Mutation Research/Reviews in Genetic Toxicology最新文献

Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(ε)-DNA adduct-forming chemicals were developed and applied to humans and animal models. The aims were to identify hitherto unknown sources and mechanisms of exogenous and endogenous DNA damage, to examine the effect of drug polymorphism on BP adduct levels, and to develop QSAR between tumorigenic potency, heritable genetic damage and structural elements of alkylating carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13–32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring (+)-anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248–6253). In smokers, a positive correlation was found between pulmonary CYP1A1-related catalytic activity (AHH) and the level of lung BPDE-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carcinogenesis, 16, 1373–1376). (ii) 3-Alkyladenines (3-alkAde): Akylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3-alkAde in urine, for which a detection method was developed (Friesen et al. (1991) Chem. Res. Toxicol., 4, 102–106; Prevost et al. (1990) Carcinogenesis, 11, 1747–1751), using immunoaffinity purification and GC-MS analysis. The usefulness of 3-alkAde analysis for the determination of the whole-body dose of alkylating agents derived from exogenous and endogenous sources was demonstrated. (iii) Etheno-DNA adduct-forming agents: Etheno(ε)-DNA base adducts (εdA, εdC, εdG) are promutagenic DNA lesions that are formed by occupational (vinyl halides) and environmental (urethane) carcinogens. An ultrasensitive detection method was developed (Nair et al. (1995) Carcinogenesis, 16, 613–617),

We compared the mechanism of action of micronuclei (MN), unstable chromosome aberrations, and 8-hydroxydeoxyguanosine (8-OHdG) levels to evaluate the genotoxicity of methyl mercuric chloride (CH₃HgCl) and mercuric chloride (HgCl₂) in human peripheral lymphocytes. The chromosome aberrations in human peripheral lymphocytes exposed to various concentrations of CH₃HgCl or HgCl₂ increased in a concentration-dependent manner and were significantly higher than the control when the cells were incubated with 1 × 10⁻⁵ M (HgCl₂) or 2 × 10⁻⁶ M (CH₃HgCl). The increase in the incidence of micronucleated lymphocytes was significant among the exposed groups, being 2 × 10⁻⁵ M (HgCl₂) and 5 × 10⁻⁶ M (CH₃HgCl) compared with the control. CH₃HgCl was about 4-fold more potent than HgCl₂. We determined the 8-OHdG levels in human peripheral blood mononuclear cells(PBMC) and found that they were significantly higher in the exposed groups at 1 × 10⁻⁵ M (HgCl₂) and 5 × 10⁻⁶ M (CH₃HgCl) compared with the control. A detectable (p < 0.05) increase in the level of 8-OHdG was induced by CH₃HgCl at a concentration that was about 50% of the amount of HgCl₂ required to produce a similar response. The data confirmed the value of the MN and/or chromosome aberration assays for assessing of HgCl₂- and/or CH₃HgCl-induced genotoxicity, and indicated that they are about the same concentration as the 8-OHdG assay. The presence of genotoxic effects in peripheral blood lymphocytes exposed to the mercuric compounds indicated by the chromosome aberrations and the MN assays could be partly due either to the disturbance of the spindle mechanism, or to the elevated level of 8-OHdG brought by the generation of reactive oxygen species.

Analyses of a data base consisting of 461 chemicals tested in the SOS chromotest with MULTICASE resulted in the development of an SAR model that displayed a highly significant concordance (87.3%) between experimental and predicted results of chemicals not included in the model. An analysis of the nature of the biophores and their modulators revealed that electrophilicity and structural features affecting: (a) accessibility of the electrophile to the nucleophilic site on the DNA; and (b) the bulkiness of the DNA adduct were factors determining the probability that a chemical would induce DNA error prone repair and if so the extent of this activity. Additional analyses indicated that there were significant mechanistic similarities between the SOS chromotest and mutations in Salmonella as determined in the standard (‘Ames’) assay.

Inhibitory activity of tetracycline against ofloxacin- and fleroxacin-induced bleaching of green and etiolized Euglena gracilis was examined. Tetracycline hydrochloride in concentrations of 83-2079 μM in the light partially inhibited the bleaching activity of 83 μM ofloxacin and of 162 μM fleroxacin. In the dark, the TC inhibition of the fluoroquinolones-induced bleaching activity was most obvious, the white colony counts were all decreased. The total inhibition of bleaching was observed in 43 μM ofloxacin and 81 μM fleroxacin both in light and darkness. Cell growth was not significantly influenced by ofloxacin, fleroxacin and tetracycline in the light or darkness. Inhibition of ofloxacin-induced euglena bleaching by tetracycline was more effective in etiolized cells. TC at 0–416 μM did not influence the growth of ofloxacin (2.15 μM)-induced Salmonella typhimurium revertants.

The ability of certain chemicals to increase the frequency of aneuploidy in mammalian oocytes elicits concern about human health and well-being. This concernment exists because aneuploidy is the most prevalent class of human genetic disorders, and very little information exists about the etiology of aneuploidy. Although there are experimental models for studying aneuploidy in female germ cells and zygotes, these models are still being validated because insufficient information exists about the biological variables that can influence the degree of chemical-induced aneuploidy. In this regard, variables such as dose, solvent, use of gonadotrophins, mode and preovulatory time of chemical administration, time of cell harvest relative to the possibility of chemical-induced meiotic delay, criteria for cytogenetic analysis and data reporting, and an introduction to differences between cell types and sexes are presented.

Besides these variables, additional information is needed about the various molecular mechanisms associated with oocyte meiotic maturation and the genesis of aneuploidy. Also, differences between the results from selected chromosome analysis and DNA-hybridization studies are presented. Based upon the various biologic endpoints measured and the differences in cellular physiology and biochemical pathways, agreement among the results from different aneuploidy assays cannot necessarily be expected.

To gain further insight into the etiology of aneuploidy in female germ cells, information is needed about the chemical interactions between endogenous and exogenous compounds and those involved with oocyte meiotic maturation.

Chromosome dosimetry, in its conventional form largely based on scoring of dicentrics and ring chromosomes in human blood lymphocytes, is the most widely distributed and reliable biological technique in radiological protection to estimate individual whole-body doses of about 100 mGy of low-LET radiation. Attempts to detect and quantify effects even of lower acute doses or protracted and chronic exposures have been repeatedly performed and the results revealed inherent limitations of this approach. Most relevant items, such as extrapolating from high-dose to low-dose effects, the influence of background frequency of dicentrics on the dose estimates, dose accumulation and concomitant temporal decline of the yields of unstable dicentrics or the statistical analyses of the data and their implications for quantifying low-level radiation exposure will be discussed in this report.

This paper reviews the information available concerning the mutagenic, teratogenic and carcinogenic effects of lithium. Such effects would be highly unlikely in an occupational setting but might be a risk to the considerable percentage of the population treated for manic-depressive disorders. It is concluded that lithium compounds have no significant clastogenic and, based on studies on microorganisms, only a doubtful mutagenic activity. Information on teratogenic effects is contradictory. While some observations in man and a few animal studies suggest that lithium in concentrations in the order of those given to patients may cause malformations, other observations do not support this claim and the risk with a carefully controlled therapy is probably small. Until more information becomes available from ongoing lithium data registries, it is probably prudent to exercise caution in treating pregnant women with lithium during the period of cardiac organogenesis. No information is available on cancer caused by treatment with lithium, and it is highly unlikely that lithium is carcinogenic.