Mutation Research/Reviews in Genetic Toxicology最新文献

Three functional elements are required for the stable transmission of eukaryotic chromosomes: replication origins, centromeres and telomeres. In the yeast Saccharomyces cerivisiae the DNA sequences defining each of these elements are known. The simplest and most widely conserved of these sequences is that of the telomere. As the name implies, the telomere is the end of a linear eukaryotic chromosome. Two of the main functions of the telomere are to prevent DNA loss as a consequence of replication and to prevent interactions with other chromosomal ends. Thus, telomeres play a major role in maintaining chromosome stability and consequently they have been considered as likely to be involved in some aspects of chromosomal aberration formation. The involvement of telomeric DNA sequences in stabilizing normal and broken chromosome ends, in ‘hot spots’ for aberration formation and in delayed chromosomal instability will be reviewed here drawing on material presented at the Workshop and the published literature.

Chromosome aberrations induced by radiation have been used for the purpose of dosimetry for a long time. Translocations are especially useful for retrospective dosimetry, since they are assumed to be stable. The method of chromosome painting (FISH) has facilitated objective scoring of aberrations considerably. Translocation frequencies, obtained by FISH, for retrospective dosimetry rely on the main assumptions of neutral selection value and that the distribution of aberrations over the chromosomes is a known function of the DNA content of the chromosomes. Data scrutinising the two above-mentioned assumptions indicate deviations from both. Other factors potentially causing problems for retrospective dosimetry, such as inter-individual variations in background and induction patterns, are discussed. Finally, a brief analysis of the statistical power of dosimetry studies shows that establishing low doses (≈ 0.25 Gy) with good precision requires a great effort, which is probably unrealistic for individual dose estimates in epidemiological studies.

The paper reviews the information available concerning the mutagenic, teratogenic and carcinogenic effects of antimony. A claim that antimony compounds could have mutagenic properties is based on insufficient and not particularly relevant data. Additional experiments, particularly with organic antimony compounds, would be desirable, but from what we know already, one may be confident that antimony is less a mutagenic risk than many other metals such as As, Cr, Ni, among others. Evidence for a carcinogenic risk of antimony in experimental animals was judged by the IARC sufficient for antimony trioxide and limited for antimony trisulfide. In man, IARC considered antimony trioxide as possibly carcinogenic. However, exposure in all studies on which these conclusions are based also involved other proven or likely carcinogenic compounds. Studies with pure antimony compounds, especially those used in therapy, need to be performed to clarify the situation. Although some indications exist that antimony trioxide could interfere with embryonic and fetal development, the studies seem not entirely conclusive. It is regrettable that, at least to our knowledge, the outcome of pregnancy in women treated with antimony compounds for leishmaniasis has not been studied. In conclusion, it appears that mutagenic, carcinogenic and teratogenic risks of antimony compounds, if they exists at all, are not very important.

Telomeres cap and protect the ends of chromosomes from degradation and illegitimate recombination. The termini of a linear template cannot, however, be completely replicated by conventional DNA-dependent DNA polymerases, and thus in the absence of a mechanisms to counter this effect, telomeres of eukaryotic cells shorten every round of DNA replication. In humans and possibly other higher eukaryotes, telomere shortening may have been adopted to limit the life span of somatic cells. Human somatic cells have a finite proliferative capacity and enter a viable growth arrested state called senescence. Life span appears to be governed by cell division, not time. The regular loss of telomeric DNA could therefore serve as a mitotic clock in the senescence programme, counting cell divisions. In most eukaryotic organisms, however, telomere shortening can be countered by the de novo addition of telomeric repeats by the enzyme telomerase. Cells which are ‘immortal’ such as the human germ line or tumour cell lines, established mouse cells, yeast and ciliates, all maintain a stable telomere length through the action of telomerase. Abolition of telomerase activity in such cells nevertheless results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Therefore, loss of terminal DNA sequences may limit cell life span by two mechanisms: by acting as a mitotic clock and by denuding chromosomes of protective telomeric DNA necessary for cell viability.

Aflatoxin B₁ (AFB₁) is classified as a group I carcinogen in humans by IARC. However, the exact mechanisms of AFB₁ hepatocarcinogenesis have not been fully elucidated. Recent studies have suggested that oncogenes are critical molecular targets for AFB₁, and AFB₁ causes characteristic genetic changes in the p53 tumor suppressor gene and ras protooncogenes. Up to date, more than 1500 human hepatocellular carcinoma (HCC) samples have been examined for p53 mutations with respect to different AFB₁ exposure levels. The most significant finding is that more than 50% of HCC patients from high aflatoxin exposure areas such as southern Africa and Qidong, China harboured a codon 249 G to T transversion in the p53 tumor suppressor gene, which is found to be consistent with the mutagenic specificity of AFB₁ observed in vitro. In contrast, this mutational pattern is not found in HCC samples from moderate or low aflatoxin exposure countries or regions. Therefore, this hot-spot mutation is believed to be a molecular fingerprint linking the initial event of AFB₁-DNA adduct formation with the ultimate development and progress of human HCC. However, some important points still remain to be explicated. First, in many of these studies, the systematic evaluation of AFB₁ exposure is rather limited and the classification of AFB₁ exposure level is speculative and confusing, without the definite evidence for the actual aflatoxin exposure level. Second, the role of hepadnaviral infection has to be considered in the induction of this unique mutational spectrum. On the other hand, ras oncogene mutations are frequently found in AFB₁-induced HCC samples in experimental animals, while the frequency of ras mutation in human HCC in contrast is much lower than that of p53. Recent studies have provided additional evidence that reactive oxygen species (ROS) and oxidative DNA damage may be involved in AFB₁-induced p53 and ras mutations. In future, follow-up cohorts exposed to different levels of AFB₁ combined with the determination of putative gene markers are much needed.

Chlorpromazine and related phenothiazine drugs have been used in human and veterinary medications for more than 40 years, predominantly as psychotropic agents. Genotoxicity reports are in many cases of relatively antiquated test design. Overall there appears to be no genotoxic activity associated with these drugs when tested under standard conditions. Limited evidence for the potential to form mutagenic nitrosation products and some indication for the ability to modulate the genotoxic action of various mutagens have been presented in the literature. UV irradiation of chlorpromazine and other chlorinated derivatives produces reactive free radicals which possess DNA damaging properties. Induction of gene mutation and chromosomal aberrations have been observed in appropriately designed photomutagenesis experiments. Enhancement but also reduction of UV induced skin tumour formation by chlorpromazine have been found. The decisive factor for the discrepant actions has not been recognized. It is clearly advisable to avoid extensive UV exposure during therapy with these drugs.

Apoptosis is one form of physiological or active cell death. The balance between cell proliferation and cell death or apoptosis not only effects organ growth but also has a profound impact on the net increase and growth of initiated cells and preneoplastic and tumor cell populations. With respect to cancer development apoptosis is becoming widely recognized as being an innate tissue defense against carcinogens by inhibiting survival and controlling growth of precancerous cell populations and tumors at different stages of carcinogenesis. Experimental data on cell birth and cell death rates help identify the mode of action of a chemical and can be incorporated into biologically based cancer models. This article describes the quantitation and regulation of apoptosis in rodent liver and how loss of regulation can have a role in hepatocarcinogenesis. A biologically-based mouse liver cancer model is presented and utilized to describe how treatment related growth effects affect the process of carcinogenesis. Advantages and limitations of biologically based cancer models in cancer research and risk assessment are discussed.