Mutation Research Letters最新文献

Cytogenetic alterations have been associated with the occurrence of many cancers. However, limited data exist to address whether increased chromosomal changes in surrogate normal tissue are similarly associated with malignancy. As part of an ongoing case-control study of lung cancer, we have studied the factors that affect sister chromatid exchange (SCE) frequency in lymphocytes from lung cancer patients. Further, we sought to investigate whether the factors that affect SCE frequencies were comparable in lung cancer cancer cases and controls. Cases had newly diagnosed, operable primary lung cancer. Controls were friends and spouses of cases. Detailed information on smoking, family history of cancer, medical history, and environmental and occupational exposures was obtained in an interviewer-administered questionnaire. Intake of antioxidants was also determined through the administration of a validated semiquantitative food frequency questionnaire. Metabolic traits studied included the polymorphic glutathione-S-transferase class mu (GST-mu) and variants of P450 isoenzymes CYP1A1 and CYP 2D6. Overall, 78 cases and 78 controls were included in the analysis. Although there was a small number of lung cancer patients who had never smoked in the study (9% of cases), these patients had higher SCE frequencies than current or former smokers. This suggests that factors associated with genomic instability may also play a role in the pathogenesis of lunc cancer. The best fit model for SCE frequency, which had been previously generated from control data alone, included age, gender, smoking, GST-mu, and vitamin A intake. However, when this model was applied to lung cancer patients, smoking was not associated with an elevated SCE frequency. Thus, it is not clear that SCE frequency data in prevalent lung cancer cases and controls are comparable.

Styrene is converted into styrene-7,8-oxide in human lymphocyte cultures, in a reaction probably mediated by oxyhemoglobin. As a consequence, styrene induces sister-chromatid exchanges (SCEs) in whole-blood lymphocyte cultures without exogenous metabolic activation systems. Another metabolic pathway that could be involved in the metabolism of styrene is cooxidation by prostaglandin-endoperoxide synthase (PES). To study the role of PES in the metabolism of styrene, human whole-blood lymphocyte cultures were treated for the entire culture time of 72-h with styrene (0.5 and 1 mM) or styrene-7,8-oxide (50 and 10 μM), in the presence and absence of 75 or 150 μM indomethacin (an inhibitor of PES) and arachidonic acid (substrate of PES). Indomethacin potentiated SCE induction by both styrene and styrene-7,8-oxide; a slight but statistically significant enhancement (16–32%; p < 0.05 – p < 0.001) was observed in all treatments with styrene and at 150 μM indomethacin in the case of styrene-7,8-oxide. At 150 μM, arachidonic acid induced a 15–20% suppression (p < 0.01) in SCE induction by both styrene (1 mM only) and styrene-7,8-oxide (100 μM only). Indomethacin or arachidonic acid did not alone influence the frequency of SCEs. The results suggest that PES acts as an inactivation rout for styrene and styrene-7,8-oxide in human whole-blood lymphocyte cultures, possibly through PES-mediated binding to glutathione.

Since transgenic mice are being used to analyze somatic and germinal mutation rates in vivo, it is of interest to know to what extent these mice are normal or abnormal in any way. During experiments designed to compare the mutational response of the transgene and an endogenous gene, Big Blue™ mice hemizygous for the transgene were bred to create a hybrid mouse in which the comparisons could be made. The fraction of these mice that inherited the transgene was 37% rather than the Memdelian expectation of 50%.

Presoaked seeds of barley Hordeum vulgare L. pretreated with cycloheximide (CH), 10⁻⁶ M or bythionine sulfoximine (BSO), 10⁻⁴ M, were exposed to methyl mercuric chloride (MMCl), 10⁻⁴ M, with or without prior conditioning with cadmium sulfate (CdSO₄), 10⁻⁴ M. Subsequently as the seeds germinated the endpoints measured were mitotic index, cells with mitotic aberrations and micronuclei (MNC) in embryonic shoot cells fixed at 40, 44, 48 and 52 h of recovery. Indicated by the significance reduction (p ≤ 0.05) of the yield of cells with aberrations or MNC, the results confirmed that CdSO₄-conditioning triggered an adaptive response to MMCl-challenge. Pretreatments of CH and BSO, whereas they potentiated the genotoxicity of MMCl, significantly prevented (p ≤ 0.05) the Cd-induced genotoxic adaptation. That underscores a possible involvement of proteins in addition to phytochelatins in the underlaying mechanisms.

Chromosomal aberration and micronucleus assays were used to investigate the extent of cytogenetic damage in peripheral blood lymphocytes from four patients in two unrelated families with hereditary megaduodenum. The frequencies of total chromosomal aberrations, which significantly correlated with those of micronuclei, were higher in the patients than in sex- and age-matched controls, with no overlapping between the two groups. The considerable chromosomal fragility in patients which hereditary megaduodenum may be a genotypic marker for preclinical diagnosis predictive of increased cancer risk.

The V-E5 cell line, a mutant V79 Chinese hamster cell line, was used to study the effect of chromosomal instability on the spectrum of gene mutations and chromosome aberrations induced by the anthracycline antibiotic adriamycin (AM). V-E5 cells showed hypersensitivity to the cytotoxic effects of AM when compared to the parental cell line. AM caused both, chromosome-type aberrations and chromatid-type aberrations in V-E5 cells. Under the same experimental conditions, gene mutations were induced at the hprt locus which mainly represented deletion mutations. The spectrum of AM-induced chromosomal aberrations and gene mutations did not show any peculiarities in comparison to normal V79 cells. It is concluded that the genomic instability in V-E5 cells does not influence the pathways leading to chromosome aberrations and gene mutations after AM treatment.

3-Chloro-4-(chloromethyl)5-hydroxy-2(5H)-furanone (CMCF), a chlorine disinfection by-product in drinking water, was mutagenic in the Salmonella/his (Ames) assay for both base-pair substitution strains (TA1535, TA100 TA102) and frameshift strains (TA97, TA98) with the highest mutagenic response observed in strain TA100 (1292 revertants/μg). The presence in TA100 of pKM101 plasmid, which enhances error-phone DNA repair, greatly increased susceptibility of CMCF mutagenicity relative to the isogenic strain TA1535 lacking pKM101. In the Chinese hamster ovary (CHO) cell hprt (6-thioguanine resistance) locus assay, the mutagenicity of CMCF (1.04 mutants/10⁶ clonable cells per μg/ml) was barely detectable because of the low mutagenicity/cytotoxicity ratio. From the present experiments it appears that CMCF acts in a manner similar to that of another drinking water mutagen, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX). However, CMFC appears to be a less potent mutagen in vitro than MX

DNA supercoiling is known to modulate the activity of numerous promoters in vitro and in vivo. Moreover, it has been reported to modulate the rate of formation of cisplatin/DNA crosslinks in vitro. In order to address the question of how the topology influences CDDP toxicity in E. coli, three mutants with altered gyrase activity which led to a decrease of about 25% in superhelical density were studied. Mutant strains gyrA₂₂₄ and gyrB₂₂₅ showed similar sensitivity to CDDP as the parental strain while the gyrB₂₂₆ mutant was resistant. This resistance was abolished in uvrA (excision-repair) and recA (recombination and SOS processes) mutant derivatives. Thus supercoiling might play a role as an indirect modulator of CDDP toxicity in bacteria by interfering with repair processes.

The frequencies of chromosome aberrations and micronuclei were evaluated to assess the induction of adaptive response to low dose ionizing radiation in each of the blood samples collected from eight different individuals. Following stimulation with phytohemagglutinin, the cells were exposed to an adaptive dose of 1 cGy X-radiation at 24 hours and a challenge dose of 150 cGy gamma radiation at 48 hours. Lymphocytes were fixed at 54 hours to examine the incidence of chromosome aberrations and at 72 hours to examine the frequency of micronuclei in cytokinesis-blocked binucleated cells. Lymphocytes from five donors, i.e., “responder”, exhibited the induction of adaptive response; their lymphocytes, which were pre-treated with 1 cGy had significantly fewer chromosome aberrations and micronuclei induced by the challenge dose at 150 cGy gamma radiation, as compared to the cells which did not receive the pre-treatment with 1 cGy. Such an induction of adaptive response was not observed in the remaining three donors, i.e., “non-responders”; the incidence of chromosome aberrations and micronuclei induced by the challenge dose of 150 cGy was not significantly different between the cells which were pre-exposed and un-exposed to 1 cGy. In all eight individuals, there was a strong positive correlation between the incidence of chromosome aberrations and micronuclei. Hence, whether or non an individual is a “responder” or “non-responder” could be assessed using either chromosome aberrations or micronuclei as the end-point. The overall pattern of response confirms the heterogeneity in adaptive response between individuals to ionizing radiation, which may in part be genetically controlled. Because of the simplicity of the technique and rapid assessment of the binucleated cells, we suggest the use of the micronucleus test as an alternative procedure in large scale population studies related to the adaptive response.

Four compounds commonly found in the human diet, allyl isothiocyanate (AITC), phenethyl isothiocyanate (PEITC) and their parent glucosinolates sinigrin and gluconasturtiin, were tested for cytotoxic and genotoxic effects in a Chinese hamster ovary cell line (CHO). The isothiocyanates were found to be more than one thousand times more cytotoxic than the glucosinolates, showing significant cytotoxic activity to concentrations below 1.0 μg/ml. AITC was unable to induce either chromosome aberrations or sister chromatid exchanges (SCEs) even at highly cytotoxic doses. In contrast, PEITC was found to induce both aberrations and SCE at concentrations of 0.9–1.2 μg/ml whilst sinigrin and gluconasturtiin induced aberrations at concentrations above 2 mg/ml.