Elevated Frequency Of Chromosomal Aberrations Research Articles

Cytogenetic biodosimetry and dose-rate effect after radioiodine therapy for thyroid cancer.

This study set out to investigate chromosomal damage in peripheral blood lymphocytes of thyroid cancer patients receiving 131I for thyroid remnant ablation or treatment of metastatic disease. The observed chromosomal damage was further converted to the estimates of whole-body dose to project the adverse side effects. Chromosomal aberration analysis was performed in 24 patients treated for the first time or after multiple courses. Blood samples were collected before treatment and 3 or 4days after administration of 2-4GBq of 131I. Both conventional cytogenetic and chromosome 2, 4 and 12 painting assays were used. To account for dose-rate effect, a dose-protraction factor was applied to calculate the whole-body dose. The mean dose was 0.62Gy (95% CI: 0.44-0.77Gy) in the subgroup of patients treated one time and 0.67Gy (95% CI: 0.03-1.00Gy) in re-treated patients. These dose estimates are about 1.7-fold higher than those disregarding the effect of exposure duration. In re-treated patients, the neglected dose-rate effect can result in underestimation of the cumulative whole-body dose by the factor ranging from 2.6 to 6.8. Elevated frequency of chromosomal aberrations observed in re-treated patients before radioiodine therapy allows estimation of a cumulative dose received from all previous treatments.

Chromosomal Aberrations in Large Japanese Field Mice (Apodemus speciosus) Captured near Fukushima Dai-ichi Nuclear Power Plant.

Since the Fukushima Dai-ichi Nuclear Power Plant accident, radiation effects on nonhuman biota in the contaminated areas have been a major concern. Here, we analyzed the frequencies of chromosomal aberrations (translocations and dicentrics) in the splenic lymphocytes of large Japanese field mice (Apodemus speciosus) inhabiting Fukushima Prefecture. A. speciosus chromosomes 1, 2, and 5 were flow-sorted in order to develop A. speciosus chromosome-specific painting probes, and FISH (fluorescence in situ hybridization) was performed using these painting probes to detect the translocations and dicentrics. The average frequency of the translocations and dicentrics per cell in the heavily contaminated area was significantly higher than the frequencies in the case of the noncontaminated control area and the slightly and moderately contaminated areas, and this aberration frequency in individual mice tended to roughly increase with the estimated dose rates and accumulated doses. In all four sampling areas, the proportion of aberrations occurring in chromosome 2 was approximately >3 times higher than that in chromosomes 1 and 5, which suggests that A. speciosus chromosome 2 harbors a fragile site that is highly sensitive to chromosome breaks induced by cellular stress such as DNA replication. The elevated frequency of chromosomal aberrations in A. speciosus potentially resulting from the presence of a fragile site in chromosome 2 might make it challenging to observe the mild effect of chronic low-dose-rate irradiation on the induction of chromosomal aberrations in A. speciosus inhabiting the contaminated areas of Fukushima.

Protective effect of Nigella sativa seeds against spermatocyte chromosomal aberrations and genotoxicity induced by carbon tetrachloride in mice.

Nigella sativa is a well-known dietary antioxidant and a valuable inhibitor of clastogenesis and carcinogenesis. The purpose of the present work was to investigate the effects of N. sativa seeds against chromosomal aberrations in primary spermatocytes and early embryonic lethality induced by CCl4 hepatotoxin in Swiss albino mice. One hundred male Swiss albino mice were randomly divided into five groups. Groups I, II, and III received only normal saline, olive oil, and aqueous suspension of N. sativa seeds (50mg/kg b.w.), while groups IV and V were orally given CCl4 dissolved in olive oil at a dose level of 1.9 (¼ LD50) alone and with aqueous suspension of N. sativa seeds (50mg/kg b.w.) alternately. Aqueous extract of N. sativa significantly reduced the elevated frequency of chromosomal aberrations induced by CCl4 in mouse primary spermatocytes. For the male-dominant lethal test, four males from each group (control and experimental) were used and each male was mated for 13days to two untreated virgin females. On days 14-16 after breeding, all the females were evaluated for incidence of pregnancy, live implants, and fetal deaths. Treatment with 1/4 LD50 of CCl4 induced positive dominant lethal mutation, reflecting a high rate of deformations in male germ cells. Interestingly, no dominant lethal mutations were recorded in females mated to male mice treated with CCl4 plus N. sativa. Under the experimental conditions of this study, our results highlight the beneficial role of N. sativa against CCl4-induced mutagenicity.

Radioecological problems of aquatic ecosystems of the chernobyl exclusion zone

The dynamics of the main contaminating radionuclides in the components of aquatic ecosystems within the Chernobyl APP exclusion zone is considered. The possible causes are analyzed for the marked increase in the specific activity of 90Sr in water and hydrobionts of the lakes at the dammed left bank of river Pripyat. Notable is the elevated frequency of chromosomal aberrations in the root meristems of aquatic higher plants (up to 17%) and in the embryonal tissues of gastropod mollusks (up to 27%), alterations in the hematological indices for gastropods, and high infestation of aquatic higher plants by parasitic fungi and gall arthropods in the most radiocontaminated reservoirs.

Approach to estimate mutagenic effect of polluted water by cytogenetic method on bioindicator species Asellus aquaticus (Isopoda)

Elevated frequency of chromosomal aberrations revealed by ana-telophase method in ponds and lakes corresponds to higher degree of anthropogenic pressure. Data obtained are compared with the influence of low-dose of ionizing radiation. Validity of the model for estimation of pollution degree and its mutagenic influence risk for human being is discussed.

Protective effect of quercetin and luteolin in human melanoma HMB-2 cells

Multifunctional effects of flavonoids are reported to be markedly connected with their structure and the functional groups in the molecule. The important role in the activity play C2–C3 double bond, hydroxyl group at C3 and the number of hydroxyl groups at phenyl ring (B). In this paper, the DNA protective free radical scavenging potential of quercetin (QU) and luteolin (LU) against H 2O 2 and their clastogenic effect alone and in combination with melphalan (MH) were investigated in human melanoma HMB-2 cells. Elevated frequency of chromosomal aberrations induced by MH, that at high doses have shown a variety of toxic side effects, was statistically decreased by studied flavonoids regarding to control (QU at the concentration of 50 μM and LU already at the concentration of 20 μM). The results concerning DNA protective potential against free radicals in HMB-2 cells demonstrated that QU and LU have significant effect in dose dependent manner. The percentage of QU protective effect is 40% at the concentration 20 μM, resp. 80% at the concentration 100 μM. Comparable values were obtained with LU. Results are correlated to their structural arrangement and organization of the hydroxyl groups.

XPD Lys751Gln Polymorphism and Etiology and Outcome of Childhood Acute Myeloid Leukemia.

Genetic polymorphism results in inter-individual variation in DNA repair capacity, and may in part account for susceptibility of a cell to genotoxic agents, and to malignancy. The DNA repair protein xeroderma pigmentosum complementation group D (XPD) is a major participant in the neucleotide excision repair pathway and is also involved in transcription initiation and in the control of cell cycle and apoptosis. Several studies have found associations between ineffective DNA repair and cancer risk. It is also thought that ineffective DNA repair may lead to additional genomic instability and tumors that are more aggressive. Several single nucleotide polymorphisms including an adenine to cytosine polymorphism leading to Lys751Gln in exon 23 of XPD have been shown to be associated with elevated frequency of chromosomal aberrations and variety of environmentally induced cancers in adults. We hypothesized that XPD polymorphism may play a role in causation of childhood AML. In addition, there are data that XPD polymorphism influences outcome of chemotherapy in adults with solid tumors. Therefore, we also evaluated its effect on outcome of AML therapy. Methods: 457 children treated for AML on CCG studies 2941 and 2961 (intensive induction with daunorubicin, idarubicin, Ara-C, 6-thioguanine, etoposide, dexamethasone, +/− fludarabine, Ara-C, idarubicin; consolidation with high-dose Ara-C and L-asparaginase or HLA-matched sibling BMT) were genotyped for XPD exon 23 polymorphism. Genotype frequencies were compared with published normal control frequencies. In addition, patient outcomes were analyzed according to genotype. Results: Comparison of gene frequencies in AML patients and reported normal controls showed similar frequencies (42.5% AA, 44.2% AC, 13.3% CC in patients vs. 44.2% AA, 45% AC, 10.8% CC in controls; p=0.54). There were no significant difference in OS (p=0.56), EFS (p=0.61), TRM (p=0.5) or relapse rate (p=0.88) between patients with 751AA genotype vs. 751AC/751CC genotypes, in contrast to reports in adult malignancies. Stratification of cases by age at diagnosis, white blood count at diagnosis, AML subtype, or cytogenetics revealed no difference in genotype frequencies. Conclusion: These data, representing the only data in pediatric AML, suggest that XPD genotype does not affect the etiology or outcome of childhood AML.

Genetic polymorphisms in DNA repair genes and possible links with DNA repair rates, chromosomal aberrations and single-strand breaks in DNA.

We analysed the associations between genetic polymorphisms in genes coding for DNA repair enzymes XPD (exon 23 A --> C, K751Q), XPG (exon 15 G --> C, D1104H), XPC (exon 15 A --> C, K939Q), XRCC1 (exon 10 G --> A, R399Q) and XRCC3 (exon 7 C --> T, T241 M) and the levels of chromosomal aberrations (CAs) and single-strand breaks (SSBs) in peripheral lymphocytes in a central European population. We also measured the irradiation-specific DNA repair rates and the repair rates of 8-oxoguanines in these individuals. An elevated frequency of CAs was observed in individuals with the XPD exon 23 A allele (AA and AC) genotypes (F = 3.6, P = 0.028, ANOVA). In multifactorial analysis of variance, the XPD exon 23 polymorphism appeared as a major factor influencing CAs (F = 4.2, P = 0.017). SSBs in DNA, on the other hand, were modulated by XPD (F = 4.3, P = 0.023), XPG (F = 4.3, P = 0.024) and XRCC1 genotypes (F = 3.0, P = 0.064). Irradiation-specific DNA repair rates (reflecting mainly base excision repair activity) were affected by XRCC1 (F = 5.9, P = 0.010) and XPC polymorphisms (F = 4.2, P = 0.046, MANOVA). Our results from this study suggest that markers of genotoxicity are associated with polymorphisms in genes encoding DNA repair enzymes.

Increased risk of cancer in radon-exposed miners with elevated frequency of chromosomal aberrations

In spite of the extensive use of cytogenetic analysis of human peripheral blood lymphocytes in the biomonitoring of exposure to various mutagens and carcinogens, the long-term effects of an increased frequency of chromosomal aberrations in individuals are still uncertain. Few epidemiologic studies have addressed this issue, and a moderate risk of cancer in individuals with an elevated frequency of chromosomal aberrations has been observed. In the present study, we analyzed data on 1323 cytogenetic assays and 225 subjects examined because of occupational exposures to radon (range of exposure from 1.7 to 662.3 working level month (WLM)). Seventy-five subjects were non-smokers. We found 36 cases of cancer in this cohort. Chromatid breaks were the most frequently observed type of aberrations (mean frequency 1.2 per 100 cells), which statistically significantly correlated with radon exposure (Spearman’s correlation coefficient R=0.22, P<0.001). Also, the frequency of aberrant cells (median of 2.5%) correlated with radon exposure (Spearman’s correlation coefficient R=0.16, P<0.02). Smoking and silicosis were not associated with results of cytogenetic analyses. The Cox regression models, which accounted for the age at time of first cytogenetic assay, radon exposure, and smoking showed strong and statistically significant associations between cancer incidence and frequency of chromatid breaks and frequency of aberrant cells, respectively. A 1% increase in the frequency of aberrant cells was paralleled by a 62% increase in risk of cancer ( P<0.000). An increase in frequency of chromatid breaks by 1 per 100 cells was followed by a 99% increase in risk of cancer ( P<0.000). We obtained similar results when we analyzed the incidence of lung cancer and the incidence other than lung cancer separately. Contrary to frequency of chromatid breaks and frequency of aberrant cells, the frequency of chromatid exchanges, and chromosome-type aberrations were not predictive of cancer.

Risk of cancer in an occupationally exposed cohort with increased level of chromosomal aberrations.

We used cytogenetic analysis to carry out a cohort study in which the major objective was to test the association between frequency of chromosomal aberrations and subsequent risk of cancer. In spite of the extensive use of the cytogenetic analysis of human peripheral blood lymphocytes in biomonitoring of exposure to various mutagens and carcinogens on an ecologic level, the long-term effects of an increased frequency of chromosomal aberrations in individuals are still uncertain. Few epidemiologic studies have addressed this issue, and a moderate risk of cancer in individuals with an elevated frequency of chromosomal aberrations has been observed. In the present study, we analyzed data on 8,962 cytogenetic tests and 3,973 subjects. We found a significant and strong association between the frequency of chromosomal aberrations and cancer incidence in a group of miners exposed to radon, where a 1% increase in frequency of chromosomal aberrations was followed by a 64% increase in risk of cancer (p < 0.000). In contrast, the collected data are inadequate for a critical evaluation of the association with exposure to other chemicals.

Enhancement of frequencies of restriction endonuclease-induced chromatid breaks by arabinoside adenine in normal human and ataxia telangiectasia cells

. The effect of ara A (9- beta -D-arabinofuranosyladenine) a potent inhibitor of DNA synthesis on the frequencies of chromatid breaks induced by restriction endonucleases (RE) has been investigated in normal human and ataxia telangiectasia (AT) lymphoblastoid cells. PvuII, PstI and BamHI, which cause blunt-ended, 3-overhang and 5-overhang cohesive-ended DNA double-strand breaks (dsb) respectively, were introduced into two AT cell lines (AT-KM and AT-PA) and a normal human (N-SW) cell line by the use of streptolysin-O poration. Controls were exposed to gamma -irradiation and similarly treated with or without ara A. Both AT cell lines were found to exhibit higher frequencies of chromatid breaks when treated with RE alone as compared with the normal cell line. The pattern of chromatid response to the three RE was shown to be similar in all three cell lines i.e. PvuII was most clastogenic while PstI and BamHI were both less effective at inducing chromosomal aberrations. Incubation of cells with ara A resulted in an increase in frequencies of chromatid breaks in PvuII and PstI treated cells but no increase was observed in BamHI treated cells. Normal cells showed most response to ara A following treatment with PvuII and PstI (enhancement ratios 4.63 and 3.75 respectively) while AT cells were affected by ara A to a lesser extent indicating a reduced expression of damage by ara A in these lines. Since ara A is a potent inhibitor of DNA synthesis, it was concluded from the elevated frequency of chromosomal aberrations in the presence of ara A that rejoining of RE-induced dsb in genomic DNA of human cells involves nucleotide insertion at dsb termini prior to ligation.

Characterization of the mus308 gene in Drosophila melanogaster.

Among the available mutagen-sensitive mutations in Drosophila, those at the mus308 locus are unique in conferring hypersensitivity to DNA cross-linking agents but not to monofunctional agents. Those mutations are also associated with an elevated frequency of chromosomal aberrations, altered DNA metabolism and the modification of a deoxyribonuclease. This spectrum of phenotypes is shared with selected mammalian mutations including Fanconi anemia in humans. In anticipation of the molecular characterization of the mus308 gene, it has been localized cytogenetically to 87C9-87D1,2 on the right arm of chromosome three. Nine new mutant alleles of the gene have been generated by X-ray mutagenesis and one was recovered following hybrid dysgenesis. Characterization of these new alleles has uncovered additional phenotypes of mutations at this locus. Homozygous mus308 flies that have survived moderate mutagen treatment exhibit an altered wing position that is correlated with reduced flight ability and an altered mitochondrial morphology. In addition, observations of elevated embryo mortality are potentially explained by an aberrant distribution of nuclear material in early embryos which is similar to that seen in the mutant giant nuclei.

Clastogenic activity of bile acids and organic acid fractions of human feces

Chloroform extracts of fecal material from 4 subjects on normal mixed western diets were fractionated to obtain an acid fraction and a hexane extract containing neutrals and bases. The acid fraction from at least 2 of the donors induced an elevated frequency of chromosomal aberrations and exchanges in Chinese hamster ovary (CHO) cells. Since acid steroids are expected to be present in the acid fraction, 5 bile acids were assayed for clastogenic activity in CHO cells. Ursodeoxycholic acid induced chromosomal aberrations and exchanges, and this effect was enhanced by the addition of a microsomal S9 mix. However, the enhancement is probably due to physical factors rather than to enzymatic activity.