Facilitative mechanisms of lead as a carcinogen

The carcinogenicity of lead compounds has received renewed attention because of continuing environmental and occupational sources of exposure in many countries. The epidemiological evidence for an association between lead exposures and human cancer risk has been strengthened by recent studies, and new data on mechanisms of action provide biological plausibility for assessing lead as a human carcinogen. Both epidemiological and mechanistic data are consistent with a facilitative role for lead in carcinogenesis, that is, lead by itself may not be both necessary and sufficient for the induction of cancer, but at a cellular and molecular level lead may permit or enhance carcinogenic events involved in DNA damage, DNA repair, and regulation of tumor suppressor and promoter genes. Some of these events may also be relevant to understanding mechanisms of lead-induced reproductive toxicity.     

Molecular epidemiology studies of carcinogenic environmental pollutants. Effects of polycyclic aromatic hydrocarbons (PAHs) in environmental pollution on exogenous and oxidative DNA damage

Exposure to high levels of environmental air pollution is known to be associated with an increased carcinogenic risk. The individual contribution to this risk derived from specific carcinogenic chemicals within the complex mixture of air pollution is less certain, but may be explored by the use of molecular epidemiological techniques. Measurements of biomarkers of exposure, of effect and of susceptibility provide information of potential benefit for epidemiological and cancer risk assessment. The application of such techniques has been mostly concerned in the past with the carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) that are associated with particulate matter in air pollution, and has showed clear evidence of genotoxic effects, such as DNA adducts, chromosome aberrations (CA) and ras oncogene overexpression, in environmentally exposed Czech and Polish populations. We are currently extending these studies by an investigation of populations exposed to environmental pollution in three European countries, Czech Republic, Slovak Republic and Bulgaria. This pays particular attention to PAHs, but also investigates the extent of radically induced (oxidative) DNA damage in the exposed populations. Policemen, bus drivers and controls, who carried personal monitors to determine their exposures to PAHs have been studied, and blood and urine were collected. Antioxidant and dietary status were assessed in these populations. Stationary monitors were also used for ambient air monitoring. Amongst the parameters studied in the biological samples were: (a) exposure biomarkers, such as PAH adducts with DNA, p53 and p21(WAF1) protein levels, (b) oxidative DNA damage, (c) the biological effect of the exposure by measurement of chromosome damage by fluorescence in situ hybridisation (FISH) or conventional methods, and (d) polymorphisms in carcinogen metabolising and DNA repair enzymes. Repair ability was also measured by the Comet assay. In vitro systems are being evaluated to characterise the genotoxicity of the organic compounds adsorbed to air particles.     

The role of reactive oxygen species and oxidative stress in environmental carcinogenesis and biomarker development

Although we have greatly benefited from the use of traditional epidemiological approaches in linking environmental exposure to human disease, we are still lacking knowledge in to how such exposure participates in disease development. However, molecular epidemiological studies have provided us with evidence linking oxidative stress with the pathogenesis of human disease and in particular carcinogenesis. To this end, oxidative stress-based biomarkers have proved to be essential in revealing how oxidative stress may be mediating toxicity induced by many known carcinogenic environmental agents. Therefore, throughout this review article, we aim to address the current state of oxidative stress-based biomarker development with major emphasis pertaining to biomarkers of DNA, lipid and protein oxidation.     

Applications of Molecular Markers in Fruit Crops for Breeding Programs—A Review

Selection and use of molecular markers for evaluation of DNA polymorphism in plants are couple of the most important approaches in the field of molecular genetics. The assessment of genetic diversity using morphological markers is not sufficient due to little differentiating traits among the species, genera or their individuals. Morphological markers are not only highly influenced by environmental factors but skilled assessment is also prerequisite to find the variations in plant genetic resources. Therefore, molecular markers are considered as efficient tools for detailed DNA based characterization of fruit crops. Molecular markers provide new directions to the efforts of plant breeders particularly in genetic variability, gene tags, gene localization, taxonomy, genetic diversity, phylogenetic analysis and also play an important role to decrease the time required for development of new and excellent cultivars. The success of molecular markers technology in genetic improvement programs depends on the close relationship among the plant breeders, biotechnologists, skilled manpower and good financial support. The present review describes application and success of molecular markers technology used for genetic improvement in different fruit crops.     

Epidemiology, cancer genetics and microarrays: making correct inferences, using appropriate designs

Different disciplines approach cancer with different study designs, techniques and established bodies of knowledge. This article identifies some established epidemiological data and methods, which are useful for cross-disciplinary molecular and genetic studies of cancer but which are ignored by some researchers. First, the international variation in cancer risk is accounted for extensively by variation in environmental exposures; it is unlikely that even minute characterization of individual genomes will provide the best assessment of cancer risk in the absence of comparably detailed information on the environment. Second, epidemiological study-design methods are sometimes the most appropriate to answer molecular questions, particularly when using techniques such as expression microarrays or proteomics to establish differences among cancer subtypes or biomarkers in the setting of a non-experimental study. In such studies, it is essential to avoid bias, control confounding and undertake accurate replication. Established epidemiological data and methods will contribute to the best use of the new molecular technology.     

Environmental genotoxicants/carcinogens and childhood cancer: bridgeable gaps in scientific knowledge

Cancer in children is a major concern in many countries. An important question is whether these childhood cancers are caused by something, or are just tragic random events. Causation of at least some children's cancers is suggested by direct and indirect evidence, including epidemiological data, and animal studies that predict early life sensitivity of humans to carcinogenic effects. Candidate risk factors include genotoxic agents (chemicals and radiation), but also diet/nutrition, and infectious agents/immune responses. With regard to likelihood of risks posed by genotoxicants, there are pros and cons. The biological properties of fetuses and infants are consistent with sensitivity to preneoplastic genotoxic damage. Recent studies of genetic polymorphisms in carcinogen-metabolizing enzymes confirm a role for chemicals. On the other hand, in numerous epidemiological studies, associations between childhood cancers and exposure to genotoxicants, including tobacco smoke, have been weak and hard to reproduce. Possibly, sensitive genetic or ontogenetic subpopulations, and/or co-exposure situations need to be discovered to allow identification of susceptible individuals and their risk factors. Among the critical knowledge gaps needing to be bridged to aid in this effort include detailed tissue and cellular ontogeny of carcinogen metabolism and DNA repair enzymes, and associations of polymorphisms in DNA repair enzymes with childhood cancers. Perinatal bioassays in animals of specific environmental candidates, for example, benzene, could help guide epidemiology. Genetically engineered animal models could be useful for identification of chemical effects on specific genes. Investigations of interactions between factors may be key to understanding risk. Finally, fathers and newborn infants should receive more attention as especially sensitive targets.     

Mycotoxins as human carcinogens—the <Emphasis Type="Italic">IARC Monographs</Emphasis> classification

Humans are constantly exposed to mycotoxins (e.g. aflatoxins, ochratoxins), mainly via food intake of plant and animal origin. The health risks stemming from mycotoxins may result from their toxicity, in particular their carcinogenicity. In order to prevent these risks, the International Agency for Research on Cancer (IARC) in Lyon (France)—through its IARC Monographs programme—has performed the carcinogenic hazard assessment of some mycotoxins in humans, on the basis of epidemiological data, studies of cancer in experimental animals and mechanistic studies. The present article summarizes the carcinogenic hazard assessments of those mycotoxins, especially aflatoxins (aflatoxin B₁, B₂, G₁, G₂ and M₁), fumonisins (fumonisin B₁ and B₂) and ochratoxin A (OTA). New information regarding the genotoxicity of OTA (formation of OTA-DNA adducts), the role of OTA in oxidative stress and the identification of epigenetic factors involved in OTA carcinogenesis–should they indeed provide strong evidence that OTA carcinogenicity is mediated by a mechanism that also operates in humans–could lead to the reclassification of OTA.     

Molecular epidemiology: new rules for new tools?

Molecular epidemiology combines biological markers and epidemiological observations in the study of the environmental and genetic determinants of cancer and other diseases. The potential advantages associated with biomarkers are manifold and include: (a) increased sensitivity and specificity to carcinogenic exposures; (b) more precise evaluation of the interplay between genetic and environmental determinants of cancer; (c) earlier detection of carcinogenic effects of exposure; (d) characterization of disease subtypes-etiologies patterns; (e) evaluation of primary prevention measures. These, in turn, may translate into better tools for etiologic research, individual risk assessment, and, ultimately, primary and secondary prevention. An area that has not received sufficient attention concerns the validation of these biomarkers as surrogate endpoints for cancer risk. Validation of a candidate biomarker's surrogacy is the demonstration that it possesses the properties required for its use as a substitute for a true endpoint. The principles underlying the validation process underwent remarkable developments and discussion in therapeutic research. However, the challenges posed by the application of these principles to epidemiological research, where the basic tool for this validation (i.e., the randomized study) is seldom possible, have not been thoroughly explored. The validation process of surrogacy must be applied rigorously to intermediate biomarkers of cancer risk before using them as risk predictors at the individual as well as at the population level.     

Genetic metabolic polymorphisms and the risk of cancer: a review of the literature

The purpose of this paper is to systematically analyse the design and results of epidemiological studies on the association between various types of cancer (lung, bladder, breast, colon, stomach) and four genetically-based metabolic polymorphisms, involved in the metabolism of several carcinogens (glutathione-S-transferase M1, debrisoquine hydroxylase, N acetyltransferase, aryl hydrocarbon hydroxylase). These inherited polymorphisms usually cause modifications in the quality or quantity of the relevant enzymes. Such enzymes are involved in the activation/inactivation of known carcinogens and seem to modify the extent to which carcinogens interact with DNA in target tissues. Two enzymes, debrisoquine hydroxylase and aryl hydrocarbon hydroxylase, activate procarcinogens to carcinogens (phase I enzymes). The other two, glutathione-S-transferase M1 and N-acetyltransferase, mainly detoxity carcinogenic substances (phase II enzymes). Because of their role as host factors (modulating the action of carcinogens), it has been hypothesized that subjects presenting a specific phenotype for such polymorphisms could be at a greater risk of developing various types of cancer. A number of epidemiological studies have investigated such associations, often with discordant results. We examine and discuss the design of the studies, and present a meta-analysis of the available data.     

Banding carcinogenic risks in developed countries: A procedural basis for qualitative assessment

Readily achieved comparative assessment of carcinogenic risks consequent upon environmental exposures may increase understanding and contribute to cancer prevention. Procedures for hazard identification and quantitative risk assessment are established, but limited when addressing novel exposures to previously known carcinogens or any exposure to agents having only suspected carcinogenic activity. To complement other means of data evaluation, a procedure for qualitative assessment of carcinogenic risk is described. This involves categorizing the relevant carcinogen and circumstances under which exposure occurs. The categories for carcinogens are those used for hazard identification and involve whether the agent is (1) a recognized carcinogen for humans; (2) probably or (3) possibly carcinogenic for humans; (4) characterized by inadequate evidence of carcinogenicity; or (5) lacking carcinogenicity. Exposure is categorized by whether it is one which (1) establishes the agent as a recognized carcinogen; (2) is taken into account in establishing carcinogenicity status; (3) is distinct from those providing clearest evidence of carcinogenicity; (4) is not characterized in relation to carcinogenicity; or (5) involves an exposure in which absence of carcinogenic outcome is observed. These two categories of evidence allow the risk inherent in a situation to be banded as indicative of a proven, likely, inferred, unknown or unlikely carcinogenic outcome, and further characterized using sub-bands. The procedure has been applied to about fifty situations. For recognized carcinogens, including asbestos and polycyclic aromatic hydrocarbons, risks consequent upon occupational exposure, the impact of point source pollution, residence near contaminated sites and general environmental exposure are allocated across the proven band and a likely sub-band. For solvents, pesticides and other compounds having less clearly established carcinogenicity, impact on residents living near a production site, or near earlier related industrial activity is allocated to certain inferred sub-bands. Unknown carcinogenic outcome, which identifies exposure to an agent with inadequate evidence of carcinogenicity rather than being indicative of equivocal or negative data in any context, indicates both the impact of certain pollutants and user-exposure to some consumer products. Situations allocated to the unlikely risk band principally involve certain consumer products. Overall, such risk assessment may be of greatest worth in focusing community attention on proven causes of cancer and associated preventive measures.     

Mutagenicity, carcinogenicity and teratogenicity of aluminium

Aluminium and its salts, which are extensively used in the household and in industry, do not constitute a carcinogenic, mutagenic or teratogenic hazard, except, perhaps, in cases of extremely high exposure. The large majority of the experiments performed to assess the carcinogenicity of aluminium in laboratory animals gave negative results or even suggested some antitumor activity. Moreover, epidemiological studies have not provided clear evidence of a carcinogenic hazard of aluminium to man, and short-term tests made in vitro and in vivo to demonstrate mutagenic activity of A1 were negative except for some experiments in plants. The embryotoxic properties suggested by the studies on birds and mammals could result from the influence of A1 on phosphate and calcium metabolism or from interference with the polymerization of microtubules.     

神经管畸形相关基因的研究进展

神经管畸形是由遗传和环境因素共同作用而导致的一种常见的出生缺陷。遗传因素中包括细胞增殖因子、转录因子及影响叶酸代谢的关键酶的基因。本文着重从动物模型和群体流行病学调查两方面,简述目前研究的热点基因及特定位点的遗传多态性与神经管畸形的关系,从而揭示多因素作用在神经管畸形病因学研究中的意义。 Progress in Researches on Neural Tube Defects Related the Genes QU Mei,LI Zhu Institute of Reproductive and Child Health of Peking University,National Reference Laboratory on Reproductive Health Research Ministry of Health,Beijing 100083,China Abstract:Neural tube defects are common birth defects which are ascribed to the combination of genetic and environmental factors.The genetic factors include cell growth factors,transformation factors and key enzymic genes involved in folate metabolism.This paper reviews the genes as focus of current investigantion and the relationship between the genetic polymorphism on the specific sites and neural tube defects based on animal model and population epidemiological study.It indicats that the multifactors play an important role in the etiology of neural tube defects. Key words：neural tube defects; genetic polymorphism     

Uncertainty Distributions for Cancer Potency Factors: Combining Epidemiological Studies with Laboratory Bioassays—the Example of Acrylonitrile

For eight chemicals or chemical mixtures with clear positive epidemiological evidence of carcinogenicity by inhalation (acrylonitrile, arsenic, benzene, beryllium, cadmium, chromium VI, coke oven emissions, and nickel), the United States Environmental Protection Agency (USEPA) uses that evidence to obtain a single best estimate of cancer potency factor. The methods used have so far been ad hoc, because of the differences in published studies, although there are common factors. In every case, the uncertainties involved in the various stages of analysis are qualitatively acknowledged, and often quantitatively estimated, but no formal attempt has been made to propagate the uncertainties. I here provide a detailed case study for acrylonitrile that (a) incorporates all estimates of uncertainty mentioned by the US EPA in their analysis and propagates that uncertainty to produce an uncertainty distribution; (b) updates the USEPA analysis to incorporate more recent epidemiological data from the same study used in their analysis.

For most of the materials known to be carcinogenic to humans (through epidemiologic evidence), there are also available cancer bioassays performed on laboratory animals. If the procedures used for estimating human carcinogenic potencies from laboratory animal bioassays are to be believed in cases where there are no human epidemiological data, their evidence should also be used where there is epidemiological evidence. A consistent method of incorporating the results of both epidemiological studies and laboratory animal bioassays into a single probability distribution for a human cancer potency is here detailed, using acrylonitrile as an example for which there is positive epidemiological data. The methods are sufficiently general to allow the incorporation of any combinations of positive and negative bioassay and epidemiological data.     

Review human papillomaviruses (HPV) in gynaecological cytology: from molecular biology to clinical testing

Molecular epidemiological and pathological studies show that different HPV types are associated with different cervical lesions allowing classification of the viruses into types associated with 'high', 'intermediate' and 'low' risk of cervical neoplasia. However, HPV infection often regresses and, where it is associated with neoplasia, is an early event. This suggests that other factors are involved in the carcinogenic process, and there is some mechanistic basis for the interaction of epidemiologically defined factors with HPV infection in the process of cervical carcinogenesis. With the refinement of techniques for HPV detection in clinical material, HPV testing is now a realistic possibility, but how this should be performed and in what clinical situation(s) is still uncertain. Particular areas of interest are: (i) the assessment of patients with borderline cytological changes or mild dyskaryosis; and (ii) the definition of those patients at greater risk of invasi ve disease. Clinical trials are needed before the utility of HPV testing can be properly assessed.     

DNA polymerase eta participates in the mutagenic bypass of adducts induced by benzo[a]pyrene diol epoxide in mammalian cells

Y-family DNA-polymerases have larger active sites that can accommodate bulky DNA adducts allowing them to bypass these lesions during replication. One member, polymerase eta (pol eta), is specialized for the bypass of UV-induced thymidine-thymidine dimers, correctly inserting two adenines. Loss of pol eta function is the molecular basis for xeroderma pigmentosum (XP) variant where the accumulation of mutations results in a dramatic increase in UV-induced skin cancers. Less is known about the role of pol eta in the bypass of other DNA adducts. A commonly encountered DNA adduct is that caused by benzo[a]pyrene diol epoxide (BPDE), the ultimate carcinogenic metabolite of the environmental chemical benzo[a]pyrene. Here, treatment of pol eta-deficient fibroblasts from humans and mice with BPDE resulted in a significant decrease in Hprt gene mutations. These studies in mammalian cells support a number of in vitro reports that purified pol eta has error-prone activity on plasmids with site-directed BPDE adducts. Sequencing the Hprt gene from this work shows that the majority of mutations are G>T transversions. These data suggest that pol eta has error-prone activity when bypassing BPDE-adducts. Understanding the basis of environmental carcinogen-derived mutations may enable prevention strategies to reduce such mutations with the intent to reduce the number of environmentally relevant cancers.     

Human genetics of tuberculosis: a long and winding road

Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.