Biomedical subjects
Publications and source records attributed to J R Connell.
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The relationship between the formation of alkylated purines in DNA and sister chromatid exchange (SCE) induction has been studied. Both exponentially growing and density-inhibited Chinese hamster (V79) cultures were treated with various doses of N-methyl-N-nitrosourea (MNU) or dimethylsulfate (DMS). The colony-forming ability and induced frequencies of SCEs were assayed. Following the exposure of density-inhibited cells to radiolabeled methylating agents these phenomena were related to the levels of 7-methylguanine (7-meGua), 0(6)-methylguanine (0(6)-meGua) and 3-methyladenine (3-meAde) in the DNA. At equitoxic doses MNU and DMS induced similar frequencies of SCEs. Since, at equitoxic doses MNU produces about 20 times more 0(6)-meGua in V79-cell DNA than does DMS, this indicates that the formation of this adduct in DNA is not critical for the induction of SCEs by these alkylating agents. Dimethylsulfate-induced SCEs may be mediated via the production of both 3-meAde and 7-meGua in the DNA; these 2 methylated purines may also be responsible for MNU-induced SCE. No one specific methylated purine was identified, therefore, as being solely accountable for the formation of SCEs. The repair of lesions in the DNA of nonreplicating V79 cells lead to a reduction in the SCE frequency on their subsequent release from the density-inhibited state. This suggests that excision repair is not responsible for the formation of SCEs.
The relationship of cytogenetic changes with the acquisition of an indefinite life span in vitro, the ability of cells to grow in soft agar and their tumourigenicity in syngeneic animals has been studied in control, trans-7,8-dihydrodiolbenzo(a)pyrene and 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)-pyrene-treated secondary cultures derived from Chinese hamster embryonic lung. Karyotype analysis revealed a sequence of chromosome changes as the cells progressed through culture. Aneuploidy, namely trisomy of chromosome 4, the long arm in particular, was an early dominant change. The possible association of this trisomy with the acquisition of immortality in vitro is implicated, although the involvement of other nonrandom chromosome changes cannot be eliminated, implying that there may be several genomic sites in the Chinese hamster which may potentially be involved with the acquisition of unlimited growth potential. Neither the ability of cells to grow in soft agar nor as tumours could be associated with any specific chromosome(s). Double minutes were observed in metaphases from the cell lines, agar colonies and tumours; their possible relationship with growth advantage is discussed.
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The ability of the 12 monomethylbenz[a]anthracene isomers, following their metabolism by using the cell-mediated activation system, to induce 8-azaguanine-resistant mutants, sister-chromatid exchanges (SCEs) and chromosomal aberrations has been measured. Both the mutagenic potency and the ability of the monomethylbenz[a]anthracenes to induce SCEs correlated with their carcinogenic activity. None of the monomethylbenz[a]anthracenes were particularly clastogenic.
Chinese hamster cells (V79) were treated, either as exponentially proliferating cultures or under conditions where they were density-inhibited, with various doses of the potent carcinogen N-methyl-N-nitrosourea (MNU) or the relatively weak carcinogen dimethylsulphate (DMS). The colony forming ability of these cells and the induced frequencies of sister chromatid exchanges (SCEs) and chromosomal aberrations were assayed. Following the exposure of density-inhibited cells to radio-labelled methylating agents (labelled in the methyl group) these phenomena were related to the levels of 7-methylguanine (7-meGua), O6-methylguanine (O6-meGua) and 3-methyladenine (3-me-Ade) in the DNA. At equitoxic doses MNU and DMS induced similar frequencies of SCEs and chromosomal aberrations. Since, at equitoxic doses, MNU produces approximately 20 times more O6-meGua in V79 cell DNA than does DMS, this indicates that the formation of O6-meGua in DNA is not a major cause of SCEs and chromosomal aberrations. DMS-induced SCEs may be mediated via the production of both 3-meAde and 7-meGua in the DNA; these two methylated purines may also be responsible for MNU-induced SCEs. Therefore, no one specific methylated purine was identified as being solely accountable for the formation of SCEs. Also, the repair of lesions in the DNA of non-replicating V79 cells leads to a reduction in the SCE frequency on their subsequent release from the density-inhibited state, suggesting that repair is not intimately responsible for their formation. No association was discernable between chromosomal aberrations and any of the three methylated purines studied.
The effect of 5 unrelated chemicals with different promoting potencies on sister chromatid exchange (SCE) induction in V79 cells was investigated. Two powerful promoters--12-O-tetradecanoylphorbol-13-acetate (TPA) and anthralin; a moderate promoter--iodoacetic acid (IAA); two weak promoters--ethyl phenylpropiolate (EPP) and cantharidin--all induced similar and low numbers of SCE. These results do not support the hypothesis that enhanced mitotic recombination is responsible for tumour promotion.
The relationship between ageing and transformation has been investigated by a serial study of the changes in cell-surface morphology as normal and carcinogen-treated cells progressed in culture. A progressive increase in the density of cell surface microvilli occurred in association with the adoption of a more rounded profile and concomitant increase in the rate of cell detachment. These changes occurred earlier after carcinogen treatment, which appeared to indicate a carcinogen-induced acceleration of ageing. The alterations have also been described as characteristic of the transformed state. The observations suggest that the expression of in vitro transformation may be the result of continuous selection from a population with genetic instability and variable morphology.
The ability of three ultimate matabolites of benzo(a)-pyrene and of 7-bromomethylbenz(a)anthracene to induce 8-azaguanine mutants, sister-chromatid exchanges and chromosome aberrations has been investigated. 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was shown to be an extremely efficient inducer of both mutants and sister-chromatid exchanges at 100% survival, whereas its geometrical isomer, 7 beta,8 alpha-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydro-benzo(a)pyrene and benzo(a)pyrene-4,5-oxide were comparatively weak. The potency of this compound, as both a mutagen and a sister-chromatid exchange inducer, gives further evidence that it may be the important carcinogenic metabolite of benzo(a)pyrene. 7-Bromomethylbenz(a)anthracene was a moderate mutagen and inducer of sister chromatid exchanges. Comparisons of the relative potencies of these four chemicals as inducers of both mutations and sister chromatid exchanges have indicated that these two phenomena are not directly related. The induction of sister chromatid exchanges also appears to be independent of the induction of chromosome aberrations.
Examples of chromic and chromate salts have been examined for their effects on a cultured Chinese hamster cell line. The responses studied were cytotoxicity, mutagenesis and clastogenesis. Chromate (hexavalent chromium) salts of both high and medium water solubility were active in producing all three classes of response, whereas an insoluble chromate salt and a soluble chromic (trivalent chromium) salt were inactive. In addition to illustrating the value of using mammalian cells in culture for screening chemicals for biological activity, the results of this study reinforce current views regarding the genotoxic properties of chromates.
Chinese hamster primary fibroblasts derived from several embryos were treated with the carcinogens benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene or N-methyl-N'-nitro-N-nitrosoguanidine. Karyotype analysis, sister chromatid exchange frequency, evidence of transformation by growth in agar, cell morphology and reaction to cytocholasin B were tested at regular intervals over many culture passages. Carcinogen treatment was found to shorten the time period before onset of permanent karyotypically changed stem and side lines and in vitro transformation. Chromosomes X, 6 and 10 were more frequently involved in all cultures in these karyotype changes which were usually preceded by a period of chromosome variation. Spontaneous chromatid aberrations and aneuploidy increased in frequency with time in culture and generally appeared prior to the expression of transformation. No specific chromosomes were involved with the different carcinogens. There was no correlation between in vitro transformation and karyotype evolution and the criteria for transformation were present independently of one another. It is suggested that the lack of correlation between the parameters tested indicates that the expression of in vitro transformation is a result of selection for growth advantage from a cell population expressing an increasing degree of genetic instability and variation with time in culture.
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