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Biomedical subjects

J M Parry

Publications and source records attributed to J M Parry.

At least 127 records · Page 7Linked to original sources
PubMed1988

A study of the induction of aneuploidy and chromosome aberrations after diazepam, medazepam, midazolam and bromazepam treatment.

Low passage-number cultured Chinese hamster cells were used to assess the ability of four benzodiazepines, namely diazepam, medazepam, midazolam and bromazepam, to induce numerical and structural chromosome aberrations. It was observed that diazepam, medazepam and midazolam treatment produced dose-dependent reductions in the number of diploid cells, with medazepam and midazolam inducing significant levels of hyperdiploidy and diazepam inducing low levels of hypodiploidy (at toxic doses). In contrast, bromazepam-treated cultures showed no significant changes in the level of aneuploidy even when exposed to toxic concentrations. All four sedatives were seen to induce low levels of chromosome aberrations, with bromazepam showing the most potent effect (albeit at a single toxic dose). These observations indicate that these structurally related benzodiazepines could be regarded as potentially genotoxic.

Aneuploidy↗
PubMed1988

Studies upon the genetic effects of environmental chemicals: the coordinated research programme of the European Economic Community.

The objectives of the European Economic Community's Environmental Research and Development Programmes are to provide a scientific basis for current environmental policy and future environmental management. This paper reviews the work and achievements of the studies carried out by the collaborating laboratories during the period 1981-1985 of the 3rd Programme within the research area 'The Genetic Effects of Environmental Chemicals'. Research efforts supported by the programme may be divided into (i) those involving the validation of current genotoxicity assays and the evaluation of their use in community regulatory activities such as the classification and labelling of chemicals, (ii) those involving the characterization of the metabolic and genotoxic profile of specific chemicals and (iii) those involving the development of new technologies suitable for the hazard identification and risk evaluation of genotoxins. Validation studies have included those of the host mediated assay (and its various modifications), unscheduled DNA synthesis assays and a variety of Drosophila genotoxicity assays. New developments include assays for the detection of chromosome aneuploidy, protocols for cell transformation studies, the detection and quantification of genotoxic lesions, techniques for the study of transplacental genotoxicity, assays for the detection of genotoxic activity in the liver and in germ cells and monitoring techniques for the assessment of both environmental quality and genotoxin exposure in individuals and in populations. The coordination of research effort, such as that described here provides an effective mechanism for the concentration of research on specific problems, for the rapid dissemination of experimental data and the transfer of technology within the European Community.

Animals↗
PubMed1987

Comparisons of tests for aneuploidy.

The fundamental problems that face us in the development of suitable assay systems for the detection of potentially aneugenic (aneuploidy-inducing) chemicals include: (a) the diversity of cellular targets and mechanisms where perturbations of structure and function may give rise to changes in chromosome number, and (b) the phylogenetic differences that exist between species in their mechanism and kinetics of cell division and their metabolic profiles. A diverse range of assay systems have been developed, which have been shown to have potential for use in the detection of either changes in chromosome number or of perturbations of the events which may be causal in the induction of aneuploidy. Chromosome number changes may be detected cytologically by karyotypic analysis, or by the use of specialised strains in which aneuploid progeny may be observed due to phenotypic differences with aneuploid parental cells or whole organisms. Techniques for the detection of cellular target modifications range from in vitro studies of tubulin polymerisation to observations of the behaviour of various cellular organelles and their fidelity of action during the division cycle. The diversity of mechanisms which may give rise to aneuploidy and the qualitative relevance of events observed in experimental organisms compared to man make it unlikely that the detection and risk assessment of the aneugenic activity of chemicals will be possible using a single assay system. Optimal screening and assessment procedures will thus be dependent upon the selection of an appropriate battery of predictive tests for the measurement of the potentially damaging effects of aneuploidy induction.

Aneuploidy↗
PubMed1987

The effects of benzodiazepines upon the fidelity of mitotic cell division in cultured Chinese hamster cells.

4 benzodiazepine sedatives, namely diazepam, medazepam, midazolam and bromazepam were investigated for their effects upon the fidelity of cell division in both low passage number and immortalised Chinese hamster cell lines. The study revealed substantial differences in the effect of these structurally related drugs upon mitosis, which may reflect different mechanisms of action of the drugs in cultured cells. Diazepam and medazepam exposure of immortal and low passage number cells resulted in the formation of monopolar mitotic spindles and subsequent metaphase arrest. The production of these spindles may be explained by the inhibition or centriole separation . In contrast, midazolam and bromazepam failed to produce observable changes in spindle structure. All 4 benzodiazepines produced significant toxicity in low passage number cells whereas, immortalised cells were more resistant to their toxic effects. They all induced metaphase chromosome dislocations in immortalised cells, whereas only diazepam and medazepam produced such effects in the low passage number cell line. In general, immortal cells appeared to be less sensitive to the toxic effects of benzodiazepines than the low passage number cells.

Animals↗
PubMed1987

Chromosome aberrations induced by nitro-, nitroso- and aminopyrenes in cultured Chinese hamster cells.

Nitropyrenes are a class of polycyclic hydrocarbons that have been shown to be potent point mutagens in the Salmonella/mammalian microsome assay. However, relatively few data have been published on their ability to induce chromosome aberrations. In this paper we report the cytogenetic activity of 1-nitropyrene, 1-nitrosopyrene, and 1-aminopyrene in cultured Chinese hamster cells (Don:Wg3h). Following treatment with 1-nitrosopyrene, high levels of both chromosome and chromatid types of aberrations were induced, the most notable effect being an increase in chromatid exchanges. Much weaker, but statistically significant, responses were also obtained for 1-nitropyrene and 1-aminopyrene.

Animals↗
PubMed1986

Toxicity and DNA damage induced by 1-nitropyrene and its derivatives in Chinese hamster lung fibroblasts.

1-Nitropyrene and its chemically synthesised derivatives were investigated for their cytotoxicity and ability to induce DNA-strand breaks in Chinese hamster lung fibroblasts. Both 1-nitrosopyrene (0.25-60 micrograms/ml) and 1-aminopyrene (0.25-25 micrograms/ml) were cytotoxic, and induced the formation of DNA lesions, which were measured as DNA single-strand breaks after sedimentation in alkaline sucrose-density gradients. Higher doses of 1-aminopyrene (25-60 micrograms/ml) inhibited the formation of DNA single-strand breaks. 1-Nitropyrene was not toxic (0.25-60 micrograms/ml) and induced low levels of detectable DNA strand breaks, whilst N-acetyl-1-aminopyrene was inactive. The post-mitochondrial supernatant fraction of Aroclor-induced rat-liver containing 4 mM NADPH (S9 mix) did not promote the activation of 1-nitropyrene. In fact DNA strand breaks induced by either 1-nitropyrene or 1-nitrosopyrene was abolished in the presence of S9 mix. The 1-nitropyrene reduced intermediate, N-hydroxy-1-aminopyrene was synthesised by the reduction of 1-nitrosopyrene with ascorbic acid. In the presence of ascorbic acid, 1-nitrosopyrene caused a 5-fold increase in the number of DNA single-strand breaks when compared to cells treated with 1-nitrosopyrene alone. The results are discussed in terms of the metabolic activation of 1-nitropyrene and 1-aminopyrene in Chinese hamster lung cells.

Animals↗
PubMed1986

The effect of Michler's ketone on cell division, chromosome number and structure in cultured Chinese hamster cells.

The industrial chemical Michler's ketone (MK) has been examined for its ability to induce abnormalities of mitotic cell division and the production of chromosomal aberrations and aneuploidy. MK was shown to produce aberrant cell division stages in cultured mammalian cells probably by interference with centrosome replication leading to the production of monopolar spindles during metaphase, and multipolar telophase spindles, in the first division after exposure. Cells in the second division after exposure to MK showed increased levels of chromosome aneuploidy which is presumed to result from aberrant cell division. There was also some evidence of increased levels of chromosome structural aberrations at concentrations of 1.5 microgram/ml.

Aneuploidy↗
PubMed1986

Genetic effects of methylmethanesulphonate during meiosis in Saccharomyces cerevisiae.

Enhanced mutagenic action after methylmethanesulphonate (MMS) treatment was found in pre-replicative meiotic yeast cells of the strain D7. The level of gene conversion after MMS treatment rose above the spontaneous level during the period of commitment to meiotic recombination, but at later times into meiosis became indistinguishable from the full meiotic level. In contrast reciprocal recombination detected between ade 2 and the centromere of chromosome XV after MMS treatment remained above the spontaneous level up to commitment to meiotic cell division with relatively high levels through meiotic prophase I. These results are discussed in relation to MMS-induced damage and its repair, particularly double-strand break repair.

Gene Conversion↗
PubMed1986

The induction of DNA adducts in mammalian cells exposed to 1-nitropyrene and its nitro-reduced derivatives.

1-Nitropyrene, 1-nitrosopyrene and 1-aminopyrene were investigated for their ability to induce covalently bound DNA adducts in calf thymus DNA and Chinese hamster lung fibroblasts. Xanthine oxidase catalysed the induction of one major and one minor DNA adduct in 1-nitropyrene- or 1-nitrosopyrene-treated calf thymus DNA, whilst 1-aminopyrene was inactive. These compounds did not form detectable DNA adducts in the absence of xanthine oxidase. The major DNA adduct produced by 1-nitropyrene and 1-nitrosopyrene in calf thymus DNA co-migrated on h.p.l.c., and the structure was consistent with that previously described by others as N-(deoxyguanosin-8-yl)-1-aminopyrene. The compounds were investigated for their ability to form DNA adducts in Chinese hamster lung fibroblasts. 1-Nitropyrene (5.2 pmol/mg DNA/h) and 1-nitrosopyrene (129 pmol/mg DNA/h) formed a single DNA adduct in Chinese hamster lung cells which co-eluted on h.p.l.c. with the C-8 deoxyguanosine adduct isolated from 1-nitropyrene-treated calf thymus DNA. 1-Nitrosopyrene was the most efficient compound investigated for the production of the C-8 guanine adducts. In contrast, 1-aminopyrene (14.7 pmol/mg DNA/h) induced the formation of a DNA adduct which did not co-elute with the C-8 guanine adduct. The data presented here suggest that 1-nitropyrene and 1-aminopyrene are metabolized to reactive intermediates which form different DNA adducts in Chinese hamster lung fibroblasts.

Animals↗
PubMed1985

Diethylstilboestrol: the binding and effects of diethylstilboestrol upon the polymerisation and depolymerisation of purified microtubule protein in vitro.

Diethylstilboestrol (DES) was shown to bind to purified microtubule (MT) protein and inhibit the binding of colchicine. The polymerisation and depolymerisation characteristics of MT protein in vitro were examined using spectrophotometry and electron microscopy. At high doses of DES the polymerisation of intact microtubules was inhibited, whilst at lower doses enhanced microtubule formation was observed. The lower doses of DES inhibit the depolymerisation of intact microtubules.

Animals↗
PubMed1984

Testing of chemicals for genetic activity with Saccharomyces cerevisiae: a report of the U.S. Environmental Protection Agency Gene-Tox Program.

The yeast Saccharomyces cerevisiae is a unicellular fungus that can be cultured as a stable haploid or a stable diploid . Diploid cultures can be induced to undergo meiosis in a synchronous fashion under well-defined conditions. Consequently, yeasts can be used to study genetic effects both in mitotic and in meiotic cells. Haploid strains have been used to study the induction of point mutations. In addition to point mutation induction, diploid strains have been used for studying mitotic recombination, which is the expression of the cellular repair activities induced by inflicted damage. Chromosomal malsegregation in mitotic and meiotic cells can also be studied in appropriately marked strains. Yeast has a considerable potential for endogenous activation, provided the tests are performed with appropriate cells. Exogenous activation has been achieved with S9 rodent liver in test tubes as well as in the host-mediated assay, where cells are injected into rodents. Yeast cells can be recovered from various organs and tested for induced genetic effects. The most commonly used genetic end point has been mitotic recombination either as mitotic crossing-over or mitotic gene conversion. A number of different strains are used by different authors. This also applies to haploid strains used for monitoring induction of point mutations. Mitotic chromosome malsegregation has been studied mainly with strain D6 and meiotic malsegregation with strain DIS13 . Data were available on tests with 492 chemicals, of which 249 were positive, as reported in 173 articles or reports. The genetic test/carcinogenicity accuracy was 0.74, based on the carcinogen listing established in the Gene-Tox Program. The yeast tests supplement the bacterial tests for detecting agents that act via radical formation, antibacterial drugs, and other chemicals interfering with chromosome segregation and recombination processes.

Aneuploidy↗
PubMed1984

The detection of mutagenic chemicals in the tissues of shellfish exposed to oil pollution.

Two species of shellfish (mussels and limpets ) were collected from two sites in West Wales (U.K.) extracted in nitric acid and monitored for the presence of mutagenic chemicals using bacterial fluctuation tests over a period of an oil pollution incident. Prior to the observation of oil pollution at the two sites no mutagenic activity could be detected in the tissue extracts. However, within three days of the observation of oil pollution, chemicals capable of inducing both base-substitution and frameshift mutation could be detected in both shellfish species. At one of the sites (St. Brides ) mutagenic activity could still be detected in samples collected 12 months after the oil pollution incident, whereas at the other sites (Dale) no activity was detectable after 12 months. The results obtained demonstrate shellfish exposed to crude oil (and dispersants ) accumulate mutagenic chemicals that persist for periods longer than pollution could be observed by visual inspection.

Animals↗
PubMed1984

Mitotic aneuploidy as a possible mechanism for tumour promoting activity in bile acids.

A range of conjugated and free bile acids were assayed for their ability to induce a variety of genetic endpoints in growing cells of yeast. None of the bile acids showed any activity in assays for the induction of mitotic crossing-over and mutation whereas the free bile acids lithocholic, chenodeoxycholic, deoxycholic and cholic acid were potent inducers of mitotic chromosome aneuploidy. In contrast, both conjugated bile acids, taurodeoxycholic and glycodeoxycholic lacked the ability to induce mitotic aneuploidy. When the potency of the free bile acids were compared, lithocholic and chenodeoxycholic acids showed higher levels of induction of mitotic aneuploidy per lethal event compared with cholic and deoxycholic acids. In view of the previously observed correlation between the ability of a chemical to induce chromosome aneuploidy and tumour promotional activity, the results indicate that the levels of free bile acids in the colon may be significant factors in the etiology of colonic cancer.

Aneuploidy↗