Mutation Research/Genetic Toxicology最新文献

Peripheral blood lymphocyte 8-hydroxy-2-deoxyguanosine (8-OHdG), were detected in 87 benzene-exposed and 30 control subjects by high performance liquid chromatograph coupled with an electrochemical detector system (HPLC-EC). The air concentration of benzene and its homologes in the workplace, urinary trans, trans-muconic acid (TTMA) as an internal dose of benzene exposure, were examined. The lymphocyte micronuclei (MN) as genotoxic and white blood cell (WBC) count as well as the myelotoxic markers of benzene were examined. Exposure to low, medium and high concentrations of benzene resulted in increased levels of 8-OHdG, which were 4.67, 26.12 and 29.89/10⁵ dG, respectively, However, the 8-OHdG level observed in the control group was 3.738/10⁵ dG). A good correlation between 8-OHdG formation and the groups exposed to external and internal benzene was observed (r= 0.77, 0.64, respectively). There was also a correlation between 8-OHdG and MN formation (r = 0.50). WBC levels were within normal range in all benzene-exposed subjects. It may be concluded that: benzene induced DNA oxidative damage in occupational exposure workers. The major factors influencing blood the 8-OHdG level were sex and toluene.

For conducting an adequate human cancer risk assessment of inorganic arsenic (As) in the low-dose region, it is important to establish its mode of action. In this context, the nature of genotoxic effects induced by this agent is of considerable interest. However, the results from such investigations in human have been conflicting. In an attempt to resolve this issue, the clastogenic and aneugenic potential of As was investigated in women and children from native population exposed to high levels (around 0.2 mg/l) of natural As via drinking water in San Antonio de los Corbes in the Andean region of Salta, Northwestern Argentina. The water did not contain elevated levels of heavy metals, such as lead or cadmium, nor was the investigated population exposed to significant industrial pollution or to pesticides. An ethnically similar control group from Rosario de Lerma, Salta, where only extremely low concentration of arsenic in drinking water could be detected, was used as a control. To evaluate the genotoxic effects in peripheral blood lymphocytes, micronuclei (MN) in binucleated cells, sister-chromatid exchanges (SCEs) and the fluorescence in situ hybridization technique (FISH) in combination with chromosome specific DNA libraries were employed. The data obtained clearly indicate a highly significant increase in the frequency of MN and of trisomy in lymphocytes from exposed children and women in comparison with controls, but no notable effects were found on the frequencies of SCEs, specific translocations, or on cell cycle progression. As supported by FISH analysis, at least a proportion of MN appears to originate from whole chromosome loss. An additional finding was the unusually low background levels of MN in unexposed individuals from this ethnic group as compared to other populations, e.g., Caucasians.

tauthor is a mutation which causes a general increase in permeability of Sacharomyces cerevisiae cells in an unspecific manner. The introduction of the tauthor mutation under homozygous conditions into the D7 diploid strain enhanced the sensitivity of the test system described by Zimmermann et al. (1975). The newly constructed strain D7tauthor responded with a four to six times higher frequency compared to the D7 strain for all genetic end-points induced with chemical mutagens (ethyl methanesulfonate, methyl methanesulfonate, hydroxyurea, benzpyrene). The increased sensitivity of D7tauthor is specific only for mutagens active in yeast, since treatment of D7tauthor cells with 5-bromouracil or 5-bromouridine, known to be non-mutagenic in yeast, did not result in the induction of any of the measured genetic alterations. Five out of 14 water samples taken from the environment induced recombinogenic events in D7tauthor, whereas all 14 water samples were without effect in the D7 test system. We concluded that D7tauthor cells show a higher sensitivity in the detection of mutagenic or carcinogenic action because of their generally enhanced permeability due to the tauthor mutation.

Fanconi anemia (FA) is a rare, autosomal recessive disorder characterized by elevated frequencies of chromosome aberrations, hypersensitivity to DNA cross-linking agents and predisposition to cancer. At least 5 complementation groups (FA-A to FA-E) underlie FA and the gene defective in FA-C (FAC) has been cloned. The mouse orthologue, Fac, maps in close proximity to the f locus, on chromosome 13, which codes for the flexed-tail mouse phenotype, raising the possibility that f and Fac are synonymous. If this were the case, flexed-tail mice could be used as mouse models for FA-C to help determine the basic defect and to evaluate clinical intervention and gene therapy. To further characterize the flexed-tail mouse, the frequency of micronuclei (a measure of chromosomal aberrations) induced by mitomycin C (MMC), an alkylating and DNA cross-linking agent, was analyzed in peripheral blood and bone marrow erythrocytes. Although a higher spontaneous micronucleus frequency was seen in flexed-tail mice in comparison to wild-type mice, the sensitivity to MMC was not elevated. This result suggests that f and Fac are different genes and that the flexed-tail mouse is not a model for FA-C.

The radiotherapy treatment of human cancer is often limited by the side effects and complications induced in normal surrounding tissues. The use of therapeutic strategies that could protect normal tissues while permitting the death of malignant neoplasm would be advantageous. Some studies have suggested that the amino acid glutamine (GLN) can serve as a conditionally essential nutrient in patients in a catabolic condition. The objective of this study was to evaluate the possible radioprotection of GLN on the frequency of chromosomal aberrations, number of metaphases with chromosomal aberrations and mitotic index in bone marrow cells of Rattus norvegicus. In this in vivo test system, GLN was administered by gavage at concentrations of 300 and 600 mg/kg body weight, in acute treatments, 30 min or 24 h before exposure to 3 Gy of whole-body gamma radiation. The results obtained in these experiments showed that GLN did not alter significantly the frequency of chromosome aberrations induced by gamma radiation under the experimental conditions used in the present study.

The alkaline single-cell gel electrophoresis assay or comet assay is a sensitive and rapid method for DNA strand breaks and detection of alkali labile sites at the single cell level, it further provides information on the presence of damage among individual cells. In this paper we explore the use of this technique utilizing exfoliated buccal mucosa cells from non-smokers (9 donors) and smokers (11 donors). The extent of DNA image length was found to be significantly increased in the smoker group (89.30 ± 16.18 μm) than in the non-smoker group (52.01 ± 10.43 μm). Our results indicate that the single-cell gel electrophoresis assay could be applied to human monitoring using exfoliated buccal epithelial cells.

Metronidazole (MTZ) is an effective agent used in the treatment of parasitic infections. Its genotoxic effects have been shown in a variety of prokaryotic systems; however, negative results have been reported in human in vivo studies. Due to its wide spread use, a study was performed to evaluate the chromosomal aberration frequencies in peripheral blood lymphocyte cultures from 10 individuals, before and after metronidazole treatment. A significant increase in the percentage of cells with chromatid and isochromatid breaks was observed after metronidazole treatment (1500 mg per day for 10 days). The percentages of cells with aberrations did not correlate with the levels of MTZ found in plasma. Individual variability was observed with respect to both the induction of aberrations and the concentration of MTZ in plasma. They could represent differences at the metabolic level, since metronidazole is known to be biotransformed by a polymorphic P450 cytochrome, and its metabolites have shown mutagenic activity.

Cytotoxic T lymphocytes (CTL) specifically reactive with the male transplantation antigen (H-Y) were used to immunoselect in vitro for antigen loss among cells from an Abelson murine leukemia virus (AbMuLV) transformed lymphoblastoid cell line. Numerous variant cell clones were recovered that had lost expression of either H-Y or the restricting major histocompatibility class I molecule, H-2D. In all experiments, low-level γ-irradiation applied prior to immunoselection increased the frequency of antigen loss, but when different time intervals between mutagenesis and immunoselection were used, the proportion of H-Y to H-2D antigen loss was affected, suggesting that the antigens selected against remain on the surface of the cell for differing amounts of time following allele loss.

Male B6C3F1 mice (8 weeks of age) were exposed by inhalation to divinylbenzene-55 (DVB-55), at target concentrations of 0, 25, 50 and 75 ppm for 6 h per day for 3 days. Following exposure the animals were killed, blood smears were prepared for micronucleus (MN) analysis, and the spleens were removed and cultured for sister chromatid exchange (SCE) and chromosome aberration (CA) analyses. DVB-55 induced a dose-dependent increase in SCE with the two highest doses reaching statistical significance. Similarly, there was a statistically significant although less pronounced increase in the frequency of CAs in splenocytes and MN in polychromatic erythrocytes. There was no indication of toxicity as measured by cell cycle kinetics in the splenocytes or the percentage of polychromatic erythrocytes in the peripheral blood smears. Thus, DVB-55 appears to be a weak genotoxicant in vivo.

Five synthetic curcuminoids and three natural curcuminoids were investigated for their antimutagenic and anti-promotional activity. The natural curcuminoids, curcumin I (diferuloylmethane), curcumin II (feruloyl-p-hydroxycin-namoylmethane) and curcumin III (bis-(p-hydroxycinnamoyl)methane) isolated from Curcuma longa were found to be potent inhibitors of mutagenesis and crotean oil-induced tumour promotion. Curcumin III produced 87.6% inhibition to 2-acetamidofluorene (2-AAF) induced mutagenesis, at a concentration of 100 μg/plate, curcumin II and curcumin I produced 70.5% and 68.3% inhibition at the same concentration. All the synthetic curcuminoids were found to inhibit 2-AAF-induced mutagenicity among which salicyl-and anisylcurcuminoids were the most active. Curcumin III was the most effective anti-promotor among natural curcuminoids. While 90% of the control animals were having papillomas on the 10th week of tumour initiation, only 10% of the curcumin III-treated animals, 20% of the curcumin II-treated animals, and 40% of the curcumin I-treated animals were having papillomas. Salicylcurcuminoid, which was causing no papillomas by the 10th week, was the most potent anti-carcinogen among the synthetic curcuminoids. Piperonal curcuminoid also exhibited anti-promotional activity.