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Showing papers on "Sister chromatid exchange published in 1998"


Journal ArticleDOI
TL;DR: It is shown that Ku70 deficiency facilitates neoplastic growth and a novel role of the Ku70 locus in tumor suppression is suggested, which is thought to be related to B but not T lymphocyte maturation.

237 citations


Journal ArticleDOI
01 Sep 1998-Genetics
TL;DR: The effects of mutations that impair S phase regulation on the ability of excision repair-defective cells to replicate irreparably UV-damaged DNA are determined and RAD9, RAD17, RAD24, and MEC3 are found to be required for UV-induced mutagenesis and RAD 9 and RAD17 are required for maximal induction of replication-dependent sister chromatid exchange.
Abstract: In wild-type Saccharomyces cerevisiae, a checkpoint slows the rate of progression of an ongoing S phase in response to exposure to a DNA-alkylating agent. Mutations that eliminate S phase regulation also confer sensitivity to alkylating agents, leading us to suggest that, by regulating the S phase rate, cells are either better able to repair or better able to replicate damaged DNA. In this study, we determine the effects of mutations that impair S phase regulation on the ability of excision repair-defective cells to replicate irreparably UV-damaged DNA. We assay survival after UV irradiation, as well as the genetic consequences of replicating a damaged template, namely mutation and sister chromatid exchange induction. We find that RAD9, RAD17, RAD24, and MEC3 are required for UV-induced (although not spontaneous) mutagenesis, and that RAD9 and RAD17 (but not REV3, RAD24, and MEC3) are required for maximal induction of replication-dependent sister chromatid exchange. Therefore, checkpoint genes not only control cell cycle progression in response to damage, but also play a role in accommodating DNA damage during replication.

143 citations


Journal ArticleDOI
TL;DR: The combined use of these two experimental tools has defined the biological consequences of 3-methyladenine, a DNA lesion produced by endogenous cellular metabolites, environmental carcinogens, and chemotherapeutic alkylating agents.

131 citations


Journal ArticleDOI
TL;DR: The results indicate that deltamethrin, in the presence of metabolic activation (+ S9mix), is able to induce DNA damage as revealed by the increasing tail moment values observed with increasing doses.

119 citations


Journal ArticleDOI
TL;DR: Recombination at dif was eliminated by a recA mutation, reflecting the role of RecA in SCE and virtually all homologous recombination in E. coli, and demonstrates the importance of both RecBCD and RecF to chromosomal recombination events in wild-type cells.
Abstract: Sister chromatid exchange (SCE) in Escherichia coli results in the formation of circular dimer chromosomes, which are converted back to monomers by a compensating exchange at the dif resolvase site. Recombination at dif is site specific and can be monitored by utilizing a density label assay that we recently described. To characterize factors affecting SCE frequency, we analyzed dimer resolution at the dif site in a variety of genetic backgrounds and conditions. Recombination at dif was increased by known hyperrecombinogenic mutations such as polA, dut, and uvrD. It was also increased by a fur mutation, which increased oxidative DNA damage. Recombination at dif was eliminated by a recA mutation, reflecting the role of RecA in SCE and virtually all homologous recombination in E. coli. Interestingly, recombination at dif was reduced to approximately half of the wild-type levels by single mutations in either recB or recF, and it was virtually eliminated when both mutations were present. This result demonstrates the importance of both RecBCD and RecF to chromosomal recombination events in wild-type cells.

113 citations


Journal ArticleDOI
TL;DR: BD exposure had no significant effects on formation of micronuclei and on comet assay parameters, and effect of smoking was observed only for HFC in BD-exposed group.
Abstract: The association of occupational exposure to 1,3-butadiene (BD) and induction of cytogenetic damage in peripheral lymphocytes was studied in 19 male workers from a monomer production unit and 19 control subjects from a heat production unit. The exposure to BD was measured by passive personal monitors. The following biomarkers were used: chromosomal aberrations (CA), sister chromatid exchanges (SCE), cells with a high frequency of SCE (HFC), micronuclei, comet assay parameters like tail length (TL) and percentage of DNA in tail [ T (%)] and polymorphisms of GSTM1 and GSTT1 genotypes. BD exposure with a median value of 0.53 mg/m 3 (range: 0.024–23.0) significantly increased (a) the percentage of cells with chromosomal aberrations in exposed vs. control groups (3.11% vs. 2.03%, P P P

96 citations


Journal ArticleDOI
TL;DR: It is determined that recombination occurs late in the cell cycle, and that resolution is blocked if cell division is inhibited with cephalexin or by a ftsZts mutation.
Abstract: The dif locus is a RecA-independent resolvase site in the terminus region of the chromosome of Escherichia coli. The locus reduces dimer chromosomes, which result from sister chromatid exchange, to monomers. A density label assay demonstrates that recombination occurs at dif, and that it requires XerC and XerD. The frequency of this recombination is approximately 14% per site per generation, which is doubled in polA12 mutants. We have determined that recombination occurs late in the cell cycle, and that resolution is blocked if cell division is inhibited with cephalexin or by a ftsZts mutation. Fluorescence microscopy has demonstrated that abnormal nucleoids are present in cells incubated in cephalexin, and this is increased in polA12 mutants.

96 citations


Journal ArticleDOI
TL;DR: Results indicated a statistically significant increase of structural aberrations, sister chromatid exchanges and G6PD activity, suggesting that the pesticides tested induce either oxidative stress or a mutagenic effect in this species.
Abstract: The genotoxic activity of the pesticides gliphosate, vinclozolin and DPX-E9636 was studied in in vitro cultures of bovine lymphocytes, using chromosome aberration (CA) and sister chromatid exchange (SCE) frequencies as genetic end-points and a variation of glucose 6-phosphate dehydrogenase (G6PD) enzyme activity as a marker of changes in the normal cell redox state. Results indicated a statistically significant increase of structural aberrations, sister chromatid exchanges and G6PD activity, suggesting that the pesticides tested induce either oxidative stress or a mutagenic effect in this species. The evaluation of both mitotic index and cell viability, after pesticide exposure, demonstrates a high cytotoxic effect which is always associated with the observed genotoxic effect.

95 citations


Journal ArticleDOI
TL;DR: The increase of G6PD activity in exposed lymphocyte cultures strongly indicated an induction of a pro‐oxidant state of the cells as an initial response to pesticide exposure.
Abstract: We analyzed chromosome aberrations (CAs), sister chromatid exchanges (SCEs), mitotic index (MI), and glucose 6-phosphate dehydrogenase (G6PD) enzyme activity in human peripheral lymphocytes from three healthy donors exposed in vitro to different concentrations of gliphosate, vinclozolin, atrazine, and DPX-E9636. The pesticides gliphosate, vinclozolin, and atrazine have been studied in a broad range of genetic tests with predominantly conflicting or negative results, whereas little is known about the genotoxicity of DPX-E9636. In our experimental conditions, each chemical compound tested produced a dose-related increase in the percent of aberrant cells and an increase of SCE/cell. Furthermore, at the highest concentrations of vinclozolin, atrazine, and DPX-E9636, we observed a significant reduction of the mitotic index. The increase of G6PD activity in exposed lymphocyte cultures strongly indicated an induction of a pro-oxidant state of the cells as an initial response to pesticide exposure.

89 citations


Journal ArticleDOI
TL;DR: DNA damage and sister chromatid exchange frequencies were measured in lymphocytes of 39 welders and 39 controls and indicate that DNA single-strand breakage and DNA-protein cross-links show different increases depending on the exposure levels for chromium and nickel.
Abstract: DNA damage (alkaline filter elution) and sister chromatid exchange (SCE) frequencies were measured in lymphocytes of 39 welders and 39 controls. The welders showed a significantly higher rate of DNA single-strand breakages and significantly elevated SCE values. These results are not in accordance with those of a former study in which only DNA-protein cross-links were measured. The different results may be explained on the basis of different exposure levels for chromium(VI) and nickel. Both methods are not specific but sensitive enough to measure genotoxic damage after occupational exposure to chromium(VI) and nickel in the range of threshold values for the workplace on a collective basis. Additionally, the results indicate that DNA single-strand breakage and DNA-protein cross-links show different increases depending on the exposure levels for chromium and nickel.

83 citations


Journal ArticleDOI
TL;DR: The data indicate that in these assays the genotoxic and cytotoxic potential of CSC from the new cigarette that primarily heats tobacco is significantly less thanCSC from Kentucky reference 1R4F and 1R5F cigarettes, which are representative of cigarettes currently sold in the US.

Journal ArticleDOI
TL;DR: Peripheral blood lymphocytes from 22 men with low average exposure to benzene and 19 control men were investigated for Sister Chromatid Exchange (SCE) frequency and micronucleus assay (MN), and frequencies were significantly increased in relation with length of employment.
Abstract: Peripheral blood lymphocytes from 22 men with low average exposure (229 μ g/m 3 =0.72 ppm) to benzene and 19 control men were investigated for Sister Chromatid Exchange (SCE) frequency. The majority of the men (21 exposed, 19 controls) were also investigated using the micronucleus assay (MN). The exposed subjects were employed at 10 different gas stations in or near the city (Bari/South Italy). SCE frequencies were significantly related with age and smoking habits, on the contrary no relation was observed between SCE and length of employment (SCE=7.41+0.03·age (*)+0.0001·length of employment (n.s.)+0.03·cigarette consumption (*); F =4.87; p F =4.138; p

Journal ArticleDOI
TL;DR: It is demonstrated that TiO2 can be transported into Chinese hamster ovary-K1 (CHO-K 1) cells and the results suggest thatTiO2 is a potential genotoxic agent.
Abstract: Titanium dioxide (TiO2) has color properties of extreme whiteness and brightness, is relatively inexpensive, and is extensively used as a white pigment in a variety of materials. TiO2, an effective blocker of ultraviolet light, is frequently added to sunscreens and cosmetic creams. However, the genotoxicity of TiO2 remains to be controversial. In this report, we have demonstrated that TiO2 can be transported into Chinese hamster ovary-K1 (CHO-K1) cells. The effects of TiO2 on induction of sister chromatid exchanges (SCE) and micronuclei (MN) were then studied in these cells. The SCE frequency in CHO-K1 cells treated with TiO2 at a nonlethal dose range (0 to 5 microM) for 24 h was significantly and dose-dependently increased. By the conventional MN assay, TiO2 at the dose ranged from 0 to 20 microM slightly increased the MN frequency in CHO-K1 cells. However, in the cytokinesis-block MN assay, the number of MN per 1000 binucleated cells was significantly and dose-dependently enhanced in CHO-K1 cells treated TiO2 at the same dose range for 24 h. These results suggest that TiO2 is a potential genotoxic agent.

Journal ArticleDOI
01 Sep 1998-Genetics
TL;DR: The observation that exchange can generate a bivalent in mitotic divisions provides support for a simple evolutionary relationship between mitosis and meiosis.
Abstract: In meiosis, the segregation of chromosomes at the reductional division is accomplished by first linking homologs together. Genetic exchange generates the bivalents that direct regular chromosome segregation. We show that genetic exchange in mitosis also generates bivalents and that these bivalents direct mitotic chromosome segregation. After FLP-mediated homologous recombination in G2 of the cell cycle, recombinant chromatids consistently segregate away from each other (x segregation). This pattern of segregation also applies to exchange between heterologs. Most, or all, cases of non-x segregation are the result of exchange in G1. Cytological evidence is presented that confirms the existence of the bivalents that direct this pattern of segregation. Our results implicate sister chromatid cohesion in maintenance of the bivalent. The pattern of chromatid segregation can be altered by providing an additional FRT at a more proximal site on one chromosome. We propose that sister chromatid exchange occurs at the more proximal site, allowing the recombinant chromatids to segregate together. This also allowed the recovery of reciprocal translocations following FLP-mediated heterologous recombination. The observation that exchange can generate a bivalent in mitotic divisions provides support for a simple evolutionary relationship between mitosis and meiosis.

Journal ArticleDOI
TL;DR: The results show that safrole is a genotoxic carcinogen in the rat liver in vivo and suggest that the cytogenetic effects of this compound may result from covalent DNA modification in theRat liver, and a useful means of evaluation of the genotoxicity of hepatocarcinogens.
Abstract: The induction of chromosome aberrations, sister chromatid exchanges (SCEs), and the formation of DNA adducts was studied in hepatocytes of F344 rats exposed in vivo to safrole. Hepatocytes were isolated 24 h after a single dose of safrole or five repeated doses (once a day) by gastric intubation and allowed to proliferate in Williams' medium E supplemented with epidermal growth factor. Cells were fixed after 48 h in culture. Safrole-DNA adducts were detected by a nuclease P1-enhanced 32P-post-labeling assay in isolated hepatocytes from the rats. While a single dose was not sufficient to induce detectable levels of chromosome aberrations at the time of assay, five repeated doses induced these changes with a maximum frequency of 13.4%, compared with the control value of 1.8%. Both a single dose and five repeated doses induced significant SCEs, to a maximum frequency of 0.81 SCEs per chromosome, while the control value was 0.59 SCEs per chromosome. Two major and two minor DNA adducts were detected after treatment with either a single dose or five repeated doses. The maximum amount of total DNA adducts was 89.8 DNA adducts/10(7) nucleotides. These results show that safrole is a genotoxic carcinogen in the rat liver in vivo and suggest that the cytogenetic effects of this compound may result from covalent DNA modification in the rat liver. This in vivo cytogenetic assay should provide a useful means of evaluation of the genotoxicity of hepatocarcinogens.

Journal ArticleDOI
TL;DR: It is suggested that GSTT1 is an important determinant of heterogeneity in individual susceptibility to chromosomal damage associated with exposure to benzene, and this study suggests that benzene-GSTT1 interaction was found in nonsmokers.
Abstract: Recent studies have shown a strong positive correlation between chromosomal aberrations and future cancer risk. Sister chromatid exchange (SCE) has been widely applied in monitoring early biological effects to assess human genetic risk of cancer at the population level. We studied 45 Chinese workers (23 in the painting workshop of a glass factory with occupational exposure to benzene, and 22 fitters and planers in the punching and planing machine workshops of a nearby shipyard without such an exposure) to examine the association between occupational exposure to benzene and SCE frequency in peripheral blood lymphocytes. We also sought to investigate whether the glutathione S-transferase class theta gene (GSTT1) affects individual susceptibility to cytogenetic damage induced by in vivo exposure to benzene or in vitro exposure to diepoxybutane. The time-weighted average concentrations of benzene were 0.71 ppm in the exposed group and 0.03 ppm in the non-exposed group. Controlling for age, gender and educational level, cigarette smoking was significantly associated with increased SCE frequencies (P < 0.05), while GSTT1 genotype was significantly associated with DEB-induced SCEs (P < 0.01). There was no relationship between benzene exposure and baseline or DEB-induced SCEs. After stratification by smoking status, the GSTT1 deletion was a significant predictor of DEB-induced SCEs for both smokers (P < 0.05) and nonsmokers (P < 0.01). A significant benzene-GSTT1 interaction was found in nonsmokers (P < 0.05). Our study suggests that GSTT1 is an important determinant of heterogeneity in individual susceptibility to chromosomal damage associated with exposure to benzene.

Journal ArticleDOI
TL;DR: A variety of parameters seemed to modulate the individual DEB-sensitivity together with the GSTT1 genotype, although the known contributing factors did not fully explain the overlap in cytogenetic response between GSTT 1 positive and null individuals.
Abstract: Although some blood parameters have been suggested to modulate in-vitro induction of sister chromatid exchanges by 1,2:3,4-diepoxybutane (DEB), a metabolite of 1,3-butadiene, the increased sensitivity has largely been assigned to a homozygous deletion of glutathione S-transferase T1 gene (GSTT1 null genotype). However, some DEB-sensitive individuals have been shown to be GSTT1 positive (having at least one undeleted GSTT1 allele). To examine potential causes for this overlap, we evaluated the effect of GSTM1, GSTP1, and GSTT1 genotypes, together with various life-style and blood parameters, on the DEB induction of sister chromatid exchanges and cells with chromosomal aberrations (aberrant cells) in lymphocyte cultures of 115 and 62 human donors, respectively. Our results supported the important role of the GSTT1 genotype in DEB sensitivity; 76% of cultures from GSTT1 null donors but only 4% of those from GSTT1 positive donors were DEB-sensitive, as defined by sister chromatid exchange measurements. The GSTT1 genotype also clearly affected DEB-induced aberrant cells, 92% of GSTT1 null and 8% of GSTT1 positive donors being sensitive to DEB. All individuals showing a high response to DEB in both sister chromatid exchange and aberrant cell analyses were GSTT1 null. Baseline aberrant cell measurements but not sister chromatid exchange measurements were marginally higher among GSTT1 null donors compared with GSTT1 positive donors. GSTM1 and GSTP1 genotypes had no influence on these cytogenetic end-points. Blood transaminases, gamma-glutamyl transferase, urea, creatinine and white blood cell count showed a clear negative association with DEB-induced aberrant cells, whereas wine drinkers had more aberrant cells than non-drinkers. A higher sister chromatid exchange-response to DEB was observed in lymphocytes from women and smokers than from men and non-smokers, respectively. Erythrocyte count correlated negatively with DEB-induced sister chromatid exchanges. Thus, a variety of parameters seemed to modulate the individual DEB-sensitivity together with the GSTT1 genotype. Although the known contributing factors accounted for a considerable part of individual variability in sister chromatid exchanges (59.4%) and aberrant cells (46.7%) in DEB treatment, they did not, however, fully explain the overlap in cytogenetic response between GSTT1 positive and null individuals.

Journal Article
TL;DR: The results indicated that FA might damage the chromosomes of human lymphocytes in students exposed to formaldehyde during an anatomy class.

Journal ArticleDOI
TL;DR: The results of this study show that biomonitoring after exposure to a mixture of antineoplastic drugs which express clastogenic and aneugenic activity should involve a battery of cytogenetic methods.
Abstract: Cytogenetic monitoring was carried out on a group of 38 nurses who reconstitute antineoplastic drugs in order to determine the extent of chromosomal damage. Genotoxic activities of antineoplastic drugs are studied by chromosome aberration assay, micronucleus assay, sister chromatid exchange (SCE) frequency high frequency cells (HFC) analysis, and mitotic activity of peripheral lymphocytes. Results confirmed that occupational exposure to a mixture of antineoplastic drugs may cause genome damages. The results of this study show that biomonitoring after exposure to a mixture of antineoplastic drugs which express clastogenic and aneugenic activity should involve a battery of cytogenetic methods.

Journal ArticleDOI
TL;DR: The results suggest that VCM workers with ALDH2 1-2/2-2 genotypes, who also smoke, may have increased risk of DNA damage.
Abstract: Vinyl chloride monomer (VCM) is a human carcinogen. However, the exact mechanism of carcinogenesis remains unclear. VCM may be metabolized by cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2) and glutathione S-transferases (GSTs). Thus workers with inherited variant metabolic enzyme activities may have an altered risk of genotoxicity. This study was designed to investigate which risk factors might affect sister chromatid exchange (SCE) frequency in polyvinyl chloride (PVC) workers. Study subjects were 44 male workers from three PVC factories. Questionnaires were administered to obtain detailed histories of cigarette smoking, alcohol consumption, occupations, and medications. SCE frequency in peripheral lymphocytes was determined using a standardized method, and CYP2E1, GSTM1, GSTT1 and ALDH2 genotypes were identified by the polymerase chain reaction (PCR). Analysis revealed that smoking status and exposure to VCM were significantly associated with increased SCE frequency. The presence of ALDH2 1–2/2–2 genotypes was also significantly associated with an elevation of SCE frequency (9.5 vs. 8.1, p

Journal ArticleDOI
TL;DR: The results of the in vivo SCE and CA assays indicate that these three antimalarial drugs are genotoxic in bone marrow cells of mice.
Abstract: Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine, were assessed in the Ames mutagenicity assay (in strains TA97a, TA100, TA102 and TA104) and in vivo sister chromatid exchange (SCE) and chromosome aberration (CA) assays in bone marrow cells of mice. These are the most commonly used antimalarial drugs available at present throughout the world. The results of the bacterial mutagenicity assays showed a very weak mutagenic effect of all three drugs in Salmonella strains TA97a and TA100 both with and without S9 mix and in TA104 only with S9 mix. The results of the in vivo SCE and CA assays indicate that these three drugs are genotoxic in bone marrow cells of mice.

Journal ArticleDOI
TL;DR: Among these compounds, the most effective in inducing cytogenetic and antineoplastic effects are the complexes [Pd(PyTsc)2] and [Pt( PyT sc)2].
Abstract: The effect of six novel complexes of Pt(II) and Pd(II) with pyridine-2-carboxyaldehyde thiosemicarbazone (HPyTsc) on sister chromatid exchange rate and human lymphocyte proliferation kinetic was studi

Journal Article
TL;DR: The data corroborate that the S-phase dependent mechanism of action of topo-I inhibitors is also applicable to SN-38, and indicate two distinct interactions ofSN-38 with DNA: immediate induction of chromatid breaks independent from DNA synthesis, and induction of Chromatid break associated with radial chromosome configurations dependent on DNA synthesis.
Abstract: Background SN-38 is the active metabolite of the topoisomerase-I (topo-I) inhibitor Irinotecan (CPT-11). Generally, topo-I inhibitors stabilize the complex between topo-I and DNA which collide with moving DNA replication forks, eventually leading to double stranded DNA damage. Therefore, topo-I inhibitors are regarded as S-phase specific. The present study investigated S-phase dependent and independent effects of SN-38. Materials and methods Effects of exposure of A2780 cells to SN-38 (2 hours) were studied by assessing DNA/protein crosslinks, DNA damage and cytogenetic aberrations. Results A close correlation (r2 = 0.97) was established between drug-induced DNA/protein crosslinks and double stranded DNA breaks. Cytogenetic analysis revealed near maximum clastogenic effects already evident immediately following 2 hours drug exposure. However, qualitatively, chromatid breaks at 24 hours were different from those at 0 hours, in that at 24 hours they were associated with radial chromosome configurations and sister chromatid exchanges. Conclusion The data corroborate that the S-phase dependent mechanism of action of topo-I inhibitors is also applicable to SN-38. The cytogenetic data indicate two distinct interactions of SN-38 with DNA: immediate induction of chromatid breaks independent from DNA synthesis, and induction of chromatid breaks associated with radial chromosome configurations dependent on DNA synthesis.

Journal ArticleDOI
TL;DR: It is established that NDGA produces antigenotoxic action in mammalian cells in vitro and in vivo and its capacity for inhibiting the rate of sister chromatid exchanges induced by methyl methanesulfonate is determined.
Abstract: Nordihydroguaiaretic acid (NDGA) is a phenolic lignan which has shown to cause a variety of actions potentially useful for human health; therefore, in this investigation we determined its capacity for inhibiting the rate of sister chromatid exchanges (SCEs) induced by methyl methanesulfonate (MMS) We tested the effect of 025, 050, 10, and 20 microM of NDGA on the damage exerted by 55 microM of MMS Cultured human lymphocytes from two female donors were used for the experiment The best result concerning its modulatory action was obtained with 10 microM of NDGA; with this dose the mean inhibitory index including both donors reached 682% The values obtained for the mitotic and proliferative indexes were not significantly modified with respect to the basal data We also used the mouse bone marrow in vivo system to evaluate the inhibitory effect of the chemical In this study we tested 10, 60, and 110 mg/kg of NDGA intraperitoneally (ip) administered 1 h before an ip injection of MMS (40 mg/kg) The best inhibitory index in this model corresponded to the dose of 11 mg/kg of NDGA (869%) The mitotic index and the average generation time showed no significant variation with respect to the control data Our study established that NDGA produces antigenotoxic action in mammalian cells in vitro and in vivo

Journal ArticleDOI
TL;DR: The results indicate that the patients with prostate cancer show a degree of chromosomal instability that might be related to a predisposition to neoplasia.

Journal ArticleDOI
TL;DR: The results demonstrate that the genotoxicity of cadmium chloride may be changed depending on the stage of the cell cycle in human lymphocytes, which may be one of the reasons of contradictory findings in the literature.
Abstract: Sister chromatid exchanges (SCEs) were analyzed in human phytohemagglutinin-activated peripheral lymphocyte cultures exposed to varying concentrations (10 −7 –10 −3 M) of cadmium chloride in vitro at two different stages of the cell cycle, G o and early S phase. When cadmium chloride was administered at the G o phase, no increase in the SCEs were observed for the doses 10 −6 and 10 −5 M. Concentrations equal to or larger than 10 −4 M cadmium chloride were lethal to human lymphocytes in our experimental conditions. A highly statistically significant increase was observed in the SCE frequency with increasing cadmium chloride concentration (10 −7 –10 −4 ) when cadmium was administered at the early S phase, which was 24 h after culture initiation. The increase in SCE frequency was higher when the cultures were terminated at 54 h, compared to termination at 72 h. In order to examine the effects of cadmium administered at the S phase on SCE frequency in different individuals, 10 −5 M concentration was used and the cultures were terminated at 54 h after culture initiation. A 2- to 3-fold increase in the SCE frequency was observed in all six individuals examined. A progressive decrease in the proliferative index was also observed by increasing cadmium chloride concentration. These results demonstrate that the genotoxicity of cadmium chloride may be changed depending on the stage of the cell cycle in human lymphocytes. This may be one of the reasons of contradictory findings in the literature.

Journal ArticleDOI
TL;DR: Findings show that the lack of the GSTT1 gene increases the genotoxic effects of SO in human whole‐blood lymphocyte cultures, suggesting that GSTT 1 is involved in the detoxification of SOIn humans.
Abstract: The genetic polymorphisms of glutathione S-transferases (GSTs), which are involved in the metabolic inactivation of various toxicants, have been suggested to be an important source of variation in individual response to genotoxic carcinogens. We have previously shown that donor GSTM1 genotype does not influence the induction of sister chromatid exchanges (SCEs) in cultured human lymphocytes by styrene-7,8-oxide (SO), a metabolite of styrene. Here, we expanded the study to GSTT1 polymorphism. SCEs were analyzed from 72-hr whole-blood lymphocyte cultures of five GSTT1 positive (at least one undeleted allele) and five GSTT1 null (gene homozygously deleted) donors, all GSTM1 positive, after a 48-hr treatment with 50 μM and 150 μM SO. SO clearly increased SCEs in cultures of all donors. The mean number of SCEs/cell induced by SO (individual mean SCEs from acetone-treated control cultures subtracted) was 1.7 (50 μM) and 1.4 (150 μM) times greater among the GSTT1 null individuals (4.83 at 50 μM, 18.98 at 150 μM) compared with the GSTT1 positive individuals (2.78 at 50 μM, 13.74 at 150 μM), the differences being statistically significant (P = 0.006 and P = 0.022, respectively). These findings show that the lack of the GSTT1 gene increases the genotoxic effects of SO in human whole-blood lymphocyte cultures, suggesting that GSTT1 is involved in the detoxification of SO in humans. Although glutathione conjugation is considered a minor metabolic pathway for SO in vivo, the high GSTT1 activity in erythrocytes may be important locally and might affect the level of genotoxic damage observed in peripheral lymphocytes of styrene-exposed reinforced plastics workers. The GSTT1 polymorphism could also influence the urinary excretion of SO-specific mercapturic acids. Environ. Mol. Mutagen. 31:311–315, 1998 © 1998 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: The data indicate that ARC-induced DNA damage is influenced by endogenous GSH level, and the failure of GSH to reduce the frequency of SCEs indicates that the mechanism of induction of CAs and S CEs by ARC are different.
Abstract: Arecoline (ARC), an alkaloid of the betel nut (Areca catechu), is a major ingredient of betel quid. The carcinogenic potentiality as well as its cell transformation ability has already been reported. Reduced glutathione (GSH), a major non-protein thiol substance plays an important role in protection of cells against the toxic effect of exogenous compounds. In order to understand the role of factors which affect ARC sensitivity, we have made an attempt to establish a relationship between ARC-induced DNA damage and the endogenous GSH status of the cells. ARC was administered to untreated and buthionine sulfoximine (BSO) (a GSH-depleting agent)-treated mice. Exogenous GSH was also added to ARC-administered mice. Cells were fixed at 20 h and both chromosome aberrations (CAs) and sister chromatid exchanges (SCEs) were scored. Both CAs and SCEs were significantly induced by ARC and the frequency of both these parameters were increased further when ARC was given to BSO-treated mice. However, GSH reduced the frequency of CAs induced by ARC but failed to do so for SCEs. The data indicate that ARC-induced DNA damage is influenced by endogenous GSH level. The failure of GSH to reduce the frequency of SCEs indicates that the mechanism of induction of CAs and SCEs by ARC are different.

Journal ArticleDOI
TL;DR: GSTT1, in addition to GSTM1, is involved in the detoxification of MEB in human whole-blood lymphocyte cultures, and the deletion of the GSTT1 gene results in reduced erythrocytic detoxification capacity, thereby increasing the genotoxic effects ofMEB.
Abstract: The influence of glutathione S-transferase T1 (GSTT1) genotype on the genotoxicity of 1,2-epoxy-3-butene (MEB), a metabolite of 1,3-butadiene, was assessed by the analysis of sister chromatid exchanges (SCEs) in 72-h human whole-blood lymphocyte cultures. The cultures were from 18 donors, representing both GSTT1 'positive' genotype (with at least one undeleted GSTT1 allele; GSTT1 activity present) and GSTT1 'null' genotype (homozygous deletion of the GSTT1 gene; no GSTT1 activity). As we have previously observed that allelism of glutathione S-transferase M1 (GSTM1) affects SCE induction by MEB in cultured lymphocytes, only individuals with the GSTM1 null genotype were included in this study. At 125 and 250 microM MEB (treatment at 24 h for 48 h), the mean frequencies of MEB-induced SCEs per cell (control level subtracted) were 4.5 (SD 1.8) and 8.9 (SD 1.0) for GSTT1 positive cell cultures (n = 13) and 5.3 (SD 1.2) and 12.5 (SD 1.1) for GSTT1 null cell cultures (n = 5) respectively, and the difference between the genotypes was statistically significant (P < 0.001) at the higher dose. All individual mean frequencies of SCEs induced by 250 microM MEB were higher in the GSTT1 null group (range 11.2-13.9) than in the GSTT1 positive group (range 7.2-10.8). The findings suggest that GSTT1, in addition to GSTM1, is involved in the detoxification of MEB in human whole-blood lymphocyte cultures. The deletion of the GSTT1 gene results in reduced erythrocytic detoxification capacity, thereby increasing the genotoxic effects of MEB.

Journal ArticleDOI
TL;DR: Control measures on the level of biological effect should be performed regularly to ensure maximum safety precautions for workers potentially exposed to genotoxic agents.
Abstract: OBJECTIVES: To investigate whether DNA damage increased in subjects possibly exposed to high amounts of antineoplastic agents. METHODS: The level of genetic damage was determined in peripheral mononuclear blood cells with the sister chromatid exchange test, the alkaline elution technique, and the cytokinesis block micronucleus test. RESULTS: The supposed increased exposure of the study subjects was caused by a malfunction of a safety hood resulting in leakage of air during preparation of an infusion of an antineoplastic drug. Two months after a new safety hood was installed, the frequencies of micronuclei and sister chromatid exchanges of exposed nurses (n = 10) were still significantly increased when compared with a matched control group (p < 0.01 and p < 0.05, one sided Wilcoxon test, respectively). In a second examination seven months later, the frequency of micronuclei had significantly decreased to control values (p < 0.05, one sided Wilcoxon test, n = 6). Moreover, the study subjects who smoked (n = 8) had significantly increased frequencies of micronuclei and sister chromatid exchanges (p < 0.01 and p < 0.05, one sided U test, respectively). No differences in the rate of DNA damage could be detected with the alkaline elution technique. CONCLUSIONS: Control measures on the level of biological effect should be performed regularly to ensure maximum safety precautions for workers potentially exposed to genotoxic agents.