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At least 19 recordsLinked to original sources
PubMed1997

The in vitro micronucleus test: a multi-endpoint assay to detect simultaneously mitotic delay, apoptosis, chromosome breakage, chromosome loss and non-disjunction.

Genotoxicity testing aims to detect a large range of genetic damage endpoints and evaluate such results in context of cell survival. The cytokinesis block micronucleus test offers the advantage to provide simultaneously information on both cell cycle progression and chromosome/genome mutations. Indeed, 1. frequencies of cytokinesis-blocked binucleated cells (and polynucleated) are good estimators of the mitotic rate; 2. frequencies of apoptotic figures in mononucleated and binucleated cells provide a measure for cell death before or after cell division; 3. combination of fluorescence in situ hybridization (FISH) for centromere/telomeres and micronucleus scoring allows discrimination between clastogenic and aneugenic events; 4. detection of FISH signals for chromosome specific sequences in both macronuclei and micronuclei, discriminates between aneuploidy due to chromosome non-disjunction or to chromosome loss. The cytokinesis block in vitro micronucleus test is thus a cytogenetic multi-test providing mechanistic information with a simple, rapid, objective, microscopical analysis.

Apoptosis↗
PubMed1999

FISH analysis of 1cen-1q12 breakage, chromosome 1 numerical abnormalities and centromeric content of micronuclei in buccal cells from thyroid cancer and hyperthyroidism patients treated with radioactive iodine.

One of the health consequences of the Chernobyl nuclear power plant accident was a radioactive iodine-related increase in the incidence of thyroid cancer in exposed children. This radioisotope is used in the treatment of thyroid cancer and hyperthyroidism patients providing a convenient opportunity to study cytogenetic damage induced by known doses of radioactive iodine in treated patients. We used pancentromeric FISH on micronuclei and chromosome 1 tandem labelling FISH to monitor overall chromosome breakage and loss, 1q12 breakage and decondensation and chromosome 1 numerical abnormalities in buccal cells from 31 radioactive iodine-exposed hyperthyroidism and thyroid cancer patients. The overall outcome of the study, with 250,000 buccal cells analysed, is that there was no radioactive iodine-related increase in the frequency of micronuclei, 1q12 breakage, 1q12 decondensation or chromosome 1 numerical abnormalities. In addition, neither age nor gender, health status nor radioactive iodine dose modulated the frequency of the above cytogenetic end points. Although several uncertainties of these emerging molecular cytogenetic methodologies will require further experimentation, we conclude that, at the reported exposure levels, radioactive iodine did not induce detectable chromosome damage in buccal cells from treated patients.

Adult↗
PubMed1980

Tumor incidence and development of autoimmune hemolytic anemia in two breeding lines of the NZB mouse strain that differ in chromosome breakage.

Increased chromosome breakage observed in NZB mice was studied. Breeding experiments with mice selected according to breakage frequencies provided evidence that the proportion of mice with high breakage (HB) and low breakage (LB) figures in the progeny depends on the phenotype of the parents. Selective breeding for the "chromosome breakage" characteristic was successful and resulted in the separation of a breeding line with LB incidence. However, the selection could not be continued beyond the fourth generation for the mice with HB incidence because of lethal factors. Comparative studies of HB mice from the HB line and LB mice from the LB line showed significant differences for tumor incidence and positivity of the Coombs' test.

Age Factors↗
PubMed1987

A conserved nucleotide sequence at the sites of developmentally regulated chromosomal breakage in Tetrahymena.

Chromosomal breakage occurs at hundreds of specific sites in Tetrahymena, including the two ends of the unique ribosomal RNA genes, during the development of the somatic macronucleus. We have identified a 15-nucleotide sequence that occurs widely in the germinal micronuclear genome and is associated exclusively with chromosomal breakage sites. When copies of this sequence were cloned and analyzed, they were found in all cases to be located at or very near sites of breakage. This general rule is further supported by the observation that in a different site in which a single nucleotide substitution is found within this sequence, no chromosomal breakage occurs. The complete sequence structure of one of the breakage junctions has also been determined in both the germinal DNA and the two somatic DNA termini. This structure reveals that the 15-nucleotide conserved sequence is located within a 54-nucleotide region that is removed following chromosomal breakage.

Animals↗
PubMed1997

Chromosomal instability in a woman with infertility and two unaffected brothers: a new familial chromosomal breakage syndrome?

Repeated chromosomal analysis of peripheral blood lymphocytes and skin fibroblasts from a woman referred for amenorrhoea, streak gonads, hyperthyroidism, adiposity and elevated alpha-fetoprotein levels but no other manifestations of known chromosomal breakage syndromes demonstrated an increased spontaneous chromosomal breakage rate (ISCBR). Chromatid and chromosomal breaks were more numerous than sporadic rearrangements and dicentric chromosomes. Exposure of the cells to mitomycin C, diepoxybutane, X-rays or UV irradiation induced an increase in chromosomal and chromatid abnormalities over that in controls. A micronucleus assay demonstrated an increase in the incidence of formation of micronuclei and the population doubling time of the fibroblasts of the proposita was delayed. Chromosomal analysis was performed on lymphocytes of the parents and of five sibs of the proposita. Two brothers had chromosomal abnormalities identical to those of the patient and elevated alpha-fetoprotein levels, however, without any clinical abnormalities. The parents were affected by only a moderate ISCBR whereas two brothers and one sister were chromosomally normal. The clinical, chromosomal and biochemical findings in this family represent a novel chromosomal instability syndrome.

Adult↗
PubMed1997

Induction of micronuclei, hyperdiploidy and chromosomal breakage affecting the centric/pericentric regions of chromosomes 1 and 9 in human amniotic fluid cells after treatment with asbestos and ceramic fibers.

This article describes the induction of micronuclei, hyperdiploidy and chromosome breakage in human amniotic cells in vitro by amosite, chrysotile and crocidolite asbestos, and ceramic fibers. The response of human (amniotic fluid cells) and rodent (Syrian hamster embryo fibroblasts, SHE) cells to fiber treatment was compared using the micronucleus assay. The data of the rodent studies were taken from a previous investigation (Dopp, E. et al. (1995) Environ. Health Perspect., 103, 268-271). All types of mineral fibers caused a significant increase of micronucleated cells. The kinetochore analysis revealed that all three types of asbestos and ceramic fibers yielded similar effects. Approximately 50% of the induced micronuclei were kinetochore-negative indicating formation through clastogenic events. Human amniotic cells were much less susceptible than SHE cells to the induction of micronuclei by mineral fibers. This again demonstrates that SHE cells are more susceptible to chromosomal changes than human amniotic fluid cells. The application of fluorescence in situ hybridization (FISH) with tandem DNA probes yielded more detailed information about specific structural chromosome aberrations in the 1 (cen-q12) and 9 (cen-q12) regions and about abnormal numbers of chromosomes in interphase human amniotic fluid cells. Using this FISH approach we found a statistically significant increase of chromosomal breakage in the pericentric heterochromatin regions of chromosomes 1 and 9 in interphase human amniotic cells after exposure to asbestos and ceramic fibers compared to control cells. The number of hyperdiploid cells was also significantly increased. Our results show that asbestos fibers as well as ceramic fibers are inducers of structural and numerical chromosomal aberrations in human amniotic fluid cells.

Amniotic Fluid↗
PubMed1976

Chromosome breakage in low birth weight newborns.

The frequency of chromosome aberrations in cells cultured from umbilical cord blood was determined for 50 low birth weight (LBW) and 50 normal birth weight (NBW) euploid newborns matched for sex, race, and maternal age. The metaphase spreads had been prepared in the course of an earlier study of frequency of aneuploidy and results are from 72-h cultures, i.e., presumably, at the second division in vitro. There were no significant differences between the two groups in the frequency of cells with chromosome breakage, chromosome gaps, or hyperdiploid cells. There was, however, a significantly higher frequency of hypodiploid cells in the LBW group. The present findings differ from those of others who have reported an increase in chromosome breakage in premature newborns.

Body Weight↗
PubMed2000

A long stringent sequence signal for programmed chromosome breakage in Tetrahymena thermophila.

Programmed chromosome breakage occurs at 50-200 specific sites in the genome of Tetrahymena thermo-phila during somatic nuclear (macronuclear) differentiation. Previous studies have identified a 15 bp sequence, the Cbs (for chromosome breakage sequence), that is necessary and sufficient to specify these sites. In this study we determined the effects of mutations in the Cbs on its ability to specify the chromosome breakage site and promote new telomere formation in conjugating cells. Twenty-one constructs with single nucleotide substitutions covering all 15 positions of the Cbs were made and tested. Fourteen of them (covering 11 positions) abolished breakage entirely, six (covering six positions, including the remaining four) caused partial loss of breakage function and one showed no detectable effect. This result indicates that the Cbs has an exceptionally long and stringent sequence requirement. It offers no evidence that the Cbs contains a separate domain for promoting new telomere formation. In addition, we found that a partially functional Cbs retained in the macronucleus does not induce chromosome breakage during vegetative growth and that excess copies of this germline-specific sequence in the somatic nucleus have little deleterious effect on cell growth.

Animals↗
PubMed1979

The influence of culture medium composition on the incidence of chromosomal breakage.

In patients with chromosomal instability and healthy subjects, significant differences were observed in the chromosomal breakage incidence in simultaneous lymphocyte cultures set up with TC medium 199, Eagle's Minimum Essential Medium, or RPMI, or RPMI 1629. The importance of the choice of culture medium for mutagenicity testing and studies of so-called spontaneous breakage is shown. Cultures incubated with TC Medium 199 showed the highest chromosomal breakage incidence.

Ascorbic Acid↗
PubMed2001

5-azacytidine induces chromosomal breakage in the root tips of wheat carrying the cuckoo chromosome 4S(L) from Aegilops sharonensis.

The cuckoo chromosome 4S(L) from Aegilops sharonensis is preferentially transmitted when introduced by hybridization into common wheat, Triticum aestivum. Gametocidal (Gc) factors carried in 4S(L) induce chromosome breakage in meiospores not containing them, ensuring their transmission to the progeny. Chromosome breakage and break-fusion-bridge (BFB) cycles can also be observed during early embryo sac development of chromosome 4S(L) addition lines to wheat, often leading to the presence of dicentric chromosomes in the subsequent progeny. However, the process responsible for inducing the primary chromosomal breaks only appears to occur during the initial divisions of the embryo and endosperm. In the presence of chromosome 4S(L), treatment with the hypomethylating agent 5-azacytidine induces chromosome breakage in root tips. This suggests that the process of chromosome fragmentation, induced by the Gc factors during early seed development, is repressed at later stages by DNA methylation.

Anaphase↗
PubMed1996

New telomere formation coupled with site-specific chromosome breakage in Tetrahymena thermophila.

Programmed chromosome breakage occurs in many ciliated protozoa and is accompanied by efficient new telomere formation. In this study, we have investigated the relationship between programmed chromosome breakage and telomere formation in Tetrahymena thermophila. Using specially constructed DNA clones containing the breakage signal Cbs in transformation studies, we have determined the locations of telomere addition around the breakage sites. They occur at variable positions, over 90% of which are within a small region (less than 30 bp) starting 4 bp from Cbs. This distribution is independent of the nucleotide sequence in the region or of the orientation of Cbs. In five of six cases determined, these sites occur at or before a T, and in the remaining case, the site occurs at or before a G. When sequences devoid of G or T are placed in this region, telomere addition still occurs within the region to maintain a similar distance relationship with Cbs. This efficient and healing process appears to be associated specifically with Cbs-directed breakage, since it does not occur when DNA ends are generated by restriction enzyme digestion. These results suggest a strong mechanistic link between chromosome breakage and telomere formation.

Amino Acid Sequence↗
PubMed2004

Lack of spontaneous and radiation-induced chromosome breakage at interstitial telomeric sites in murine scid cells.

Interstitial telomeric sites (ITSs) in chromosomes from DNA repair-proficient mammalian cells are sensitive to both spontaneous and radiation-induced chromosome breakage. Exact mechanisms of this chromosome breakage sensitivity are not known. To investigate factors that predispose ITSs to chromosome breakage we used murine scid cells. These cells lack functional DNA-PKcs, an enzyme involved in the repair of DNA double-strand breaks. Interestingly, our results revealed lack of both spontaneous and radiation-induced chromosome breakage at ITSs found in scid chromosomes. Therefore, it is possible that increased sensitivity of ITSs to chromosome breakage is associated with the functional DNA double-strand break repair machinery. To investigate if this is the case we used scid cells in which DNA-PKcs deficiency was corrected. Our results revealed complete disappearance of ITSs in scid cells with functional DNA-PKcs, presumably through chromosome breakage at ITSs, but their unchanged frequency in positive and negative control cells. Therefore, our results indicate that the functional DNA double-strand break machinery is required for elevated sensitivity of ITSs to chromosome breakage. Interestingly, we observed significant differences in mitotic chromosome condensation between scid cells and their counterparts with restored DNA-PKcs activity suggesting that lack of functional DNA-PKcs may cause a defect in chromatin organization. Increased condensation of mitotic chromosomes in the scid background was also confirmed in vivo. Therefore, our results indicate a previously unanticipated role of DNA-PKcs in chromatin organisation, which could contribute to the lack of ITS sensitivity to chromosome breakage in murine scid cells.

Animals↗
PubMed1994

Chromatin structure determines the sites of chromosome breakages in Plasmodium falciparum.

Spontaneous chromosome breakages are frequently observed in the human malaria parasite Plasmodium falciparum and are responsible for the generation of novel phenotypes, which may contribute to the pathogenicity and virulence of this protozoan parasite. The identification of a hot spot of chromosome breakage within the coding region of the KAHRP gene revealed that these events do not occur randomly but follow a regular pattern with a periodicity of 155 bp. This phasing corresponds to the average repeat unit of P. falciparum nucleosomes. Furthermore, breakage events preferentially occur within the linker regions of nucleosomes, as demonstrated by mapping endonuclease hypersensitive sites of chromatin. These data suggest that, in P. falciparum, the chromatin structure is involved in the molecular process of chromosome breakage, a mechanism that may be common in other eukaryotes.

Animals↗
PubMed1986

A chromosomal breakage syndrome with profound immunodeficiency.

The chromosomal breakage syndromes--ataxia-telangiectasia, Fanconi's anemia, and Bloom's syndrome--are associated with growth failure, neurologic abnormalities, immunodeficiency, and an increased incidence of malignancy. The relationship between these features is unknown. We recently evaluated a 21-year-old female with more severe chromosomal breakage, immunodeficiency, and growth failure than in any of the mentioned disorders. As of November 1985, the patient remains clinically free of malignancy. At age 18, the patient's weight was 22.6 kg (50th percentile for seven years), height was 129 cm (50th percentile for eight years), and head circumference was 42 cm (50th percentile for six months). Laboratory studies demonstrated a marked decrease in both B and T cell number and function. The peripheral blood contained 400 to 900 lymphocytes/microL with 32% T11 cells, 17% T4 cells, and 21% T8 cells. The proliferative responses to phytohemagglutinin (PHA), pokeweed mitogen, and concanavalin A were less than 10% of control. There were 1% surface IgM positive cells, and serum IgG was 185 mg/dL, IgM 7 mg/dL, IgA 5 mg/dL. In lymphocyte cultures stimulated with the T cell mitogens PHA, phorbol ester, and interleukin 2, 55% of the banded metaphases demonstrated breaks or rearrangements. The majority of the breaks involved four fragile sites on chromosomes 7 and 14, 7p13, 7q35, 14q11, and 14q32. These are the sites of the genes for the T cell-antigen receptor and the immunoglobulin heavy chain and are sites of gene rearrangement in lymphocyte differentiation. Epstein-Barr virus stimulated B cells and fibroblast cultures also demonstrated a high incidence of breaks, but the sites were less selective. These findings suggest that the sites of chromosomal fragility in the chromosomal breakage syndromes may be informative and that factors other than the severity of the immunodeficiency or the high incidence of chromosomal damage may contribute to the occurrence of malignancy in the chromosomal breakage syndromes.

Adult↗
PubMed1983

The mei-9a test for chromosome loss in Drosophila: a review of assays of 21 chemicals for chromosome breakage.

In Drosophila, detection of chemical-induced chromosome breakage for many compounds in conventional chromosome loss or reciprocal translocation (RT) tests requires considerably higher concentrations than for sex-linked recessive lethals, or fails entirely even at concentrations giving substantial to high rates of recessive lethals. Accordingly, relatively high LDs may be necessary before evidence of chromosome breakage is observed raising questions of "false positives" resulting, for example, from aberrant metabolic effects/products not found at lower concentrations. In the test for chromosome loss, definitive scoring is made in F1 progeny. In contrast, an F2 and often an F3 is required to bring the RT test to completion. Further, the RT test is prone to "false negatives" in many cases unless testing is carried out on sperm stored in the female for several days (or longer). Accordingly, efforts in this laboratory have been directed toward improvements in the sensitivity of the test for chromosome loss. Major advances have been made by using excision repair deficient mei-9a females as P1 females to which treated males are mated. For purposes of testing, ring-X males carrying the doubly marked Y chromosome, BSYy+, were treated or not, mated for 3 days with ordinary (repair-proficient) females (the conventional test) or with mei-9a females (the mei-9a test) and all P1s discarded. Data are reported for this period only--viz, on unstored sperm. F1 progeny were scored for complete loss (CL) of the X or Y (loss is principally of the ring-X) and partial loss of the Y (PL)--viz, loss of BS or y+. Partial loss of the Y chromosome was taken as strong evidence of chromosome breakage, whereas loss of the ring-X was regarded alternatively as break-related or resulting from the production of sister chromatid exchanges. Of the 21 compounds tested, 17 are classified as carcinogens and four are unknown in this regard. At the concentration reported, 21/21 compounds were positive for CL+PL and 21/21 for PL in the mei-9a test. At the same concentration, only 10/20 compounds were positive for CL and PL and 2/21 compounds for PL with repair proficient females; the mei-9a test is clearly more sensitive than the conventional test for chromosome breakage.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Recent advances in chromosome breakage syndromes and their diagnosis.

Chromosome instability is a characteristic cytogenetic feature of a number of genetically determined disorders collectively called as the chromosome breakage syndromes or DNA-repair disorders. They are characterized by susceptibility to chromosomal breakages, increased frequency of breaks and interchanges occurring either spontaneously or following exposure to various DNA-damaging agents. These diseases are a group of genetic disorders sharing a number of features. They are all autosomal recessive, show an increased tendency for chromosomal aberrations and to develop malignancies. The principal diseases in this group having a diverse etiology and clinical manifestations include Fanconi anemia (FA), ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), Bloom syndrome (BS), xeroderma pigementosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The underlying defect in these syndromes is the inability to repair a particular type of DNA damage. A number of repair disorder phenotypes are caused by more than one gene. The diagnosis of these syndromes is made by the characteristic clinical features specific to each disease, but the definitive diagnosis is achieved by laboratory investigations such as cytogenetic, biochemical and molecular methods. The importance of prenatal diagnosis and our experience are discussed in this article.

Ataxia Telangiectasia↗
PubMed1983

Folic acid and chromosome breakage. I. Implications for genotoxicity studies.

Chromosome breakage is significantly lower in culture medium containing folic acid than in medium that does not. This effect is similar to that observed in studies of chromosome fragile sites and suggests that fragile sites and some types of chromosome breakage may share a common mechanism. It also suggests that high non-physiological levels of folic acid in many commonly used culture media may artifactually decrease chromosome breakage.

Cells, Cultured↗