ISSN:0893-6692    

DOI:10.1002/em.2850210202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0893-6692    

DOI:10.1002/em.2850210203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0893-6692    

DOI:10.1002/em.2850210204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe much larger number of cell divisions between zygote and sperm than between zygote and egg, the increased age of fathers of children with new dominant mutations, and the greater evolution rate of pseudogenes on the Y chromosome than of those on autosomes all point to a much higher mutation rate in human males than in females, as first pointed out by Haldane [Ann Eugen 13:262–271, 1947] in his classical study of X‐linked hemophilia. The age of the father is the main factor determining the human spontaneous mutation rate, and probably the total mutation rate.The total mutation rate inDrosophilamales of genes causing minor reduction in viability is at least 0.4 per sperm, and may be considerably higher. The great mutation load implied by a rate of ≈ 1 per zygote can be greatly ameliorated by quasi‐truncation selection.Corresponding data are not available for the human population. The evolution rate of pseudogenes in primates suggests some 102new mutations per zygote. Presumably the overwhelming majority of these are neutral, but even the approximate fraction is not known.Statistical evidence inDrosophilashows that mutations with minor effects cause about the same heterozygous impairment of fitness as those that are lethal when homozygous. The magnitude of heterozygous effect is such that almost all mutant genes are eliminated as heterozygotes before ever becoming homozygous. Although quantitative data in the human species are lacking, anecdotal information supports the conclusion that partial dominance is the rule here as well. This suggests that if the human mutation rate were increased or decreased, the effects would be spread over a period of 50–100 generations. © 1993 Wiley

ISSN:0893-6692    

DOI:10.1002/em.2850210205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe cytokinesis‐block micronucleus assay was used to investigate the induction of chromosomal damage by bleomycin in G0human lymphocytes. A dose‐dependent increase in the frequency of micronuclei was observed in binucleate cells, and the frequency approached 0.5 micronuclei per cell at the highest dosage tested. The distribution of micronuclei among cells was overdispersed, rather than fitting a Poisson distribution. Even at the highest dosage, more than two‐thirds of the cells did not contain micronuclei, while some cells were highly damaged, containing more than 4 micronuclei percell. © 1993 Wiley‐L

ISSN:0893-6692    

DOI:10.1002/em.2850210206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractDimethylsulfoxide (DMSO) and WR‐1065 are radioprotectors, in that they reduce the effectiveness with which ionizing radiation causes genetic damage. Unlike their protective effects with radiation, these agents potentiate the induction of micronuclei by bleomycin in the cytokinesis‐block assay in G0human lymphocytes. High concentrations of DMSO (1 M) are required to cause potentiation. In contrast, WR‐1065 causes dose‐dependent potentiation at relatively low concentrations (1.25 to 10 mM). Cytogenetic analysis supports the results from the micronucleus assay, showing higher levels of genetic damage induced by the combination of bleomycin with DMSO or WR‐1065 than by bleomycin alone. Possible mechanisms of potentiation are proposed. © 1993 Wiley

ISSN:0893-6692    

DOI:10.1002/em.2850210207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractEffects of methyl methanesulfonate (MMS) on mouse testicular cell kinetics and sperm chromatin structure were determined flow cytometrically. Mice were exposed to a single ip injection of saline containing 0 or 150 mg/kg MMS, Relative ratios of 1N, 2N and 4N testicular cells were not affected until 22 days postexposure. Ratios of 1N cell types were altered from 13 to 22 days and were near normal by 25 days. This study revealed an MMS induced alteration of chromatin structure in testicular, elongated spermatids by the sperm chromatin structure assay (SCSA), a flow cytometric measure of the susceptibility of acridine orange stained sperm DNA to denaturation in situ. The SCSA also detected alterations in cauda sperm chromatin structure at 3 days, which was 8 days prior to alterations in sperm head morphology, indicating the increased sensitivity of the SCSA. SCSA data were practically similar whether measuring either fresh or frozen/thawed sperm, or whether measured by two different types of flow cytometers: a) laser driven, orthogonal optical axis; or b) low cost mercury arc lamp system with epiillumination. The data support the model of Sega and Owens [Mutat Res 111:227–244:1983] that MMS alkylates cysteine ‐SH groups in sperm protamines, thereby destabilizing sperm chromatin structure and leading to broken chromosomes and mutations. © 1993 Wiley‐Lis

ISSN:0893-6692    

DOI:10.1002/em.2850210208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractIn a previous study we showed that the formation of O6‐ethylguanine (O6‐EtGua) in the DNA of CHO cells in culture correlated with mutations induced by ethylnitrosourea (ENU) and diethylsulfate (DES) at the hypoxanthine‐guanine‐phosphoribosyltransferase (hprt) locus but not at the Na, K‐ATPase locus. This study was extended to another ethylating agent, ethyl methanesulfonate (EMS). DNA adduct formation and induction of mutation at the two gene loci were determined simultaneously in CHO cells after EMS exposure. The extent of ethylation at the N7and O6positions of guanine and at the N3site of adenine were measured and the possible correlations with 6‐thioguanine resistance (6‐TGr) and ouabain resistance (ouar) mutations were investigated. A good correlation between the levels of ethylation at O6guanine and mutation frequency athprtgene by all three ethylating agents was observed. In the case of the ouarlocus, the frequency of O6‐EtGua adducts correlated with mutation induction by EMS and ENU but not by DES. Although both EMS and DES have similar reaction mechanisms, these results highlight differences in their mutational specificity. The comparison of this type of analysis with mutational spectra revealed that correlation studies may be inadequate to analyse multi‐component phenomena like mutation formation. © 19

ISSN:0893-6692    

DOI:10.1002/em.2850210209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractForty‐nine chemicals were tested in a mouse bone marrow micronucleus test that employed three daily exposures by intraperitoneal injection. Bone marrow samples were obtained 24 hr following the final exposure. Twenty‐five rodent carcinogens and 24 noncarcinogens were selected randomly from the 44 carcinogens and 29 noncarcinogens used by Tennant et al. (Science 236:933–941, 1987) to evaluate the performance of four in vitro genetic toxicity tests. As in that study of in vitro tests, the micronucleus tests were conducted with coded chemicals and test results (positive or negative) were determined prior to decoding. This study was conducted as part of an effort to assess the ability of the micronucleus test to discriminate between rodent carcinogens and noncarcinogens and to determine its potential role, in combination with other short‐term tests, in identifying genotoxic chemicals that present a carcinogenic hazard.Nine chemicals were judged to be positive in the micronucleus test. This relatively low number of positive results, along with published and unpublished results from rodent micronucleus and chromosome aberration assays on several of these 49 chemicals, contributed to the conclusion that a single micronucleus test protocol is not adequate to detect all chemicals capable of inducing chromosomal damage in the bone marrow. However, a combination of two relatively simple assays such as theSalmonellaand micronucleus tests can provide important information on the genetic toxicity of test chemicals and may provide guidance on the need for and the nature and extent of further toxicity studies. © 1993 Wiley

ISSN:0893-6692    

DOI:10.1002/em.2850210210

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractWe tested six additional chemicals (acetaldehyde, benomyl, diethylstilboestrol, diethylstilboestrol dipropionate, griseofulvin, and mercaptoethanol) for in vitro systems of the coordinated programme to study aneuploidy induction sponsored by the Commission of the European Communities in two in vitro test systems.UsingSaccharomyces cerevisiaeD61.M (mitotic chromosomal malsegregation assay), benomyl showed a dose‐dependent increase in the frequency of chromosomal malsegregation with a lowest effective dose tested (LEDT) of 30 μg/ml (0.1 mM). Diethylstilboestrol (DES) showed solvent‐dependent effects. DES dissolved in ethanol induced an increase in chromosomal malsegregation as well as in the frequency of total resistant colonies (mutations and recombinations) with a LEDT arround 13 μg/ml (0.048 mM). Using dimethylsulfoxide as the solvent, no increases were observed with DES up to 333 μg/ml (1.24 mM). Acetaldehyde induced an increase in chromosomal malsegregation with the cold treatment protocol (LEDT: 1.25 μl/ml (21 mM) and 0.75 μ/ml (13 mM), respectively) but no increase with the overnight protocol (highest dose tested (HDT): 1.75 μ/ml; 30 mM). Concerning the frequency of total cycloheximide‐resistant colonies (mutations and recombinations) increases were obtained with both protocols. The other three compounds were negative when tested up to toxic doses (survival below 10%), up to the maximum solubility in the solvent used or up to heavy precipitation in the incubation mix. The HDT were 333 μ/ml (0.88 mM) for diethylstilboestrol dipropionate, 1,600 μg/ml (4.5 mM) for griseofulvin and 0.5 μl/ml (7 mM) for mercaptoethanol.Concerning effects on porcine brain tubulin assembly in vitro, diethylstilboestrol and griseofulvin inhibited the assembly process. The IC30% (30% inhibition concentration) values were 12.5 μM and 100 μM for DES and griseofulvin, respectively. Mercaptoethanol showed no effects up to 50 mM. © 199

ISSN:0893-6692    

DOI:10.1002/em.2850210211

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY