Mutation Research/Reviews in Genetic Toxicology最新文献

{"title":"The roles of telomeres and telomerase in cell life span","authors":"Christopher M. Counter","doi":"10.1016/S0165-1110(96)90006-8","DOIUrl":"10.1016/S0165-1110(96)90006-8","url":null,"abstract":"<div><p>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 <em>somatic</em> 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.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"366 1","pages":"Pages 45-63"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90006-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19886267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin hepatocarcinogenesis","authors":"Han-Ming Shen,&nbsp;Choon-Nam Ong","doi":"10.1016/S0165-1110(96)90005-6","DOIUrl":"10.1016/S0165-1110(96)90005-6","url":null,"abstract":"<div><p>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 <em>p</em>53 tumor suppressor gene and <em>ras</em> protooncogenes. Up to date, more than 1500 human hepatocellular carcinoma (HCC) samples have been examined for <em>p</em>53 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 <em>p</em>53 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, <em>ras</em> oncogene mutations are frequently found in AFB₁-induced HCC samples in experimental animals, while the frequency of <em>ras</em> mutation in human HCC in contrast is much lower than that of <em>p</em>53. Recent studies have provided additional evidence that reactive oxygen species (ROS) and oxidative DNA damage may be involved in AFB₁-induced <em>p</em>53 and <em>ras</em> mutations. In future, follow-up cohorts exposed to different levels of AFB₁ combined with the determination of putative gene markers are much needed.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"366 1","pages":"Pages 23-44"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90005-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19886266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apoptosis and cancer risk assessment","authors":"Thomas L. Goldsworthy,&nbsp;Rory B. Conolly,&nbsp;Ronny Fransson-Steen","doi":"10.1016/S0165-1110(96)90013-5","DOIUrl":"10.1016/S0165-1110(96)90013-5","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"365 1","pages":"Pages 71-90"},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90013-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19865429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research paperEditorial introduction","authors":"V. Dellarco, D. Jacobson-Kram","doi":"10.1016/s0165-1110(96)90008-1","DOIUrl":"https://doi.org/10.1016/s0165-1110(96)90008-1","url":null,"abstract":"","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"55 37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80713968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosome aberrations, micronuclei, aneuploidy, sister chromatid exchanges, and cancer risk assessment","authors":"James D. Tucker ,&nbsp;R.Julian Preston","doi":"10.1016/S0165-1110(96)90018-4","DOIUrl":"10.1016/S0165-1110(96)90018-4","url":null,"abstract":"<div><p>This paper describes the four cytogenetic endpoints most frequently used in hazard identification assays as the first step in the risk assessment process. These are structural chromosome aberrations, micronuclei, aneuploidy, and sister chromatid exchanges. The biological mechanisms involved in the formation of the alterations observed in each assay are briefly discussed. Variations in and recent improvements to each assay are described, with an emphasis on the use of molecular techniques to improve the sensitivity of the assay, and to allow for detection of specific alterations that are, or could be, associated with cancer induction. This, in turn, will make the data obtained in the cytogenetic assays more useful in cancer and genetic risk assessment. Thus, the aim of this paper is to encourage cytogeneticists to design their experiments in such a way that the data obtained will be of maximum possible benefit for characterizing and quantifying adverse human health effects, particularly cancer.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"365 1","pages":"Pages 147-159"},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90018-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19864171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Future approaches to genetic toxicology risk assessment","authors":"Rosalie K. Elespuru","doi":"10.1016/S0165-1110(96)90021-4","DOIUrl":"10.1016/S0165-1110(96)90021-4","url":null,"abstract":"<div><p>Short-term genetic toxicology tests were developed for the purpose of identifying chemical carcinogens in the environment. After two decades of development and validation, the tests are well-established in routine testing schemes, but our views of their utility for safety evaluation have undergone re-assessment. The correlation between identified mutagens and identified carcinogens has turned out to be significantly less than one. Processes or mechanisms that are not directly genotoxic appear to play a role in carcinogenesis. While short term test data are still components of the assessment of carcinogenic risk, genetic damage also has been recognized as important in its own right, in relation to heritable genetic risk and other health-related effects, such as aging, reproductive failure and developmental toxicity. The revolution in molecular biology and genetic analysis occurring over the past 20 years has contributed to the wealth of new information on the complexities of cell regulation, differentiation, and the carcinogenic process. These technologies have provided new experimental approaches to genetic toxicology assessments, including transgenic cell and animal models, human monitoring, and analysis of macromolecular interactions at environmentally relevant exposures. The potential exists for the development of more efficient and more relevant genetic toxicology testing schemes for use assessing human safety. A delineation of contemporary needs, a modern view of the elements of cancer induction, and an examination of new assays and technologies may provide a framework for integrating new approaches into current schemes for evaluating the potential genetic and carcinogenic risk of environmental chemicals.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"365 1","pages":"Pages 191-204"},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90021-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19864174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genotype of the human cancer cell: Implications for risk analysis","authors":"Jerry R. Williams,&nbsp;James Russell,&nbsp;John F. Dicello,&nbsp;Mack H. Mabry","doi":"10.1016/S0165-1110(96)90010-X","DOIUrl":"10.1016/S0165-1110(96)90010-X","url":null,"abstract":"<div><p>An extremely large database describes genotypes associated with the human cancer phenotype and genotypes of human populations with genetic predisposition to cancer. Aspects of this database are examined from the perspective of risk analysis, and the following conclusions and hypotheses are proposed: (1) The genotypes of human cancer cells are characterized by multiple mutated genes. Each type of cancer is characterized by a set of mutated genes, a subset from a total of more than 80 genes, that varies between tissue types and between different tumors from the same tissue. No single cancer-associated gene nor carcinogenic pathway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and provide a model for associating cancer rates with induced genetic changes. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of putative carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce these events varies significantly. There is a paradox between the observed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggesting events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hyperproliferation and hypermutation may be such events. (4) Four sets of data suggest that hypermutation may be an important carcinogenic process. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or to increase mutation in hypermutable cells. (5) High-dose exposure to carcinogens in model systems changes patterns of gene expression and may induce protective effects through delay in cell progression and other processes that affect mutagenesis and toxicity. Paradigms in risk analysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effects of test agents at environmental levels. Characteristics of the human cancer genotype suggest that approaches to risk analysis must be broadened to consider the multiplicity of carcinogenic pathways and the relative roles of hyperproliferation and hypermutation. Further, estimation of risk to general human populations must consider effects on hypersusceptible individuals. The extrapolation of effects over wide exposure levels is an imprecise process.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"365 1","pages":"Pages 17-42"},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90010-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19865426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA adducts: biological markers of exposure and potential applications to risk assessment","authors":"David K. La,&nbsp;James A. Swenberg","doi":"10.1016/S0165-1110(96)90017-2","DOIUrl":"10.1016/S0165-1110(96)90017-2","url":null,"abstract":"<div><p>DNA adducts have been investigated extensively during the past decade. This research has been advanced, in part, by the development of ultrasensitive analytical methods, such as ³²P-postlabeling and mass spectrometry, that enable detection of DNA adducts at concentrations as low as one adduct per 10⁹ to 10¹⁰ normal nucleotides. Studies of mutations in activated oncogenes such as <em>ras</em>, inactivated tumor suppressor genes such as <em>p53</em>, and surrogate genes such as <em>hprt</em> provide linkage between DNA adducts and carcinogenesis. The measurement of DNA adducts, or molecular dosimetry, has important applications for cancer risk assessment. Cancer risk assessment currently involves estimating the probable effects of carcinogens in humans based on results of animal bioassays. Estimates of risk are then derived from mathematical models that fit data of tumor incidence at the high animal exposures and extrapolate to probable human exposures that may be orders of magnitude lower. Molecular dosimetry could extend the observable range of mechanistic data several orders of magnitude lower than can be achieved in carcinogenesis bioassays. This measurement also compensates automatically for individual and species differences in toxicokinetic factors, as well as any nonlinearities that affect the quantitative relationships between exposure and molecular dose. As a result, molecular dosimetry can provide a basis for conducting high- to low-dose, route-to-route, and interspecies extrapolations. The incorporation of such data into risk assessment promises to reduce uncertainties and produce more accurate estimates of risk compared to current methods.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"365 1","pages":"Pages 129-146"},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90017-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19864170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk estimation from somatic mutation assays","authors":"John A. Heddle,&nbsp;Roy R. Swiger","doi":"10.1016/S0165-1110(96)90015-9","DOIUrl":"10.1016/S0165-1110(96)90015-9","url":null,"abstract":"<div><p>The ability to quantify somatic mutations in vivo provides a new source of toxicological information that is relevant to the assessment of cancer risk. The major experimental factors that influence the mutant frequency are age, time after treatment, treatment protocol, and tissue analyzed. In untreated mice, the mutant frequency increases very rapidly with age from conception to birth, more slowly from birth to adulthood, and very slowly thereafter. All somatic tissues studied so far in adults have similar mutant frequencies. The time after treatment (expression time) is the most important experimental variable. The minimum time for expression varies from one tissue to another. To be valid, comparisons between tissues and treatments must be made after complete expression of the mutations. Unfortunately, the minimum expression time has not been characterized in most tissues. Since carcinogens are tissue specific, and many chemicals are distributed in the body in complex patterns, it is to be expected that there will be differences in the frequency of mutation induced in different tissues. As yet this has not been extensively studied. Since the mutations detected by the transgenic assays are neutral, the mutants should accumulate as the integral of the mutation rate. Hence chronic treatment protocols should be more effective than acute and subacute protocols whenever they permit substantially larger doses to be delivered. Such protocols are more relevant to human exposure and are preferable for dose extrapolations. The importance of transcription in determining mutation rates is not yet known, but it is noteworthy that the transgenes are not transcribed whereas the loci involved in carcinogenesis are. The mutation spectrum is important for quantitative risk estimation. Risk estimation must also take into account the spectrum of mutations that are involved in the carcinogenic process in the tissue and the spectrum of mutations that are detectable by the assay. New assays are being used to quantify mutations in vivo in order to understand the carcinogenic process, to search for the environmental factors involved in human cancer, and to evaluate the carcinogenic hazard qualitatively.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"365 1","pages":"Pages 107-117"},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90015-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19864168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of in vitro cell transformation assays to predict the carcinogenic potential of chemicals","authors":"Robert J. Isfort,&nbsp;Robert A. LeBoeuf","doi":"10.1016/S0165-1110(96)90019-6","DOIUrl":"10.1016/S0165-1110(96)90019-6","url":null,"abstract":"<div><p>Genotoxicity test batteries have become a standard tool for identifying chemicals that may have potential carcinogenic risk to humans. It is now apparent, however, that the use of genotoxicity batteries for assessing carcinogenic potential has limitations including an overall low specificity and a limited ability to detect carcinogens acting via ‘nongenotoxic’ mechanisms. In vitro cell transformation models, because they measure a chemical's ability to induce preneoplastic or neoplastic endpoints regardless of mechanism, may fulfil the current need for an in vitro biologically relevant model with increased predictiveness for determining carcinogenic potential. This review will focus on data demonstrating the similarities of chemically induced cell transformation in vitro to carcinogenesis in vivo. Furthermore, a growing database demonstrating a high overall correlation between cell transformation results with those of the rodent bioassay will also be discussed. Finally, the inclusion of cell transformation approaches for assessing the carcinogenic potential of chemicals relative to currently used genotoxicity batteries will be presented.</p></div>","PeriodicalId":100940,"journal":{"name":"Mutation Research/Reviews in Genetic Toxicology","volume":"365 1","pages":"Pages 161-173"},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1110(96)90019-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19864172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}