Higher Incidence Of Chromosomal Aberrations Research Articles

Effect on Antioxidants and Chromosomal Aberrations in the Offspring of Methyl Isocyanate Exposed Population of Bhopal

Bhopal gas tragedy was one of the worst industrial disasters that produced short-term as well as long-term health effects in the exposed population. The present study is an attempt to know about the genomic damage as well as the level of antioxidant caused by Methyl Isocyanate in the offspring of the exposed population and to know about the frequency of chromosomal aberrations in them. Offspring’s of the Methyl Isocyanate Exposed individuals living in the vicinity of 1.5 km from the Union Carbide’s pesticide plant were selected randomly from the study. Equal number of age (20 years – 50 years), sex (male / female) and locality matched non-exposed individuals were also enrolled as controls. All the subjects were non smokers and not employed at any type of chemical industry or a radiation department. Cytogenetic analysis was performed by standard protocol of lymphocyte culture as per as Moorhead et al. Chromosomal aberrations were observed. The antioxidant level of Vitamin E and Blood Glutathione was also recorded. Student’s t-test was performed to test the significance difference between means of chromosomal aberrations. The means were considered to be statistically significant at 1% level of probability. It was observed that the level of antioxidants (both Vitamin E by Jargar et al. and Blood Glutathione by Beutler et al.) was highly significant in the MIC Exposed and MIC Exposed F2 Generation Population as compared to MIC Non-Exposed Population. But, significant difference between MIC Exposed and MIC Exposed F2 Generation Population was observed. The mean percentage of normal metaphase in the Exposed group was significantly higher (p < 0.0001) as compared to Non-Exposed. Besides this, chromosomal aberrations (dicentrics and double minutes) were recorded at mitotic metaphase and were statistically elevated in the MIC Exposed Population. The present study indicates that the genomic instability still persists at a higher intensity among the Bhopal Gas Survivors. The higher incidence of chromosomal aberrations may act as the intermediate processes in the pathway of the progression of any genetic disorders and cancers. Hence, our study suggests that the Exposed Populations and their Offspring’s is more vulnerable and gas affected.
 Keywords: Chromosomal aberrations, Methyl isocyanate, Bhopal gas tragedy, Long-term genotoxicity, Exposed Population

Molecular Genetic Abnormalities in the Pathogenesis of Hematologic Malignancies and Corresponding Changes in Cell Signaling Systems

Hematological disorders include a wide spectrum of malignancies of hematopoietic and lymphoid tissues. The genetic changes underlying the pathogenesis of the diseases are specific for each disease. High incidence of chromosomal aberrations (deletion, translocation, insertion) is one of the principal characteristics of oncohematological diseases. In addition, mutations in individual genes or blocking of normal regulation of gene functioning in relation to epigenetic events can occur. Progression of oncohematological diseases could be a result of accumulation of different genetic abnormalities. Modern classification of malignancies of hematopoietic and lymphoid tissues is based on the analysis of clinical data, morphological and functional characteristics of tumor cells and identification of specific cytogenetic and molecular-genetic changes. A large number of genetic abnormalities specific for certain types of hematological malignancies has been discovered to date. It allows to optimize the treatment strategy, as well as to design, test and introduce to the clinical practice a number of targeted drugs (inhibitors of chimeric proteins formed as a result of trans-locations and triggering the malignant cell transformation). Drugs based on monoclonal antibodies (Rituximab, Alemtuzumab, etc.) or low molecular weight compounds (Imatinib, Bortezomib, Carfilzomib) form this group of medications. The knowledge about not only specific gene abnormalities but also about the corresponding changes in cell efferent signaling pathways could be of great interest for the development of new targeted molecules or the repurposing of known chemotherapeutic agents. The present review compares genetic aberrations in diseases listed in the 2008 WHO classification (amended in 2016) of hematopoietic and lymphoid tissue malignancies and main changes in cell signaling pathways associated with malignant transformation of hematopoietic cells.

Evaluation of the serum catalase and myeloperoxidase activities in chronic arsenic-exposed individuals and concomitant cytogenetic damage

Chronic arsenic exposure through contaminated drinking water is a major environmental health issue. Chronic arsenic exposure is known to exert its toxic effects by a variety of mechanisms, of which generation of reactive oxygen species (ROS) is one of the most important. A high level of ROS, in turn, leads to DNA damage that might ultimately culminate in cancer. In order to keep the level of ROS in balance, an array of enzymes is present, of which catalase (CAT) and myeloperoxidase (MPO) are important members. Hence, in this study, we determined the activities of these two enzymes in the sera and chromosomal aberrations (CA) in peripheral blood lymphocytes in individuals exposed and unexposed to arsenic in drinking water. Arsenic in drinking water and in urine was used as a measure of exposure. Our results show that individuals chronically exposed to arsenic have significantly higher CAT and MPO activities and higher incidence of CA. We found moderate positive correlations between CAT and MPO activities, induction of CA and arsenic in urine and water. These results indicate that chronic arsenic exposure causes higher CAT and MPO activities in serum that correlates with induction of genetic damage. We conclude that the serum levels of these enzymes might be used as biomarkers of early arsenic exposure induced disease much before the classical dermatological symptoms of arsenicosis begin to appear.

Genotoxic assessment in peripheral blood lymphocytes of post-polio individuals using sister chromatid exchange analysis and micronucleus assay

Environmental pollution is a complex issue because of the diversity of anthropogenic agents, both chemical and physical, that have been detected and catalogued. The consequences to biota from exposure to genotoxic agents present an additional problem because of the potential for these agents to produce adverse change at the cellular and organism levels. Past studies in virus have focused on structural damage to the DNA of environmental species that may occur after exposure to genotoxic agents and the use of this information to document exposure and to monitor remediation. In an effort to predict effects at the population, community and ecosystem levels, in the present study, we attempt to characterize damage occurring through genotoxic agents like 5-bromo-2-deoxyuridine, BrdU, using sister chromatid exchange technique and the formation of micronuclei (MN) in the peripheral lymphocytes of the post-polio syndrome sequelae affected by poliovirus. Analysis of structural chromosomal aberrations (CAs) and involvement of the specific chromosome break were pursued in this study. They revealed a significantly higher incidence of CAs (chromatid and chromosome breaks) in patients compared with controls, where the specific chromosome break has emerged as specific. Also, the maximum numbers of breaks were found to be in chromosome 1 at the position 1p36.1. The results also suggest a correlation between CAs and content of MN.

Assessment of the genotoxicity of atenolol in human peripheral blood lymphocytes: Correlation between chromosomal fragility and content of micronuclei

The antihypertensive drug atenolol was found to induce chromosome loss, detected as micronuclei in the peripheral lymphocytes of treated patients. The fundamental question which chromosomes the micronuclei were derived from remains to be answered. Analysis of structural chromosomal aberrations (CAs) and expression of fragile sites (FS) were pursued in this study. They revealed a significantly higher incidence of chromosomal aberrations (chromatid and chromosome breaks) in patients compared with controls, where 10 FS emerged as specific. Also, the band 17q12–21, where known fragile sites have not been reported, was only expressed in atenolol-treated patients. Fluorescence in situ hybridization using chromosome-specific probes revealed the preferential involvement of chromosomes 7, 11, 17 and X in the micronuclei (MN) of patients. The results also suggest a correlation between chromosomal fragility and content of MN, and support the findings for a linkage between hypertension and a locus on chromosome 17.

Cataract in Occupationally Exposed Workers

Objective: The objective of this study was the determination of criteria for recognition of a presenile cataract as a professional disease in healthcare personnel exposed to small doses of ionizing radiation. Method: The study included 3240 health workers in the medical centers of Serbia in the period 1992–2002. A total of 1560 workers were employed in the zone (group A) and 1680 out of ionizing radiation zone (group B). From group A, two groups had been selected: 1. Group A–1: Health workers in the ionizing radiation zone who contracted lens cataract during their years of service while the dosimeter could not reveal higher absorbed doses (A–1 = 115); 2. Group A–2: Health workers in the ionizing radiation zone with higher incidence of chromosomal aberrations and without cataract (A–2 = 100). Results: More significant incidence of cataract was found in group A, χ 2 = 65.92; p < 0.01. Radiation risk was higher in health workers in radiation zone than in others, the relative risk is 4.6. Elevated blood sugar...

Successful Microinsemination of Rabbit Oocytes with Round Spermatids.

Although the first report for rabbit offspring by round spermatid injection (ROSI) has already been published in 1994, the production of rabbit ROSI offspring is considered difficult due to the high incidence of chromosomal aberrations. The ROSI oocytes need to be activated artificially because sperm-borne oocyte-activating factor, SOAF, is present in elongating spermatids and spermatozoa but not round spermatids, and metaphase-promoting factor, MPF, in the oocytes causes premature chromosome condensation in injected spermatid nuclei. The present study was designed to investigate the effect of oocyte activation regimens on developmental ability of rabbit ROSI oocytes. Round spermatid cells were isolated from seminiferous tubules of Japanese White rabbits (Kbs:JW) with proven fertility and resuspended in GL-PBS (PBS supplemented with 5.6 mM glucose, 5.4 mM sodium lactate and 0.01% PVP). Oocytes were recovered from oviductal ampullae of Kbs:JW females superovulated with 3 AU FSH and 75 IU hCG, and were freed from cumulus cell layers. An individual round spermatid was introduced into the denuded oocyte using a piezo-driven micromanipulator. For activation regimens, oocytes were subjected to 5-min treatment with 5-10 μM ionomycin in RPMI1640/DMEM (RD) medium 50 min before ROSI (Group-1; n=108) or 10 min after ROSI (Group-2; n=87), 50 min before and 10 min after ROSI (Group-3; n=82), or 50 min before and 10 min after ROSI followed by incubation for 1 h in the RD medium and subsequent 1 h in the RD medium supplemented with 5 mg/ml cycloheximide and 2 mM 6-dimethylaminopurine (Group-4; n=131). All activation treatments were performed at 38.5°C. Oocytes microinjected with ejaculated spermatozoa (intracytoplasmic sperm injection; ICSI) were served as controls (Group-5; n=163). The ROSI/ICSI oocytes were cultured in TCM199+20% fetal bovine serum for 22-24 h at 38.5°C in 5% CO2 in air. Oocytes cleaving to the 2-8 cell stage were selected for oviductal transfer to recipient rabbits. The activation regimens influenced cleavage rate of microinseminated oocytes (39, 29, 51, 68 and 60% in the Group-1, -2, -3, -4 and -5, respectively). The cleavage rate of ROSI oocytes in Group-4 (68%) was not significantly different from that of ICSI oocytes (60%), but higher than those of ROSI oocytes in the Group-1 (39%) and Group-2 (29%). However, proportions of advanced 4-8 cell-stage embryos among the cleaved ROSI embryos (45, 36, 43 and 52% in the Group-1, -2, -3 and -4, respectively) were significantly lower than that of ICSI embryos (67% in the Group-5). Caesarean section of recipient rabbits 4 weeks after the embryo transfer showed the presence of implantation signs in the Group-3 (2%) and Group-4 (9%), and full-term development only in the Group-4 (7%). The control ICSI (Group-5) resulted in implantation signs at 4% and full-term development at 8%. All the full-term offspring derived from the ROSI (n=6) / ICSI (n=8) appeared to be normal. In conclusion, rabbit ROSI oocytes were capable of developing into full-term when the oocytes were activated with a combined treatment of ionomycin and cycloheximide + 6-dimethylaminopurine.

Cytogenetic features of de novo CD5‐positive diffuse large B‐cell lymphoma: Chromosome aberrations affecting 8p21 and 11q13 constitute major subgroups with different overall survival

De novo CD5-positive diffuse large B-cell lymphoma (CD5(+)DLBCL) is regarded as a different clinicopathological entity from CD5-negative DLBCL (CD5(-)DLBCL) and mantle cell lymphoma (MCL). Because only a few published cytogenetic studies of de novo CD5(+)DLBCL are available, we investigated chromosomal changes in 23 Japanese patients who had de novo CD5(+)DLBCL. A characteristic of cytogenetic abnormalities in de novo CD5(+)DLBCL was a high incidence of chromosomal aberrations affecting 8p21 and 11q13. Major chromosomal breakpoints were concentrated at 8p21, 11q13, and 3q27. Patients with 8p21 aberrations showed aggressive clinical features, including advanced stage of disease, elevated serum LDH level, poor performance status, and an inferior survival curve compared with patients who had 11q13 changes (P = .043). Chromosomal abnormalities of both 8p21 and 11q13 were not observed in the same patient, and each abnormality showed different chromosomal gains and losses. These results indicate that de novo CD5(+)DLBCL may occur in previously unidentified subgroups that differ in their chromosomal abnormalities. The conflicting results of previous studies on prognosis may thus be explained in part by the differences in chromosomal changes.

ATR Enforces the Topoisomerase II-dependent G2 Checkpoint through Inhibition of Plk1 Kinase

An ATR-dependent G(2) checkpoint responds to inhibition of topoisomerase II and delays entry into mitosis by sustaining nuclear exclusion of cyclin B1-Cdk1 complexes. Here we report that induction of this checkpoint with ICRF-193, a topoisomerase II catalytic inhibitor that does not cause DNA damage, was associated with an ATR-dependent inhibition of polo-like kinase 1 (Plk1) kinase activity and a decrease in cyclin B1 phosphorylation. Expression of constitutively active Plk1 but not wild type Plk1 reversed ICRF-193-induced mitotic delay in HeLa cells, suggesting that Plk1 kinase activity is important for the checkpoint response to ICRF-193. G(2)/M synchronized normal human fibroblasts, when treated with ICRF-193, showed a decrease in cyclin B1 phosphorylation and Plk1 kinase activity despite high cyclin B1-Cdk1 kinase activity. G(2) fibroblasts that were treated with caffeine to override the checkpoint response to ICRF-193 displayed a high incidence of chromosomal aberrations. Taken together, these results suggest that ATR-dependent inhibition of Plk1 kinase activity may be one mechanism to regulate cyclin B1 phosphorylation and sustain nuclear exclusion during the G(2) checkpoint response to topoisomerase II inhibition. Moreover, the results demonstrate an important role for the topoisomerase II-dependent G(2) checkpoint in the preservation of human genomic stability.

Amplificación del oncogén ccnd1 y contenido celular de adn en los carcinomas epidermoides de cabeza y cuello

Cyclin d1 protein (encoded by the ccnd1 gene) contributes to the progression of the cell cycle in the g1/s checkpoint. Cyclin d1 overexpression (for instance as a consequence of ccnd1 amplification) might result in loss of control over genetic damage at this point and in an accumulation of chromosomal aberrations. In this work we analyze whether ccnd1 amplification is associated with a higher incidence of alterations in cellular Dna content. 31 squamous cell carcinomas of the head and neck were studied. ccnd1 amplification was determined by polymerase chain reaction. Cellular Dna content was determined by flow cytometry. ccnd1 amplification was found in 6 (19%) cases. Thirteen (42%) cases were diploid and 18 (58%) were aneuploid. Two (33%) of the 6 cases with ccnd1 amplification were aneuploid compared with 16 (64%) of the cases without ccnd1 amplification (P=0.36). We conclude that ccnd1 amplification is not associated to a higher incidence of chromosomal aberrations in squamous cell carcinomas of the head and neck.

Induction of chromosomal instability in mouse hemopoietic cells by fetal irradiation

Mice were exposed to 0.25–1.5 Gy of gamma radiation on day 14 or 17 of gestation and chromosomal aberrations were scored in the bone marrow at 12 months of age. Irradiation had resulted in low peripheral blood counts, while some animals developed very high leukocyte counts. Exposed animals showed a significant dose dependent increase in the number of aberrant metaphases, compared to unexposed animals. Fragments and polyploidy were the major types of aberrations. Mice with abnormally high blood leukocyte counts showed a higher incidence of chromosomal aberrations, especially high levels of polyploidy than in animals with low blood counts. It is concluded that radiation induced genomic instability in the fetal hemopoietic cells of mouse is transmitted to postnatal and adult bone marrow which may lead to the development of hematological disorders, including malignancies.

Increased frequency of congenital chromosomal aberrations in female partners of couples undergoing intracytoplasmic sperm injection.

We evaluated the frequency of congenital chromosomal aberrations in a sample of 305 couples included in an intracytoplasmic sperm injection (ICSI) programme. Twenty individuals (3.3%) with congenital chromosomal abnormalities could be identified. The following types of abnormalities were observed: reciprocal translocations (n = 7), Robertsonian translocations (n = 3), inversions (n = 3), other structural aberrations (n = 4) and sex chromosome aberrations (n = 3). The rate of chromosomally abnormal males (10/305, 3.3%) lay within the expected range for patients with reduced semen quality. Surprisingly, 50% (10/20) of all abnormal karyotypes were contributed by the female partner of ICSI patients. These data confirm the higher incidence of chromosomal aberrations in infertile populations as compared with the baseline population risk. Additionally, the data imply that in some cases of male factor infertility a hidden female chromosomal factor may be present, which cannot be identified by standard clinical evaluation. In conclusion, we recommend chromosomal analysis in both partners of couples undergoing ICSI treatment.

Cytogenotoxicities of sublimed urethane gas to the mouse embryo

Urethane (ethyl carbamate) which has long been used for commonly used drugs and has proven to be useful in the formation of products in every-day use, is volatile, and small amounts sublime spontaneously. Pregnant ICR mice were maintained in the vinyl chamber (45 liter) which was ventilated 4 times per hour. To inhale urethane gas, air was passed first through a glass bottle containing 500 g of crystalline urethane and then into the vinyl chamber. Concentration of the sublimed urethane gas in the chamber was 1.28 ± 0.08 mg/l, and sublimed urethane gas produced significantly high incidence of chromosomal aberrations in the cells of whole embryo, when mice inhaled it for 48 h from day 9 to day 11 of pregnancy. High and significant incidence of chromosomal aberrations (36.0%) was detected in the embryo 3 h after urethane gas inhalation, but decreased to 5.3% at 24 h after exposure and showed no significant differences from controls after 48 h, while the incidence in bone marrow cells from the adult (pregnan) mice was lower (21.5%) at 3 h after exposure but a significant increase remained until 72 h after exposure. A majority of chromosomal aberrations was chromatid types. As a consequence of cellular damages by urethane gas inhalation during pregnancy, significantly high incidence of fetal deaths and congenital malformations (cleft palate, polydactyl, tail anomaly etc.) was induced in the offspring. Thus, we must be aware of the risk of volatile chemicals, because it is difficult to perceive and avoid hazardous exposure via respiration.

Cytogenetic damage and occupational exposure: II. Exposure to petroleum exhaust.

A cytogenetic survey was conducted on personnel exposed to petroleum exhaust fumes (vapour and smoke at automobile workshops). The incidence of chromosomal aberrations (CAs) in this population was evaluated. A total of 1.15 +/- 0.22 aberrations were encountered in the exposed group as compared with 0.47 +/- 0.12 aberrations in the age matched controls. The increase in CAs in the exposed group was highly significant (P < 0.01, test of variance). A strongly positive correlation between increasing exposure duration and a higher incidence of CAs was apparent. No stratification for a higher incidence of CAs on the basis of smoking and/or alcoholic habits could be made in the exposed group.

Cytogenetic damage in peripheral blood lymphocytes of cancer patients prior to radiotherapy

In a study comprised of 79 cancer patients selected for determining chromosomal damage to peripheral blood lymphocytes before, during, and after radiotherapy, four patients revealed chromosome aberrations prior to radiotherapy in 5% of the cells examined. The most common anomalies were dicentric chromosomes and translocations of unidentified chromosomal material on the long or short arm. We attribute this high incidence of chromosomal aberrations before radiotherapy to a combination of various external factors that are known to cause such cytogenetic injury.

Clastogenic effect of pesticides in peripheral lymphocytes of cotton-field workers

We studied clastogenic effects in peripheral lymphocytes of cotton-field workers who were exposed to different pesticides. All the cells were grown in RPMI 1640 medium for 48 and 72 h. The type of aberrations observed in the exposed group are gaps, breaks, dicentrics, exchanges, rings and polyploidy. The frequency of total chromosomal aberrations increased significantly in male pesticide applicators when compared to controls. A significant decrease in mitotic index was observed in the exposed group as compared to the control group. The 48-h cultures showed high incidence of chromosomal aberrations and low mitotic index when compared to 72-h cultures. The difference in chromosomal aberrations between 48- and 72-h cultures was not significant. 24 out of 26 individuals showed ill health effects such as severe giddiness and nervous disorders.

Cytogenetic effects of pulsing electromagnetic field of human lymphocytes in vitro: chromosome aberrations, sister-chromatid exchanges and cell kinetics

Exposure of human lymphocyte cultures to a pulsing electromagnetic field (PEMF; 50 Hz, 1.05 mT) for various duration (24, 48 and 72 h) resulted in a statistically significant suppression of mitotic activity and a higher incidence of chromosomal aberrations. Furthermore, the shorter exposure times (24 and 48 h) did not cause a significant delay in cell turnover (cell proliferation index) or an increase in the baseline frequency of sister-chromatid exchanges (SCE). However, cultures continuously exposed to PEMF for 72 h exhibited significant reduction of the cell proliferation index (CPI) and an elevation of SCE rate. The results suggest that exposure to PEMF may induce a type of DNA lesions that lead to chromosomal aberrations and cell death but not to SCE, except probably at longer exposure times.

Chromosomal abnormalities in a selected population in Kurume.

Chromosomal aberrations were evaluated between 1974 and 1987 in 1077 individuals, consisting of 1042 pediatric patients and 35 adults who visited Kurume University Medical Center. Chromosomal aberrations were detected in 187 out of the 1042 (18%) children. These 187 children exhibited at least 108 types of symptoms or syndromes which were suggestive of chromosomal aberrations. Chromosomal aberrations were suspected in 757 pediatric patients who presented with 22 types of symptoms or syndromes. Among these 757, a total of 187 patients with chromosomal aberrations were identified, resulting in an overall incidence of 24.7% (187/757). Autosomal aberrations were demonstrated in 150 out of 672 children in whom autosomal aberrations had been suspected, yielding a detection ratio of 22.3% (150/672), whereas sex chromosome aberrations were found in 37 patients out of 85 who were suspected of possible sex chromosome aberrations, with a detection rate of 43.5% (37/85). The detection rate of chromosome aberrations was almost 20 to 30 times higher than that in the random surveys carried out by others in general newborn populations. This high detection rate suggests that a high incidence of chromosomal aberrations may be encountered in medical centers to which patients at risk with respect to chromosomal aberration syndromes are referred by local physicians. Chromosomes were analyzed also in a total of 37 adults, consisting of 26 women and 9 men, who had had abortions. The age at which abortions had occurred ranged from 23 to 39 years in women, and 25 to 35 years in men, respectively. Twelve women and 6 men out of the 35 people exhibited normal karyotypes. The satellite associations of D group and G group chromosomes were observed in 15 out of the 35 people.

Chromosome aberrations in 500 couples referred for in-vitro fertilization or related fertility treatment.

Cytogenetic studies were performed in 500 couples referred for in-vitro fertilization or gamete (zygote) intra-Fallopian transfer. Thirteen individuals (1.3%) with chromosomal abnormalities were found. Four major types of anomalies were observed: reciprocal translocations (n = 3), inversions (n = 2), iso-Xq chromosomes (n = 2) and sex chromosome number mosaics (n = 4). Moreover two males with respectively a 47,XYY and a 47,XY,mar+ karyotype were identified. These data pointed to a higher incidence of chromosomal aberrations in this infertile population as compared to a neonatal population without obvious chromosomal pathology. Analysis of the chromosomes which were involved in hyperdiploidy and hypodiploidy in the 30,000 metaphases evaluated, showed a high proportion of cells that had lost or gained an X-chromosome. A puzzling finding was the statistically significant low incidence of 45,X metaphases (0.9%) in women of couples treated on andrological indication as compared to the frequency of 45,X chromosome complements in women with tubal disease (4.0%) or of couples with an idiopathic (4.3%) or mixed female and male (6.7%) indication.

True breeding tobacco lines with new morphological phenotypes obtained from X-Irradiated protoplasts

Tobacco (Nicotiana tabacum) plants regenerated from dihaploid and amphidiploid (normal) protoplasts after X-irradiation showed several morphological alterations in vegetative and reproductive organs. The inheritance of these alterations was followed in sexual progeny. Despite a high incidence of chromosomal aberrations in the M1 plants, true breeding lines with specific morphological alterations were obtained. The utilization of such lines for the elucidation of the control mechanisms regulating morphogenesis is discussed.