonium tetrafluoroborate (TBAF4 0.1,mol L,1) for quinoline (,1.95,V) and pyridine (,2.52,V) vs. Ag|AgCl|KClsat reference electrode. The proposed DPV method displayed a good linear response from 0.10 to 300,mg L,1 and a limit of detection (LOD) of 5.05 and 0.25,,g L,1 for quinoline and pyridine, respectively. Using the method of standard additions, the simultaneous determination of quinoline and pyridine in gasoline samples yielded 25.0±0.3 and 33.0±0.7,mg L,1 and in diesel samples yielded 80.3±0.2 and 131±0.4,mg L,1, respectively. Spike recoveries were 94.4±0.3% and 101±0.5% for quinoline and pyridine, respectively, in the fuel determinations. This proposed method was also compared with UV-vis spectrophotometric measurements. Results obtained for the two methods agreed well based on F and t student's tests. [source] Comparative mutagenic effects of structurally similar flavonoids quercetin and taxifolin on tester strains Salmonella typhimurium TA102 and Escherichia coli WP-2 uvrAENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 6 2009Patrudu S. Makena Abstract Quercetin (QT) and Taxifolin (TF) are structurally similar plant polyphenols. Both have been reported to have therapeutic potential as anti-cancer drugs and antioxidants. Mutagenic effects of QT and TF were evaluated using Salmonella typhimurium TA102 and Escherichia coli WP-2 uvrA tester strains. Either in the presence or absence of S9 mix, QT was mutagenic to TA102 and WP2 uvrA. However, the mutagenicity of QT was significantly enhanced in the presence of S9 mix. Likewise, in the presence of Iron (Fe2+) and NADPH generating system (NGS) and absence of S9 mix, QT induced significantly high mutations in both TA102 and WP-2 uvrA. Mutagenicity of QT decreased in both strains in the presence of Iron (Fe2+) or NGS alone. TF was not mutagenic in the presence or absence of S9 mix in both TA102 and WP-2 uvrA 2, regardless of the presence of iron or NGS. Incorporation of antioxidants (ascorbate, superoxide dismutase (SOD), catalase (CAT)) and/or iron chelators (desferroxamine (DF) and ethylenediamine-tetraacetate (EDTA)) in the test systems markedly decreased QT-induced mutations in both tester strains. These results suggest that QT but not TF, could induce mutations in the presence or absence of rat liver S9 or Iron (Fe2+) and NGS in both tester strains by redox cycling and Fenton reactions to produce oxygen free radicals. Our results indicate that a minor structural variation between the two plant polyphenols could elicit a marked difference in their genotoxicities. These results provide a basis for further study into the potential use of QT in combination with iron supplements. Environ. Mol. Mutagen. 2009. © 2009 Wiley-Liss, Inc. [source] Evidence that 4-aminobiphenyl, benzidine, and benzidine congeners produce genotoxicity through reactive oxygen speciesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 5 2007Patrudu S. Makena Abstract 4-Aminobyphenyl (4-Ab), benzidine (Bz), and Bz congeners were evaluated for their ability to induce genotoxicity through an oxidative mechanism. The mutagenicity of these compounds was tested in the presence and absence of Aroclor 1254-induced rat S9 mix using Salmonella typhimurium tester strain TA102, which is sensitive to agents producing reactive oxygen species (ROS). In the presence of S9, 4-Ab, Bz, N -acetyl-benzidine, and 3,3,-dimethoxybenzidine were strongly mutagenic in TA102, whereas, 3,3,,5,5,-tetra-methylbenzidine, 3,3,-dimethylbenzidine (O -tolidine), and N,N,-diacetylbenzidine were not mutagenic. In addition, 3,3,-dichlorobenzidine and 4,4,-dinitro-2-biphenylamine were directly mutagenic in TA102. Incorporation of the free radical and metal scavengers, catalase, superoxide dismutase (SOD), butylated hydroxytolune (BHT), and ethylenediamine tetraacetic acid (EDTA) reduced the mutagenic responses of 4-Ab and Bz, whereas heat-inactivated catalase and SOD had no effect. 4-Ab and Bz also induced lipid peroxidation in the presence of S9 mix as shown using the thiobarbituric acid reactive substances assay. The results of this study indicate that 4-Ab and Bz induce mutations through the induction of ROS. Environ. Mol. Mutagen., 2007. © 2007 Wiley-Liss, Inc. [source] Genotoxicity of nitrosulfonic acids, nitrobenzoic acids, and nitrobenzylalcohols, pollutants commonly found in ground water near ammunition facilitiesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2006Tamara Grummt Abstract 2-Amino-4,6-dinitrobenzoic acid (2-A-4,6-DNBA), 4-amino-2,6-dinitrobenzoic acid (4-A-2,6-DNBA), 2,4,6-trinitrobenzoic acid (2,4,6-TNBA), 2-amino-4, 6-dinitrobenzylalcohol (2-A-4,6-DNBAlc), 4-amino-2,6-dinitrobenzylalcohol (4-A-2,6-DNBAlc), 2,4-dinitrotoluol-5-sulfonic acid (2,4-DNT-5-SA), 2,4-dinitrotoluol-3-sulfonic acid (2,4-DNT-3-SA), and 2, 4-dinitrobenzoic acid (2,4-DNBA) are derivatives of nitro-explosives that have been detected in groundwater close to munitions facilities. In the present study, the genotoxicity of these compounds was evaluated in Salmonella/microsome assays (in strains TA100 and TA98, with and without S9 and in TA98NR without S9), in chromosomal aberration (CA) tests with Chinese hamster fibroblasts (V79), and in micronucleus (MN) assays with human hepatoma (HepG2) cells. All compounds except the sulfonic acids were positive in the bacterial mutagenicity tests, with 2,4,6-TNBA producing the strongest response (8023 revertants/,mol in TA98 without S9 activation). 2-A-4,6-DNBA was a direct acting mutagen in TA98, but negative in TA100. The other positive compounds were ,1,3 orders of magnitude less mutagenic than 2,4,6-TNBA in TA98 and in TA100; relatively strong effects (,50,400 revertants/,mol) were produced by the benzylacohols in the two indicator strains. With the exception of 2,4-DNBA, the mutagenic responses were lower in the nitroreductase-deficient strain TA98NR than in the parental strain. 2,4-DNBA produced a marginally positive response in the V79-cell CA assay; the other substances were devoid of activity. Only the benzoic acids were tested for MN induction in HepG2 cells, and all produced positive responses. As in the bacterial assays, the strongest effect was seen with 2,4,6-TNBA (significant induction at ,1.9 ,M). 4-A-2,6-DNBA was positive at 432 ,M; the weakest effect was observed with 2,4,-DNBA (positive at ,920 ,M). The differences in the sensitivity of the indicator cells to these agents can be explained by differences in the activities of enzymes involved in the activation of the compounds. The strong responses produced by some of the compounds in the human-derived cells suggest that environmental exposure to these breakdown products of nitro-explosives may pose a cancer risk in man. Environ. Mol. Mutagen., 2006. © 2005 Wiley-Liss, Inc. [source] Light-dependent mutagenesis by benzo[a]pyrene is mediated via oxidative DNA damageENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3 2005Su-Ryang Kim Abstract Benzo[a]pyrene (B[a]P) is an environmental carcinogenic polycyclic aromatic hydrocarbon (PAH). Mammalian enzymes such as cytochrome P-450s and epoxide hydrase convert B[a]P to reactive metabolites that can covalently bind to DNA. However, some carcinogenic compounds that normally require metabolic activation can also be directly photoactivated to mutagens. To examine whether B[a]P is directly mutagenic in the presence of light, we exposed Salmonella typhimurium strains with different DNA repair capacities to B[a]P and white fluorescent light at wavelengths of 370,750 nm. B[a]P plus light significantly enhanced the number of His+ revertants. Mutagenesis was completely light-dependent and required no exogenous metabolic activation. The order of mutability of strains with different DNA repair capacities was strain YG3001 (uvrB, mutMST) , strain TA1535 (uvrB) > strain YG3002 (mutMST) > strain TA1975. The uvrB gene product is involved in the excision repair of bulky DNA adducts, and the mutMST gene encodes 8-oxoguanine (8-oxoG) DNA glycosylase, which removes 8-oxoG from DNA. Introduction of a plasmid carrying the mOgg1 gene that is the mouse counterpart of mutMST substantially reduced the light-mediated mutagenicity of B[a]P in strain YG3001. B[a]P plus light induced predominantly G:C , T:A and G:C , C:G transversions. We propose that B[a]P can directly induce bulky DNA adducts if light is present, and that the DNA adducts induce oxidative DNA damage, such as 8-oxoG, when exposed to light. These findings have implications for the photocarcinogenicity of PAHs. Environ. Mol. Mutagen., 2005. © 2005 Wiley-Liss, Inc. [source] Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2004Julie E. Goodman Abstract Nitric oxide (NO·), which is generated under chronic inflammatory conditions that predispose individuals to cancer, has paradoxical effects. NO· can activate p53, which can result in anti-carcinogenic effects, or it can be mutagenic and increase cancer risk. We explored the mechanisms by which NO· induced p53 activation in vitro and found that NO· induced p53 accumulation and phosphorylation, particularly at ser-15, via ATM and ATR kinases, which then led to cell cycle arrest at G2/M. We next examined proteins in these pathways in both inflamed and normal human colon tissue. Inducible nitric oxide synthase (iNOS) levels and p53-P-ser15 levels were positively correlated with the degree of inflammation and with each other. Additionally, the p53 targets, HDM-2 and p21 (WAF1), were present in ulcerative colitis (UC) colon, but undetectable in normal colon, consistent with activated p53. We also found higher p53 mutant frequencies of both G:C , A:T transitions at the CpG site of codon 248 and C:G , T:A transitions at codon 247 in lesional colon tissue from UC cases versus nonlesional tissue from these cases or colon tissue from normal adult controls. Consistent with nitrosative stress and the deamination of 5-methylcytosine, p53 mutations were also detected in sporadic colon cancer tissue and were associated with iNOS activity in these tissues. These studies identified a potential mechanistic link between NO· and p53 in UC and sporadic colon cancer. Environ. Mol. Mutagen. 44:3,9, 2004. Published 2004 Wiley-Liss, Inc. [source] Photomutagenicity of thiabendazole, a postharvest fungicide, in bacterial assaysENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2003Mie Watanabe-Akanuma Abstract We investigated the photomutagenicity of thiabendazole (TBZ), a postharvest fungicide commonly used on imported citrus fruits. Using UVA light (320,400 nm), we irradiated bacterial cultures with or without TBZ in a 24-well multiplate. UVA-irradiation without TBZ was not mutagenic to the tester strains, nor was unirradiated TBZ. TBZ was strongly photomutagenic in Escherichia coli WP2uvrA and WP2uvrA/pKM101 strains, weakly photomutagenic in Salmonella typhimurium TA100 and TA98, and not photomutagenic in S. typhimurium TA1535 and TA1538. The photomutagenicity of TBZ was more evident in WP2uvrA/pKM101, which carries the trpE65 ochre mutation (TAA), than in TA100, which carries the hisG46 missense mutation (CCC). In E. coli WP3101,WP3106 and the corresponding pKM101-containing strains, photoactivated TBZ induced predominantly G:C,A:T transitions and A:T,T:A transversions. In the plasmid-containing strains only, TBZ induced a moderate number of A:T,G:C transitions and a few A:T,C:G and G:C,T:A transversions. The observation that UVA-irradiated TBZ mutated both G:C and A:T basepairs may explain why WP2uvrA/pKM101 was more sensitive to its mutagenicity than TA100. TBZ that was irradiated before it was added to the WP2uvrA/pKM101 cells was not photomutagenic, which suggests that the photomutagenic products of TBZ were unstable or rapidly reacted with other molecules before being incorporated into cells. Environ. Mol. Mutagen. 41:92,98, 2003. © 2003 Wiley-Liss, Inc. [source] Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity testsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2002M. Vijayaraj Reddy Abstract 3-Methylindole (3MI), melatonin (Mel), serotonin (Ser), and tryptamine (Tryp) were evaluated in vitro for their potential to induce DNA adducts, DNA strand breaks, chromosomal aberrations (Abs), inhibition of DNA synthesis, and mutations. All compounds produced DNA adducts in calf thymus DNA in the presence of rat liver S9. In cultured rat hepatocytes, all produced DNA adducts but none induced DNA strand breaks. In Chinese hamster ovary cells, 3MI and Mel produced DNA adducts, Abs, and inhibition of DNA synthesis with and without S9, except that Mel without S9 did not form adducts. Ser formed DNA adducts, was an equivocal Abs inducer, and suppressed DNA synthesis. Tryp induced neither adducts nor Abs, but did suppress DNA synthesis with S9. Ser and Tryp were less cytotoxic than 3MI and Mel. Mel, Ser, and Tryp failed to induce mutations in Salmonella and E. coli strains with or without S9. 3MI and Mel produced DNA adducts but not mutations in Salmonella TA100 with S9. 3MI and its metabolite indole 3-carbinol also did not induce mutations in a shuttle vector system in human cells. The lack of correlation between DNA adducts and other genotoxicity endpoints for these indole compounds may be due to the higher sensitivity of the 32P-postlabeling adduct assay or it may indicate that the indole-DNA adducts per se are not mutagenic and are not able to induce strand breaks or alkali-labile lesions. The indole-induced Abs may result from cytotoxicity and suppression of DNA synthesis with minimal if any contribution from DNA adducts. Environ. Mol. Mutagen. 40:1,17, 2002. © 2002 Wiley-Liss, Inc. [source] Human exposure to heterocyclic amine food mutagens/carcinogens: Relevance to breast cancer ,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2-3 2002James S. Felton Abstract Heterocyclic amines produced from overcooked foods are extremely mutagenic in numerous in vitro and in vivo test systems. One of these mutagens, 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP), induces breast tumors in rats and has been implicated in dietary epidemiology studies as raising the risk of breast cancer in humans. Efforts in our laboratory and others have centered on defining the exposure to PhIP and other dietary mutagens derived from cooked food. We accomplish this by analyzing the foods with a series of solid-phase extractions and HPLC. We have developed an LC/MS/MS method to analyze the four major human PhIP metabolites (sulfates and glucuronides) following a single meal containing 27 ,g of cooking-produced PhIP in 200 g of grilled meat. Although the intake of PhIP was similar for each of eight women, the total amount excreted in the urine and the metabolite profiles differed among the subjects. It appears that adsorption (digestion) from the meat matrix, other foods in the diet, and genetic differences in metabolism may contribute to the variation. The four major metabolites that can be routinely assayed in the urine are N2 -OH-PhIP- N2 -glucuronide, PhIP- N2 -glucuronide, 4,-PhIP-glucuronide, and N2 -OH-PhIP- N3-glucuronide. This work is suited to investigate individual exposure and risk, especially for breast cancer, from these potent dietary mutagens. Environ. Mol. Mutagen. 39:112,118, 2002. Published 2002 Wiley-Liss, Inc. [source] Oxidative mutagenicity of polar fractions from polycyclic aromatic hydrocarbon,contaminated soilsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2008Joanna Park Abstract Soils at hazardous waste sites contain complex mixtures of chemicals and often are difficult to characterize in terms of risk to human and ecological health. Over time, biogeochemical processes can decrease the apparent concentrations of pollutants but also can lead to accumulation of new products for which toxicity and behavior in the environment are largely unknown. A bioassay-directed fractionation technique was used to assess the contribution of redox-active bacterial metabolites to the toxicity of soil contaminated with polycyclic aromatic hydrocarbons (PAHs). A reverse mutation assay with Escherichia coli WP2 uvrA/pKM101 (IC188) and E. coli WP2 uvrA oxyR/pKM101 (IC203) was used to screen fractions for genotoxicity. Strain IC203 carries the ,oxyR30 mutation, which prevents the expression of antioxidant proteins in response to oxidative stress and increases its reversion by compounds that generate reactive oxygen species (ROS). Polar fractions of PAH-contaminated soil extracts were mutagenic to strain IC203 but not to strain IC188, suggesting the involvement of ROS in genotoxicity. Genotoxic potencies ranged from 300 to 1,700 revertants per milligram of fraction. Catalase was able to decrease IC203 reversion, implicating the involvement of hydrogen peroxide as a key ROS. Oxidized PAH compounds, including quinones, were identified in the mutagenic fractions but were not by themselves mutagenic. Deasphalted whole extracts and recombined fractions were not mutagenic, indicating that interactions between compounds in different fractions can mitigate genotoxicity. [source] Mutagenicity of nitroaromatic degradation compoundsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2003Ranjit S. Padda Abstract The mutagenicity of 2,4-dinitrotoluene (24DNT), and 2,6-dinitrotoluene (26DNT), and their related transformation products such as hydroxylamine and amine derivatives, which are formed by Clostridium acetobutylicum, were tested in crude cell extracts using Salmonella typhimurium TA100. A previous publication already reported the mutagenic activities of 2,4,6-trinitrotoluene (TNT) and its related hydroxylamine derivatives in this test system. A time course of the mutagenicity during the anaerobic transformation of TNT, 24DNT, and 26DNT was also investigated under the same conditions to compare with the results from the pure compounds. The monohydroxylamino intermediates 2-hydroxylamino-4-nitrotoluene (2HA4NT), 4-hydroxylamino-2-nitrotoluene (4HA2NT) and 2-hydroxylamino-6-nitrotoluene (2HA6NT) formed during anaerobic transformation of dinitrotoluenes were proven to be mutagenic in the Ames test using Salmonella typhimurium TA100. This study reports that 4HA2NT is the most stable derivative, whereas 2HA4NT and 2HA6NT are less stable and these intermediates are mutagenic in the Ames test. Both 24DNT and 26DNT and their final metabolites 2,4-diaminotoluene (24DAT) and 2,6-aminotoluene (26DAT) appeared nonmutagenic. In a time-course study of TNT degradation, the temporal sample containing 85% of 2,4-dihydroxylamino-6-nitrotoluene (24HA6NT) is most mutagenic. These observations suggest that the bioremediation approach for treatment of 24DNT and 26DNT should be carried past the hydroxylamino intermediate. [source] Degradation and formation of polycyclic aromatic compounds during bioslurry treatment of an aged gasworks soilENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2003Staffan Lundstedt Abstract The goals of this study were to investigate the relative degradation rates of polycyclic aromatic compounds (PACs) in contaminated soil, and to assess whether persistent oxidation products are formed during their degradation. Samples were taken on five occasions during a pilot-scale bioslurry treatment of soil from a former gasworks site. More than 100 PACs were identified in the soil, including unsubstituted polycyclic aromatic hydrocarbons (PAHs), alkylated PAHs (alkyl-PAHs), heterocyclic PACs, and oxygenated PAHs (oxy-PAHs), such as ketones, quinones, and coumarins. During the treatment, the low molecular weight PAHs and heterocyclics were degraded faster than the high molecular weight compounds. The unsubstituted PAHs also appear to have degraded more quickly than the corresponding alkyl-PAHs and nitrogen-containing heterocyclics. No new oxidation products that were not present in the untreated soil were identified after the soil treatment. However, oxy-PAHs that were present in the untreated soil were generally degraded more slowly than the parent compounds, suggesting that they were formed during the treatment or that they are more persistent. Two oxidation products, 1-acenaphthenone and 4-oxapyrene-5-one, were found at significantly higher concentrations at the end of the study. Because oxy-PAHs can be acutely toxic, mutagenic, or carcinogenic, we suggest that this group of compounds should also be monitored during the treatment of PAH-contaminated soil. [source] Mutagenicity and disinfection by-products in surface drinking water disinfected with peracetic acidENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2002Silvano Monarca Abstract The aims of this research were to study the influence of peracetic acid (PAA) on the formation of mutagens in surface waters used for human consumption and to assess its potential application for the disinfection of drinking water. The results obtained using PAA were compared to those found with sodium hypochlorite (NaClO) and chlorine dioxide (ClO2). The Ames test, root anaphase aberration assay, and root/micronuclei assay in Allium cepa and Tradescantia/micronuclei test were used to evaluate the mutagenicity of disinfected samples. Microbiological tests were also performed, and disinfection by-products (DBPs) were identified using gas chromatography/mass spectrometry (GC/MS). A slight bacterial mutagenicity was found in raw lake and river water, and similar activity was detected in disinfected samples. A plant test revealed genotoxicity in raw river water, and microbiological analysis showed that PAA has bactericidal activity but lower than that of the other disinfectants. The DBPs produced by PAA were mainly carboxylic acids, which are not recognized as mutagenic, whereas the waters treated with the other disinfectants showed the presence of mutagenic/carcinogenic halogenated DBPs. However, additional experiments should be performed with higher concentrations of PAA and using water with higher organic carbon content to better evaluate this disinfectant. [source] Monitoring river sediments contaminated predominantly with polyaromatic hydrocarbons by chemical and in vitro bioassay techniquesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2001Jan Vondrá Abstract Extracts of sediment samples collected from the Morava River and its tributaries (Czech Republic) were examined for mutagenic, dioxin-like, and estrogenic activities. Moreover, the human leukemic HL-60 cell line was tested as a potential model for the detection of effects of environmental contaminants on cell proliferation and differentiation processes. Analytical data indicate that the sediments were contaminated predominantly with polycyclic aromatic hydrocarbons (PAHs) and phthalate esters. The sums of concentrations of 16 U.S. Environmental Protection Agency priority PAHs ranged from 0.8 to 13.2 ,g/g and those of phthalates reached up to 3,000 ng/g, while only low levels of chlorinated hydrocarbons were found. The main goal of the present study was to determine effects of PAH prevalence on in vitro bioassays, with special emphasis on dioxin-like activity. The dioxin-like activity was tested using a reporter gene assay based on chemical-activated luciferase expression (the CALUX assay). Significant dioxin-like activity (2.6,40.1 ,g/g benzo[a]pyrene equivalents and 5.9,48.2 ng/g 2,3,7,8-tetrachlorodibenzo- p -dioxin equivalents) was detected in all samples, and the results obtained with various exposure times or with both crude and PAH-deprived extracts indicate that the response was probably caused almost exclusively by the presence of high concentrations of PAHs. This corresponds with results of chemical analyses and indicates that various exposure times would allow a discrimination between dioxin-like activities of persistent compounds and easily metabolized aryl hydrocarbon (Ah) receptor inducers. Only sediment extracts containing the highest concentrations of PAHs were mutagenic, as determined by the umu assay. Estrogenic activity was found in several samples (4.75,22.61 pg/g estradiol equivalents) using cells stably transfected with an estrogen-responsive element linked to a luciferase promoter. Noncytotoxic doses of extracts had no effects on HL-60 cell proliferation, while two of the tested crude extracts significantly enhanced their all- trans retinoic acid-induced differentiation. These activities were not associated with phthalate esters and/or PAHs. Our results indicate that cellular and biochemical in vitro assays based on various specific modes of action may yield data complementary to results of mutagenicity tests and that they could be useful in environmental risk assessment. High levels of PAHs are apparently associated with dioxin-like and mutagenic activities rather than with estrogenic activity. [source] Comment on: Tattooing of skin results in transportation and light-induced decomposition of tattoo pigmentsEXPERIMENTAL DERMATOLOGY, Issue 1 2010Gregor B. E. Jemec Abstract:, Decorative tattoos have become a common feature of many societies. Their popularity appears mainly driven by fashion, and scant attention has been paid to any associated risk. The risks can be associated either with the tattooees' proclivity for risk taking in general, or with the substances used in the tattoos. It is well established that tattoo pigments wander widely in the body after they have been injected, and research now suggests that azo pigments may become mutagenic after exposure to either natural light or laser light. This may not only affect the risk profile of tattoos themselves, but also tattoo removal using lasers. [source] Specific transcriptional responses induced by 8-methoxypsoralen and UVA in yeastFEMS YEAST RESEARCH, Issue 6 2007Michčle Dardalhon Abstract Treatment of eukaryotic cells with 8-methoxypsoralen plus UVA irradiation (8-MOP/UVA) induces pyrimidine monoadducts and interstrand crosslinks and initiates a cascade of events leading to cytotoxic, mutagenic and carcinogenic responses. Transcriptional activation plays an important part in these responses. Our previous study in Saccharomyces cerevisiae showed that the repair of these lesions involves the transient formation of DNA double-strand breaks and the enhanced expression of landmark DNA damage response genes such as RAD51, RNR2 and DUN1, as well as the Mec1/Rad53 kinase signaling cascade. We have now used DNA microarrays to examine genome-wide transcriptional changes produced after induction of 8-MOP/UVA photolesions. We found that 128 genes were strongly induced and 29 genes strongly repressed. Modifications in gene expression concern numerous biological processes. Compared to other genotoxic treatments, c. 42% of the response genes were specific to 8-MOP/UVA treatment. In addition to common DNA damage response genes and genes induced by environmental stresses, a large fraction of 8-MOP/UVA response genes correspond to membrane-related functions. [source] Genetic polymorphisms in alcohol metabolism, alcohol intake and the risk of stomach cancer in Warsaw, PolandINTERNATIONAL JOURNAL OF CANCER, Issue 9 2007Fang Fang Zhang Abstract Genetic variations increasing blood levels of acetaldehyde, the first metabolite of alcohol, refrain their carriers from drinking alcohol but may also put them at increased risk of cancer because of the mutagenic and carcinogenic effect of acetaldehyde. In a population-based study of 305 cases and 428 controls in Warsaw, Poland, we evaluated the effect of polymorphisms in alcohol metabolizing genes, including ADH1B (Ex9+5C>T, Ex3+23A>G, Ex3+58A>T and Ex9+77A>G), ADH1C (Ex8-56A>G and Ex6-14G>A) and ALDH2 (Ex1+82A>G), on levels of alcohol drinking and susceptibility of stomach cancer. We found that among control subjects frequency of alcohol drinking varied by alcohol metabolizing genotype. In particular, the weekly consumption of individuals carrying the AA, GA and GG genotypes of ALDH2 Ex1+82A >G polymorphism were 3.75, 2.26 and 1.53 drinks, respectively (p= 0.04). However, none of the assessed polymorphisms in these 3 genes had a measurable effect on stomach cancer risk. When stratified by ALDH2 Ex1+82A>G polymorphism, alcohol-related increases in stomach cancer risk were restricted to individuals with the AG/GG genotypes, with a more than 2-fold risk among daily drinkers (OR = 2.63, 95% CI = 1.00,6.88) and 3-fold risk (OR = 3.66, 95% CI = 1.19,11.24) among those with 40 or more drink-years. In summary, our results suggested that the ALDH2 Ex1+82 G allele may be functionally deficient in eliminating acetaldehyde and discourage alcohol drinking. Furthermore, heavy drinkers of alcohol who were genetically prone to accumulate acetaldehyde may face an increased risk of stomach cancer. © 2007 Wiley-Liss, Inc. [source] Genotoxicity of pyrrolizidine alkaloids,,JOURNAL OF APPLIED TOXICOLOGY, Issue 3 2010Tao Chen Abstract Pyrrolizidine alkaloids (PAs) are common constituents of many plant species around the world. PA-containing plants are probably the most common poisonous plants affecting livestock and wildlife. They can inflict harm to humans through contaminated food sources, herbal medicines and dietary supplements. Half of the identified PAs are genotoxic and many of them are tumorigenic. The mutagenicity of PAs has been extensively studied in different biological systems. Upon metabolic activation, PAs produce DNA adducts, DNA cross-linking, DNA breaks, sister chromatid exchange, micronuclei, chromosomal aberrations, gene mutations and chromosome mutations in vivo and in vitro. PAs induced mutations in the cII gene of rat liver and in the p53 and K- ras genes of mouse liver tumors. It has been suggested that all PAs produce a set of (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H -pyrrolizine-derived DNA adducts and similar types of gene mutations. The signature types of mutations are G,:,C , T,:,A transversion and tandem base substitutions. Overall, PAs are mutagenic in vivo and in vitro and their mutagenicity appears to be responsible for the carcinogenesis of PAs. Published in 2010 by John Wiley & Sons, Ltd. [source] Concordant loss of heterozygosity of DNA repair gene, hOGG1, in melanoma in situ and atypical melanocytic hyperplasiaJOURNAL OF CUTANEOUS PATHOLOGY, Issue 6 2008Shayesteh Pashaei Background:, One major risk factor for cutaneous melanoma is chronic sun-exposure and oxidative stress. Among various oxidative DNA damages, 8-oxoquanine is the most abundant and is potentially mutagenic if not sufficiently repaired. The human 8-oxoquanine DNA glycosylase 1 (hOGG1) gene specifically repairs 8-oxoguanine, and this gene shows frequent loss of heterozygosity (LOH) in human tumors. In this study, we investigate whether hOGG1 LOH occurs in melanoma in situ (MIS) and adjacent atypical melanocytic hyperplasia (AMH). Methods:, Twelve skin biopsies with MIS and adjacent AMH were included. DNA samples derived from manual microdissection of tissues were subjected to polymerase chain reaction amplification using three fluorescent-labeled microsatellite makers, followed by fragment analysis. Results:, Five of 12 cases were informative for both telomeric (3S1297) and centromeric (3S1289 or 3S1300) markers, bordering the hOGG1 locus. Among them, four (80%) MIS and three (60%) AMH showed hOGG1 LOH at both markers. Conclusions:, These results shows that LOH at hOGG1 gene is associated with MIS and AMH and suggest that the hOGG1 gene may play a role in melanocytic tumor progression. [source] Polycyclic aromatic hydrocarbons in smoked cheeseJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 8 2008Marie Suchanová Abstract BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) represent a group of organic compounds containing two or more aromatic rings. Their control in the human food chain is required due to the mutagenic and carcinogenic potential, exhibited in vertebrates. In the present study, the occurrence of PAHs in 36 cheeses smoked by various processes was investigated. RESULTS: PAH concentrations (sum of 15 US EPA PAHs) found in samples smoked under controlled industrial conditions were at level 0.11 µg kg,1, whereas in ,home-made' cheeses, the PAH content was up to 10 times higher. A similar trend was observed for B[a]P, a marker compound representing carcinogenic PAHs. While its levels in commercial products prepared by controlled smoking technologies were close to the limit of quantification (0.03 µg kg,1); in household samples, the B[a]P content ranged from 0.6 to 0.9 µg kg,1. Significantly higher amounts of PAHs (up to three to six times) were found in surface layers as compared to internal parts of cheese. CONCLUSION: Although smoked cheese is a popular food, only several papers have focused on PAH levels in these products. This paper evaluates the contribution of different smoking technologies to PAH contamination of several cheeses and thus can help in a risk assessment associated with their consumption. Moreover, the study shows the concentration ratios of selected PAHs, from which the type of smoking technology can be indicated. The results obtained in this study also supported the suggestion of the EU Scientific Committee on Food to use benzo[a]pyrene as an indicator of the occurrence of higher-molecular mass PAHs. Copyright © 2008 Society of Chemical Industry [source] Evaluation of mutagenic and antimutagenic properties of some bioactive xanthone derivatives using Vibrio harveyi testLETTERS IN APPLIED MICROBIOLOGY, Issue 3 2010Abstract Aims:, Drug safety evaluation plays an important role in the early phase of drug development, especially in the preclinical identification of compounds' biological activity. The Vibrio harveyi assay was used to assess mutagenic and antimutagenic activity of some aminoalkanolic derivatives of xanthone (1,5), which were synthesized and evaluated for their anticonvulsant and hemodynamic activities. Methods and Results:, A novel V. harveyi assay was used to assess mutagenic and antimutagenic activity of derivatives of xanthone 1,5. Two V. harveyi strains were used: BB7 (natural isolate) and BB7M (BB7 derivative containing mucA and mucB genes on a plasmid pAB91273, products of these genes enhance error-prone DNA repair). According to the results obtained, the most beneficial mutagenic and antimutagenic profiles were observed for compounds 2 and 3. A modification of the chemical structure of compound 2 by the replacement of the hydroxy group by a chloride improved considerably the antimutagenic activity of the compound. Thus, antimutagenic potency reached a maximum with the presence of tertiary amine and chloride atom in the side chain. Conclusions:, Among the newly synthesized aminoalkanolic derivatives of xanthone with potential anticonvulsant properties, there are some compounds exhibiting in vitro antimutagenic activity. In addition, it appears that the V. harveyi assay can be applied for primary mutagenicity and antimutagenicity assessment of compounds. Significance and Impact of the Study:, The obtained preliminary mutagenicity and antimutagenicity results encourage further search in the group of amino derivatives of xanthone as the potential antiepileptic drugs also presenting some antimutagenic potential. Furthermore, V. harveyi test may be a useful tool for compounds safety evaluation. [source] Lead promotes abasic site accumulation and co-mutagenesis in mammalian cells by inhibiting the major abasic endonuclease Ape1,MOLECULAR CARCINOGENESIS, Issue 2 2007Daniel R. McNeill Abstract Lead is a widespread environmental toxin, found in contaminated water sources, household paints, and certain occupational settings. Classified as a probable carcinogen by the International Agency for Research on Cancer (IARC), lead promotes mutagenesis when combined with alkylating and oxidizing DNA-damaging agents. We previously reported that lead inhibits the in vitro repair activity of Ape1, the major endonuclease for repairing mutagenic and cytotoxic abasic sites in DNA. We investigated here whether lead targets Ape1 in cultured mammalian cells. We report a concentration-dependent inhibition of apurinic/apyrimidinic (AP) site incision activity of Chinese hamster ovary (CHO) AA8 whole cell extracts by lead. In addition, lead exposure results in a concentration-dependent accumulation of AP sites in the genomic DNA of AA8 cells. An increase in the oxidative base lesion 8-oxoguanine was observed only at high lead levels (500 µM), suggesting that non-specific oxidation plays little role in the production of lead-related AP lesions at physiological metal concentrations,a conclusion corroborated by "thiobarbituric acid reactive substances" assays. Notably, Ape1 overexpression in AA8 (hApe1-3 cell line) abrogated the lead-dependent increase in AP site steady-state levels. Moreover, lead functioned cooperatively to promote a further increase in abasic sites with agents known to generate AP sites in DNA (i.e., methyl methansulfonate (MMS) and hydrogen peroxide (H2O2)), but not the DNA crosslinking agent mitomycin C. Hypoxanthine guanine phosphoribosyltransferase (hprt) mutation analysis revealed that, whereas lead alone had no effect on mutation frequencies, mutagenesis increased in MMS treated, and to a greater extent lead/MMS treated, AA8 cells. With the hApe1-3 cell line, the number of mutant colonies in all treatment groups was found to be equal to that of the background level, indicating that Ape1 overexpression reverses MMS- and lead-associated hprt mutagenesis. Our studies in total indicate that Ape1 is a member of an emerging group of DNA surveillance proteins that are inhibited by environmental heavy metals, and suggest an underlying mechanism by which lead promotes co-carcinogenesis. Published 2006 Wiley-Liss, Inc., [source] Loss of heterozygosity of DNA repair gene, hOGG1, in renal cell carcinoma but not in renal papillary adenomaPATHOLOGY INTERNATIONAL, Issue 6 2008Neriman Gokden The kidney is constantly exposed to free radicals due to its active metabolism and processing of toxic metabolites. Among 20 or so free radical-induced DNA lesions, 8-oxoquanine is the most abundant and is potentially mutagenic if not sufficiently removed. The human 8-oxoquanine DNA glycosylase 1 (hOGG1) gene repairs 8-oxoguanine and resides at 3p25,26, which has frequent loss of heterozygosity (LOH) in clear cell,renal cell carcinoma (CC-RCC). Even though some studies found similar genetic alterations between renal papillary adenomas (PA) and papillary RCC (PRCC), no studies have been conducted to compare the alterations of hOGG1 gene in PA, PRCC and CC-RCC. To further explore the relationship between CC-RCC, PRCC and PA at the genetic level LOH of hOGG1 gene was investigated in these three groups. It was found that 8/8 PRCC (100%) and 8/9 CC-RCC (88%) had evidence of hOGG1 LOH, whereas all four PA (0%) were devoid of hOGG1 LOH. It is concluded that deletion of hOGG1 gene occurs commonly in PRCC and CC-RCC but not in renal cortical PA. Further studies are warranted to further explore the exact roles of hOGG1 gene in the development and progression of RCC. [source] DNA Damage, Apoptosis and Langerhans Cells,Activators of UV-induced Immune Tolerance,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2008Laura Timares Solar UVR is highly mutagenic but is only partially absorbed by the outer stratum corneum of the epidermis. UVR can penetrate into the deeper layers of the epidermis, depending on melanin content, where it induces DNA damage and apoptosis in epidermal cells, including those in the germinative basal layer. The cellular decision to initiate either cellular repair or undergo apoptosis has evolved to balance the acute need to maintain skin barrier function with the long-term risk of retaining precancerous cells. Langerhans cells (LCs) are positioned suprabasally, where they may sense UV damage directly, or indirectly through recognition of apoptotic vesicles and soluble mediators derived from surrounding keratinocytes. Apoptotic vesicles will contain UV-induced altered proteins that may be presented to the immune system as foreign. The observation that UVR induces immune tolerance to skin-associated antigens suggests that this photodamage response has evolved to preserve the skin barrier by protecting it from autoimmune attack. LC involvement in this process is not clear and controversial. We will highlight some basic concepts of photobiology and review recent advances pertaining to UV-induced DNA damage, apoptosis regulation, novel immunomodulatory mechanisms and the role of LCs in generating antigen-specific regulatory T cells. [source] Absence of mutagenic effects of a particular Symphytum officinale L. liquid extract in the bacterial reverse mutation assayPHYTOTHERAPY RESEARCH, Issue 3 2010Birgit Benedek Abstract Comfrey (Symphytum officinale L.) root is traditionally used for the topical treatment of contusions, strains and sprains. Besides allantoin and rosmarinic acid, which are discussed as pharmacologically active principles, the drug contains pyrrolizidine alkaloids (PAs) known for their hepatotoxic, carcinogenic and mutagenic properties. The topical herbal medicinal products Kytta-Salbe® f and Kytta-Plasma® f contain a PA-free liquid extract from comfrey root as active substance. The aim of this study was to demonstrate the absence of genotoxic effects of this special extract in the bacterial reverse mutation assay (Ames test). Briefly, comfrey root liquid extract was investigated for its ability to induce gene mutations in Salmonella typhimurium strains TA 98, TA 100, TA 102, TA 1535 and TA 1537 with and without metabolic activation using the mammalian microsomal fraction S9 mix. Reference mutagens were used to check the validity of the experiments. Comfrey root fluid extract showed no biologically relevant increases in revertant colony numbers of any of the five tester strains, neither in the presence nor in the absence of metabolic activation. In conclusion, the comfrey root fluid extract contained in Kytta-Salbe® f and Kytta-Plasma® f was not mutagenic in the bacterial reverse mutation assay. Copyright © 2009 John Wiley & Sons, Ltd. [source] Antigenotoxic effect of extract from Cynara cardunculus L.PHYTOTHERAPY RESEARCH, Issue 1 2008E. Miadokova Abstract The extract of artichoke Cynara cardunculus L. (CCE) was investigated for its potential antigenotoxic and antioxidant effects using four experimental model systems. In the Saccharomyces cerevisiae mutagenicity/antimutagenicity assay, CCE significantly reduced the frequency of 4-nitroquinoline- N -oxide-induced revertants at the ilv1 locus and mitotic gene convertants at the trp5 locus in the diploid Saccharomyces cerevisiae tester strain D7. In the simultaneous toxicity and clastogenicity/anticlastogenicity assay, it exerted an anticlastogenic effect against N-nitroso- N,-methylurea-induced clastogenicity in the plant species Vicia sativa L. On the contrary, despite CCE not being mutagenic itself, in the preincubation Ames assay with metabolic activation, it significantly increased the mutagenic effect of 2-aminofluorene in the bacterial strain Salmonella typhimurium TA98. In the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay, CCE exhibited considerable antioxidant activity. The SC50 value representing 0.0054% CCE corresponds to an antioxidant activity of 216.8 µm ascorbic acid which was used as a reference compound. Although the mechanism of CCE action still remains to be elucidated, different possible mechanisms are probably involved in the CCE antigenotoxic effects. It could be concluded that CCE is of particular interest as a suitable candidate for an effective chemopreventive agent. Copyright © 2007 John Wiley & Sons, Ltd. [source] Development of tRNA synthetases and connection to genetic code and diseasePROTEIN SCIENCE, Issue 10 2008Paul Schimmel Abstract The genetic code is established by the aminoacylation reactions of aminoacyl tRNA synthetases, where amino acids are matched with triplet anticodons imbedded in the cognate tRNAs. The code established in this way is so robust that it gave birth to the entire tree of life. The tRNA synthetases are organized into two classes, based on their active site architectures. The details of this organization, and other considerations, suggest how the synthetases evolved by gene duplications, and how early proteins may have been statistical in nature, that is, products of a primitive code where one of several similar amino acids was used at a specific position in a polypeptide. The emergence of polypeptides with unique, defined sequences,true chemical entities,required extraordinary specificity of the aminoacylation reaction. This high specificity was achieved by editing activities that clear errors of aminoacylation and thereby prevent mistranslation. Defects in editing activities can be lethal and lead to pathologies in mammalian cells in culture. Even a mild defect in editing is casually associated with neurological disease in the mouse. Defects in editing are also mutagenic in an aging organism and suggest how mistranslation can lead to mutations that are fixed in the genome. Thus, clearance of mischarged tRNAs by the editing activities of tRNA synthetases was essential for development of the tree of life and has a role in the etiology of diseases that is just now being understood. [source] Differential adduction of proteins vs. deoxynucleosides by methyl methanesulfonate and 1-methyl-1-nitrosourea in vitro,RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 4 2005Fagen Zhang The reactions of two model mutagenic and carcinogenic alkylating agents, N -methyl- N -nitrosourea (MNU) and methyl methanesulfonate (MMS), with proteins and deoxynucleosides in vitro, were investigated. The protein work used an approach involving trypsin digestion and high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI-MS/MS). This technique permitted identification of the specific location of protein adduction by both MNU and MMS with commercial apomyoglobin and human hemoglobin, under physiological conditions. MNU treatment resulted in predominantly carbamoylation adducts on the proteins, but in contrast only methylated protein adducts were found following treatment with MMS. Further analyses, using TurboSequest®, and the Scoring Algorithm for Spectral Analysis (SALSA), revealed that MNU carbamoylation was specific for modification of either the N-terminal valine or the free amino group in lysine residues of apomyglobin and human hemoglobin. However, MMS methylation modified the N-terminal valine and histidine residues of the proteins. Despite their clear differences in protein modifications, MNU and MMS formed qualitatively the same methylated deoxynucleoside adduct profiles with all four deoxynucleosides in vitro under physiological conditions. In light of their different biological potencies, where MMS is considered a ,super clastogen' while MNU is a ,super mutagen', these differences in reaction products with proteins vs. deoxynucleosides may indicate that these two model alkylating agents work via different mechanisms to produce their mutagenic and carcinogenic effects. Copyright © 2005 John Wiley & Sons, Ltd. [source] | ||||||||||||||||