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PubMed1989

Co-administration of ascorbic acid with cyclophosphamide (CPA) to pregnant mice inhibits the clastogenic activity of CPA in preimplantation murine blastocysts.

Cyclophosphamide (CPA) administered at a dose of 15 mg/kg body weight to pregnant inbred CBA/CaH mice 60 h after copulation significantly elevated the incidence of structural chromosomal aberrations and sister-chromatid exchanges in 96 h blastocysts. When ascorbic acid (800 mg/kg body weight) was co-administered with CPA (15 mg/kg) using different injection sites, the incidence of structural chromosomal aberrations and the number of aberrant metaphases were significantly lower as compared to the CPA-exposed embryos, but still significantly higher than untreated controls. Sister-chromatid exchanges were not significantly different in embryos exposed to CPA only when compared to those exposed to CPA and ascorbic acid. In terms of the developmental potential of embryos, pregnant mice injected with both CPA and ascorbic acid had significantly fewer resorptions per mouse, and a significantly higher number of viable fetuses retrieved on the 18th day of gestation when compared to mice injected with CPA alone. The data in this study demonstrate that the co-administration of ascorbic acid with CPA to pregnant mice ameliorates the CPA-induced clastogenicity and improves the developmental potential of these embryos. This study suggests that some of the CPA-induced genotoxicity is due to the generation of reactive oxygen molecules, but further research is necessary before this can be firmly concluded.

Animals↗
PubMed2005

Chromosomal fragility, structural rearrangements and mobile element activity may reflect dynamic epigenetic mechanisms of importance in neurobehavioural genetics.

Advances in human genome analyses have not yet allowed identification of specific genetic mechanisms underlying the expression of human neurobehavioural disorders. There is an increasing awareness that several genes may contribute to behavioural phenotypes and these genes appear to interact in as yet undetermined ways. It has been suggested that the problem needs elucidation from an epigenetic, gene expression perspective. Cytogenetic instability manifesting as chromosomal fragile sites, translocations, duplications, deletions and inversions, when co-occurring with neurobehavioural disorders, may offer a doorway to the investigation of such chromatin level, regulatory region, epigenetic processes. Due to earlier indications of non-specificity of chromosomal aberrations, poor phenotype:genotype correlations and a shift to analysing candidate coding regions on high resolution map level, the only utility of chromosomal breakpoints came to be seen as harbouring possible candidate genes of interest when segregating together with particular neurobehavioural disorders. More recent findings of the expression of highly specific subsets of fragile sites in association with Tourette and Rett syndromes need to be extended to other neurobehavioural disorders to ascertain whether observed patterns can be considered representative of 'chromatin endophenotypes' correlating with discrete sets of neurobehavioural symptoms. Environmental/epigenetic factors could affect the chromatin characteristics of the genome arising through DNA strand breakage, mobile element activity and retroinsertion, establishing new architectural features of regulatory control networks very rapidly in comparison to coding region evolution rates. Microarray-based techniques for the genome-wide mapping of in vivo protein-DNA interactions offer increasingly comprehensive views of genetic and epigenetic regulatory networks. It may be informative to include functionally significant chromatin structural variation analyses when considering candidate genes for neurobehavioural disorders.

Cell Cycle↗
PubMed2000

Gene structure and chromosomal mapping of human epithelial calcium channel.

The epithelial Ca(2+) channel, ECaC, represents the rate-limiting step of vitamin D(3)-regulated Ca(2+) (re)absorption in kidney and intestine, and provides, therefore, a new candidate gene for Ca(2+)-related disorders. To supply the basis for direct mutation analysis, we report here the structure of the human ECaC gene (ECAC1(2)). It consists of 16 exons spanning 25 kb with introns ranging from 98 to 8500 bp. The 5'-flanking region of ECAC1 contains four putative vitamin D(3)-responsive elements. At positions -92 and -13 transcription initiation sites were identified, but the former lacks the canonical TATA or CAAT boxes. ECAC1 was mapped to chromosome 7q35 by fluorescent in situ hybridization, reassigning a previous radiation hybrid mapping to 7q31.1-2. The gene of a recently identified rat intestine homologue of ECaC, named Ca(2+) transporter 1, was found juxtaposed to the ECaC gene, indicating that both genes are the products of evolutionary local gene duplication.

Amino Acid Sequence↗
PubMed2001

Application of molecular cytogenetic techniques in a case study of human cutaneous metastatic melanoma.

Consistent structural chromosome rearrangements have rarely been identified in adult solid tumors. The introduction of advanced molecular cytogenetic techniques has provided new ways of analyzing highly complex karyotypes commonly encountered in these malignancies. This study describes a detailed molecular cytogenetic analysis of a sporadic human cutaneous melanoma biopsy, M92-047, using a combination of G-banding, fluorescence in situ hybridization (FISH), chromosome microdissection, and comparative genomic hybridization (CGH). G-banding revealed that this tumor was composed primarily of closely related near-diploid and near-tetraploid cell subpopulations containing several clonal numerical and structural chromosome alterations. Fluorescence in situ hybridization using whole chromosome painting probes and chromosome arm painting probes, was employed to verify the rearranged chromosomes; dic(1;4), der(8)t(1;8), and der(15)t(6;15), whereas marker chromosomes dic(8;1;16), der(12)t(9;12), and der(17)t(13;17) were discerned by chromosome microdissection and subsequent reverse in situ hybridization (rev ish) analysis. Comparative genomic hybridization illustrated DNA copy number changes in good agreement with the karyotypic analysis. Although this line exhibits recurrent alterations representative of melanoma, two unique breakpoints--1p13 and 8p21--were identified in two different rearranged chromosomes, suggesting potentially important regions for further dissection by molecular genetic techniques. This report demonstrates the advantages of combining multiple techniques in order to obtain a detailed description of cytogenetic changes in melanoma.

Aged↗
PubMed2006

A unique configuration of genome-wide DNA methylation patterns in the testis.

In the mammalian lifecycle, the two periods of genome-wide epigenetic reprogramming are in the early embryo, when somatic patterns are set, and during germ cell development. Although some differences between the reprogrammed states of somatic and germ cells have been reported, overall patterns of genomic methylation are considered to be similar. Using restriction landmark genomic scanning to examine approximately 2,600 loci distributed randomly throughout the genome, we find that the methylation status of testicular DNA is highly distinct, displaying eightfold the number of hypomethylated loci relative to somatic tissues. Identification and analysis of >300 loci show that these regions are generally located within nonrepetitive sequences that are away from CpG islands and 5' regions of genes. We show that a contributing factor for these differences is that the methylation state of non-CpG-island DNA is correlated with the regional level of GC content within chromosomes and that this relationship is inverted between the testis and somatic tissues. We also show that in Dnmt3L-deficient mice, which exhibit infertility associated with abnormal chromosomal structures in germ cells, this unique testicular DNA methylation pattern is not established. These special properties of testicular DNA point to a broad, distinct epigenetic state that may be involved in maintaining a unique chromosomal structure in male germ cells.

Animals↗
PubMed1989

Effect of heterocyclic amines and beef extract on chromosome aberrations and sister chromatid exchanges in cultured human lymphocytes.

Two of the major bacterial mutagens formed in heated meat products, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline or the basic fraction of beef extract induced a low frequency of sister chromatid exchanges in human lymphocyte cultures in the presence of metabolic activation. Structural chromosome aberrations were not induced at comparable high concentrations in human lymphocytes with intact repair system, suggesting that repair or induction of point mutations are involved in the DNA-damaging effect of heterocyclic amines rather than structural chromosome aberrations. Accordingly it may be concluded that mammalian cells with both intact repair and enzyme systems are more relevant than bacterial systems for evaluating the carcinogenic potential of heterocyclic amines.

Animals↗
PubMed2006

Grape seed extract prevents gentamicin-induced nephrotoxicity and genotoxicity in bone marrow cells of mice.

The protection conferred by grape seed extract against gentamicin-induced nephrotoxicity and bone marrow chromosomal aberrations have been evaluated in adult Swiss albino mice. The activity of reduced glutathione peroxidase (GSH peroxidase), the levels of glutathione (GSH) and lipid peroxidation as malondialdehyde (MDA) in the kidneys homogenates, serum urea and creatinine were measured, and in addition the changes in kidney histology and bone marrow chromosomes were investigated. Gentamicin (80 mg/kg b.wt. intraperitoneally for 2 weeks) induced kidney damage as indicated from a pronounced changes in kidney histology, a significant increase in serum urea and creatinine and MDA content in the kidney homogenate. While the activity of the antioxidant enzyme GSH peroxidase and the level of GSH were significantly decreased. Gentamicin induced genotoxicity indicated by increased the number of aberrant cells and different types of structural chromosomal aberrations (fragment, deletion and ring chromosome) and showed no effect on mitotic activity of the cell. Pretreatment with grape seed extract (7 days) and simultaneously (14 days) with gentamicin significantly protected the kidney tissue by ameliorating its antioxidant activity. Moreover, grape seed extract significantly protected bone marrow chromosomes from gentamicin induced genotoxicity by reducing the total number of aberrant cells, and different types of structural chromosomal aberrations. It could be concluded that grape seed extract acts as a potent antioxidant prevented kidney damage and genotoxicity of bone marrow cells.

Animals↗
PubMed1990

Structure and chromosome assignment of the murine p36 (calpactin I heavy chain) gene.

p36 is a major substrate of both viral and growth factor receptor associated protein kinases. This protein has recently been named calpactin I heavy chain since it is the large subunit of a Ca2(+)-dependent phospholipid and actin binding heterotetramer. The primary structure of p36 has been determined from analysis of cloned cDNA. The protein contains 338 amino acids, has an approximate molecular weight of 39,000, and is comprised of several distinct domains, including four 75 amino acid repeats. From two overlapping cosmid clones isolated from different mouse genomic liver libraries, the complete intron/exon structure of the p36 gene was determined and the 5' and 3' noncoding regions of the gene were analyzed. The coding and 3' untranslated region of the p36 gene contains 12 exons which range in size from 48 to 322 base pairs (bp) with an average size of 107 bp. The repeat structures found at the protein level are not delineated by single exons, but the N-terminal p11-binding domain is encoded by a single exon. Structural mapping of the gene demonstrated that the lengths of the first two introns in the coding region are together approximately 6 kilobases (kb), while the other introns range in size from 600 to 3600 bp with an average size of 1650 bp. The p36 gene is at least 22 kb in length and has a coding sequence of approximately 1 kb, representing only 4.5% of the gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2002

Comparative analysis of DNA breakage, chromosomal aberrations and apoptosis induced by the anti-herpes purine nucleoside analogues aciclovir, ganciclovir and penciclovir.

Nucleoside analogues have been used in antiviral therapy and suicide cancer gene therapy. Therefore, it is of importance to compare their potential cytotoxic and genotoxic action. Using metabolically competent CHO cells expressing the thymidine kinase gene of herpes simplex virus type 1 (CHO-HSVtk cells) as a model system, the induction of DNA breaks was compared with the induction of structural chromosomal aberrations and apoptosis/necrosis after exposure to the anti-herpes nucleoside analogues aciclovir (ACV), ganciclovir (GCV) and penciclovir (PCV). After continuous treatment of CHO-HSVtk cells with the drugs, LD(10) in a colony-forming assay was 50, 0.5 and 1 microM for ACV, GCV and PCV, respectively, with GCV to be the most potent agent as determined at a given dose level. There was a remarkable difference in the activity of the agents to kill HSVtk expressing and non-expressing cells: the difference in cellular sensitivity of HSVtk(+) versus HSVtk(-) cells at LD(10) level was 7-fold for ACV, 60-fold for GCV and 400-fold for PCV. The drugs were shown to be strong inducers of apoptosis that was analysed as to concentration- and time-dependence; they induced to only very low extent necrosis. The agents were also highly potent in the induction of DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) (as measured by single cell gel electrophoresis (SCGE)) and chromosomal aberrations. Although PCV induced DNA DSBs with a kinetics and frequency similar to that of GCV, it caused mostly condensation defects instead of "typical" structural chromosomal aberrations. For the drugs used, the frequency of apoptotic cells and the induction of abnormal mitoses appear to be related indicating genotoxic effects induced by the agents to be involved in cell killing due to apoptosis.

Acyclovir↗
PubMed1989

Cytogenetic studies on preimplantation mouse embryos exposed to methylnitrosourea in vivo.

Since exposure of mice to methylnitrosourea (MNU) during the preimplantation period can induce malformations and an increased postnatal death rate, direct embryotoxic effects were studied in preimplantation embryos shortly after treatment of pregnant mice on days 2 and 3 of gestation with single i.p. injections of 2.5, 5.0, and 10.0 mg/kg MNU. Embryos exposed to MNU for 24 h after treatment on day 2 showed a significant reduction of cell number and induction of sister chromatid exchange (SCE) frequency, but no structural chromosomal aberrations or inhibition of development during culture. Embryos exposed to MNU in vivo for 3 h on day 3 showed significantly reduced cell numbers, a significant inhibition of development in culture, and an increase in structural chromosome aberrations. Due to the high cytotoxicity of MNU, determination of SCE was not possible. The results indicate that MNU reaches preimplantation mouse embryos shortly after maternal treatment and that malformations seen at term and postnatal effects are probably induced by the direct action of MNU on early embryos. Furthermore, the importance of the time interval chosen for evaluation of toxicologic endpoints in preimplantation embryos is demonstrated.

Animals↗
PubMed1997

Genotoxic activity of praziquantel.

Praziquantel is a synthetic drug with a remarkable activity against parasites, particularly treamatodes and cestodes. Initial genotoxicity tests used a spectrum of endpoints including tests in bacteria, yeasts, mammalian cells and Drosophila and each one gave negative results. Effects on reproductive cells of mice were negative as well. However, host mediated studies in mice and humans were contradictory and a comutagenic effect with several mutagens and carcinogens was found. Later studies, including monitoring in humans and pigs have shown that Praziquantel induces a greater frequency of hyperploid lymphocytes as well as structural chromosomal aberrations, but not in all the individuals treated. In vitro studies have demonstrated that Praziquantel can induce micronuclei in syrian hamster embryonic (SHE) cells and in lymphocytes of some individuals. The same was found about structural chromosomal aberrations. Fetal death and fetal resorption were found when Praziquantel was administered in high doses to pregnant rats between the 6th and 10th day of gestation. Due to its efficiency as a parasiticide, Praziquantel is in use in Latin-American, Asiatic, African and East-European countries where infections by trematodes and cestodes are frequent. However, the extensive use of Praziquantel in multiple reinfections, in non-infected and non-diagnosed individuals for prevention, in higher doses or repeated doses for cysticercosis treatment and in individuals exposed to environmental mutagens, in conjunction with new findings about its metabolism and genotoxic properties, make it necessary to further evaluate the potential of this drug not only to be mutagenic per se, but to contribute in the development of neoplasm.

Animals↗
PubMed1996

Mixed testicular germ cell tumors: monoclonal or polyclonal.

Testicular germ cell tumors (TGCT) of adolescents and adults are, for clinical and pathological reasons, divided in seminomas (SE) and nonseminomatous germ cell tumors (NS). Whether and to what degree these two entities are pathogenetically related is still controversial and a matter of debate. TGCT may contain both SE and NS components. Cytogenetic studies of the SE and NS components of these mixed TGCT might shed light on the pathogenetic relationship between both components. Separate cytogenetic analysis was performed on both components of three cases of mixed TGCT with both SE and NS components. The karyotypes of both components were compared with each other. In one case, the SE and NS component share eight different structural chromosomal abnormalities, indicating that the SE and NS component are pathogenetically closely related and have a common neoplastic pathway for a considerable length. Both components of the other two cases have, respectively, i(12p) and no structural chromosomal abnormalities in common. Our results, together with data from the literature, indicate that in mixed TGCT with SE and NS components, both components may have either a monoclonal or a polyclonal origin.

Adolescent↗
PubMed1992

Structure and chromosomal localization of the mammalian agrin gene.

Agrin, a component of the synaptic basal lamina, has been shown to induce clustering of ACh receptors on the surface of muscle fibers. Analysis of cDNAs isolated from a rat embryonic spinal cord library demonstrated that agrin contains domains similar to regions of protease inhibitors, laminin and epidermal growth factor. The domain structure of agrin is further revealed here in an analysis of the agrin gene. Two additional internal repeated sequences are defined: one rich in cysteine residues with no homology to other proteins, and another similar to the laminin G domain, which is involved in heparin binding. Alternative RNA splicing at two positions in the gene predicts up to eight possible forms of the agrin protein. The gene (symbol AGRN/Agrn) has been assigned to chromosome 1 region pter-p32 in human and to mouse chromosome 4.

Agrin↗
PubMed1995

Human glucokinase regulatory protein (GCKR): cDNA and genomic cloning, complete primary structure, and chromosomal localization.

Null mutations in the glucokinase (GCK) gene can cause autosomal dominant type 2 diabetes (maturity onset diabetes of the young, MODY); however, MODY is genetically heterogeneous. In both liver and pancreatic islet, glucokinase is subject to inhibition by a regulatory protein (GCKR). Given the role of GCK in MODY, GCKR is itself a candidate type 2 diabetes susceptibility gene. Here we describe the structure of full-length (2.2 kb) cDNA for human GCKR, from the hepatoblastoma cell line HepG2. The human GCKR translation product has 625 amino acids and a predicted molecular weight of 68,700. It has 88% amino acid identity to rat GCKR. Yeast artificial chromosomes (YAC clones) containing human GCKR were isolated, and the gene was mapped to Chromosome (Chr) 2p23 by fluorescent in situ hybridization and somatic cell hybrid analysis.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Murine 12(R)-lipoxygenase: functional expression, genomic structure and chromosomal localization.

A cDNA, recently cloned (by Krieg et al. (1998)) from mouse skin, was shown to encode a 12(R)-lipoxygenase. When expressed in HEK cells, the recombinant protein converted methyl arachidonate into the corresponding 12-HETE ester which was shown to be the R-enantiomer by chiral phase chromatography. Neither arachidonic acid nor linoleic acid were substrates for the recombinant protein. The structure of the 12(R)-lipoxygenase gene is unique among all animal lipoxygenases in that it is divided into 15 exons and 14 introns spanning approximately 12.5 kb. By interspecific backcross analysis, the 12(R)-lipoxygenase gene was localized to the central region of mouse chromosome 11.

Animals↗
PubMed2001

Structure and chromosome location of the mouse P2X(1) purinoceptor gene (P2rx1).

P2X(1) receptors are ATP-gated cation channels that mediate the fast, purinergic component of sympathetic nerve-smooth muscle neurotransmission in the mouse vas deferens and may serve comparable functions in the urinary bladder and the arteries. The gene for mouse P2X(1) (P2rx1) was cloned and its genomic structure defined by sequencing. The gene spans about 10 kb and consists of 12 exons. All splice sites conformed to the GT-AG motif and the exon-intron boundaries were largely conserved with other members of the P2X gene family so far cloned. A single transcription-starting site was identified by 5' RACE analysis, 233 bp upstream of the translation start site. The P2X(1) gene maps to the central region of mouse chromosome 11.

Animals↗
PubMedDate not supplied

Acute cytogenetic effects of antineoplastic drugs on peripheral blood lymphocytes in cancer patients chromosome aberrations and micronuclei.

AIMS AND BACKGROUND: The aim of the present study was to evaluate the individual sensitivity of cancer patients to different antineoplastic drugs administered in standard protocols by assessing their acute cytogenetic effects on peripheral blood lymphocytes. METHODS AND STUDY DESIGN: In 12 patients undergoing cancer chemotherapy, acute cytogenetic effects on peripheral blood lymphocytes were evaluated by analysis of structural chromosome aberrations and micronuclei. All patients were given antineoplastic drugs, mainly as polychemotherapy. The frequencies of both cytogenetic biomarkers determined after the first chemotherapy cycle were compared with their pre-treatment (baseline) values. RESULTS: All chemotherapy protocols employed induced clear cytogenetic effects in both tests studied. The results obtained indicate interindividual variations between cytogenetic damage in peripheral blood lymphocytes among cancer patients. Statistically significant increases in the total number of structural chromosome aberrations and micronuclei in lymphocytes analyzed after chemotherapy compared to pre-therapy samples were observed in almost all patients studied. The highest level of chromosome damage as well as the highest incidence of micronuclei was observed following administration of the ACOP protocol (adriamycin, cyclophosphamide and vincristine). The proportions of signal-positive and signal-negative micronuclei were evaluated using DAPI staining, while silver staining revealed Ag-NOR+ and Ag-NOR- micronuclei. In some patients the incidence of signal-positive and Ag-NOR+ micronuclei after treatment was increased, indicating a more pronounced susceptibility of particular chromosomes to damage caused by antineoplastic drugs. CONCLUSIONS: With regard to the results obtained we may conclude that both parameters used in the present study on peripheral lymphocytes are sensitive biomarkers and can be successfully employed for biomonitoring of acute cytogenetic effects induced by antineoplastic drugs in standard clinical protocols for cancer treatment.

Adult↗
PubMed2005

Uneven distribution of expressed sequence tag loci on maize pachytene chromosomes.

Examining the relationships among DNA sequence, meiotic recombination, and chromosome structure at a genome-wide scale has been difficult because only a few markers connect genetic linkage maps with physical maps. Here, we have positioned 1195 genetically mapped expressed sequence tag (EST) markers onto the 10 pachytene chromosomes of maize by using a newly developed resource, the RN-cM map. The RN-cM map charts the distribution of crossing over in the form of recombination nodules (RNs) along synaptonemal complexes (SCs, pachytene chromosomes) and allows genetic cM distances to be converted into physical micrometer distances on chromosomes. When this conversion is made, most of the EST markers used in the study are located distally on the chromosomes in euchromatin. ESTs are significantly clustered on chromosomes, even when only euchromatic chromosomal segments are considered. Gene density and recombination rate (as measured by EST and RN frequencies, respectively) are strongly correlated. However, crossover frequencies for telomeric intervals are much higher than was expected from their EST frequencies. For pachytene chromosomes, EST density is about fourfold higher in euchromatin compared with heterochromatin, while DNA density is 1.4 times higher in heterochromatin than in euchromatin. Based on DNA density values and the fraction of pachytene chromosome length that is euchromatic, we estimate that approximately 1500 Mbp of the maize genome is in euchromatin. This overview of the organization of the maize genome will be useful in examining genome and chromosome evolution in plants.

Chromosome Mapping↗