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At least 19 recordsLinked to original sources
PubMed1999

Lack of p53-mediated G1 arrest in response to an environmental carcinogen.

The environmental carcinogen, 5-methylchrysene, is a component of cigarette smoke. Its reactive metabolite, anti-5-methylchrysene-1, 2-dihydrodiol-3,4-epoxide (5-MeCDE) mainly reacts with the N(2)-position of guanine residues in the DNA molecule. In this study, we demonstrate that the tumor suppressor protein p53 is stabilized in response to DNA damage by 5-MeCDE but fails to induce the cells' protective mechanism of G1 arrest in the human breast carcinoma cell line, MCF-7. In contrast, actinomycin D treatment of these cells did lead to G1 arrest. Western analyses revealed that, though both actinomycin D and 5-MeCDE treatment stabilized p53, only trace levels of p21(waf1/cip1) were seen in the latter case. This lack of p21(waf1/cip1) expression in 5-MeCDE-treated cells is attributed to a stealth characteristic of this environmental carcinogen that allows it to damage DNA and still escape the p53-mediated cellular defense mechanism of G1 arrest.

Blotting, Western↗
PubMed2004

[Environmental carcinogens and p53 gene mutation].

P53 gene is the most prominent tumor suppressor gene in human cancer among those genes that have been found till now. It not only acts as a tumor suppressor gene, but also participates in many cellular functions: cell cycle control, DNA damage and repair, gene transcription and cell apoptosis. The studies on the etiology of cancer show that 60-90% of human cancer are caused by the carcinogens in ambient environment. In the carcinogenic process, environmental carcinogens or pre-carcinogens can cause the changes in p53 gene and protein, the mutation spectra of p53 gene varies with the different carcinogens and cancer type. In these years, many studies on p53 suppressor gene were reported. This article reviews some of the major carcinogens in ambient environment which can affect the p53 gene and protein, and the carcinogenic effects of them.

Aflatoxin B1↗
PubMed2000

Metabolic genotype in relation to individual susceptibility to environmental carcinogens.

Earlier research indicates that within the human population there are considerable differences in the response to the carcinogenic activity of environmental carcinogens. Genetic polymorphism associated with several variants of the gene products participating in the biotransformation of various xenobiotics (including carcinogens) found in human populations constitutes a major cause of those differences. Enzymes coded by different variants of the same gene can differ in their catalytic activities. Up to the present time, most information on the effect of genetic polymorphism on the individual's ability to activate or deactivate environmental carcinogenic xenobiotics, and the associated risk of cancer, has been collected from studies of cytochromes P-450 belonging to gene families CYP1, CYP2 and CYP3, and of glutathione S-transferases and N-acetyltransferases. As carcinogen metabolism comprises a chain of chemical reactions involving numerous enzymes and enzyme-coding genes, research performed hitherto is able to offer only a very limited explanation of the associations between genetic polymorphism and the individual's susceptibility to cancer.

Carcinogens, Environmental↗
PubMed1994

Application of integrated genetic monitoring: the optimal approach for detecting environmental carcinogens.

Short-term in vitro genetic toxicity assays have not fulfilled their anticipated role in predicting the carcinogenicity of environmental agents reliably and economically. A reduction in emphasis from nonanimal systems to relevant animal assays and population monitoring will help to reestablish the credibility of this field. An analysis of the various steps in the carcinogenic process indicates the biological responses occurring during these stages can be utilized for early detection of environmental carcinogens. Emphasis should be placed on using the earliest significant response that indicates genetic damage (e.g., gene mutations and chromosome alterations). Assays that detect pregenomic damage (e.g., adduct formation), without evidence of subsequent heritable genetic alterations, may produce misleading results for risk assessment and should not be considered as stand-alone monitoring procedures. Late biological responses may occur in tissues or organs where genetic damage may be difficult to measure, and the opportunity for intervention diminishes as we approach the clinical outcome. For example, analyzing localized cells that contain activated protooncogenes and inactivated tumor suppressor genes, although they further document adverse response from exposure to carcinogens, may be of greater value for indicating clinical outcome than for genetic monitoring. With few notable exceptions, the window of opportunity for genetic monitoring is the period after exposure where genetic damage is evident and where circulating lymphocytes can faithfully record this damage. An ongoing study of butadiene-exposed workers illustrates an optimum protocol, where multiple assays can be carried out and correlated with both external and internal measurements of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Butadienes↗
PubMed1993

Human respiratory disease: environmental carcinogens and lung cancer risk.

Inhalatory intake of environmental agents may have adverse effects on health, the lung being the first target. Therefore, an increased risk of lung cancer and respiratory disease is in general considered as an indication of environmental health problems related to exposure to industrial emissions, traffic exhaust and smog. Classical epidemiological studies of the association between exposure to ambient air pollutants and respiratory dysfunctions and studies with laboratory animals have failed to demonstrate the distinct proof of risk for the general population that would be needed to form a basis for high impact environmental policy measures. Here, as an example, we describe the uncertainty in assessing risks of lung cancer associated with environmental exposure to polycyclic aromatic hydrocarbons. The recently introduced methodology of molecular cancer epidemiology is considered to yield more information on the relationship between exposure to environmental carcinogens and tumour development. Recent advances in the study of carcinogen (polycyclic aromatic hydrocarbon) dosimetry at the DNA level in combination with proto-oncogenic activation in humans are described.

Animals↗
PubMed1979

The Clearinghouse for Environmental Carcinogens of the National Cancer Institute, USA.

The NCI Clearinghouse for Environmental Carcinogens acts as an advisory body to the Carcinogenesis Testing Program of that Institute. It consists of 30 members, from academic institutions, labour organizations, consumer groups and industry. They are divided into three groups: the Chemical Selection group establishes priorities for compounds to be tested; the Experimental Design group decides on the test procedures and parameters to be used; and the Data Evaluation/Risk Assessment group review data from completed tests, for deficiencies in experimental design or conduct, the nature of the lesions produced and the statistical analysis of the results, and gives a critical opinion of the test.

Carcinogens, Environmental↗
PubMed2002

Identification of N-(deoxyguanosin-8-yl)-4-azobiphenyl by (32)P-postlabeling analyses of DNA in human uroepithelial cells exposed to proximate metabolites of the environmental carcinogen 4-aminobiphenyl.

DNA adducts formed in human uroepithelial cells (HUC) following exposure to N-hydroxy-4-aminobiphenyl (N-OH-ABP), the proximate metabolite of the human bladder carcinogen 4-aminobiphenyl (ABP), were analyzed by the (32)P-postlabeling method. Two adducts detected by (32)P-postlabeling were previously identified as the 3',5'-bisphospho derivatives of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP) and N-(deoxyadenosin-8-yl)-4-aminobiphenyl (dA-C8-ABP) (Frederickson S et al. [1992] Carcinogenesis 13: 955-961; Hatcher and Swaminathan [1995b] Carcinogenesis 16: 295-301). In contrast to the dG-C8-ABP adduct, which was 3'-dephosphorylated by nuclease P1, dA-C8-ABP was resistant to nuclease P1, thus providing an enrichment step before postlabeling. Autoradiography of the two-dimensional thin-layer chromatogram of the postlabeled products obtained following nuclease P1 digestion revealed several minor adducts, one of which has been identified in the present study. Postlabeling analyses following nuclease P1 digestion of the products obtained from the reaction of N-acetoxy-4-aminobiphenyl with deoxyguanosine-3'-monophosphate (dGp) demonstrated the presence of this minor adduct. The 3'-monophosphate derivative of the adduct was subsequently chromatographically purified and subjected to spectroscopic analyses. Based on proton NMR and mass spectroscopic analyses of the synthetic product, the chemical structure of the adduct has been identified as N-(deoxyguanosin-N(2)-yl)-4-azobiphenyl (dG-N==N-ABP). (32)P-Postlabeling analysis of the nuclease P1-enriched DNA hydrolysate of HUCs treated with N-OH-ABP or N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) showed the presence of the dG-N==N-ABP adduct. It was also detected in calf thymus DNA incubated with HUC cytosol and N-OH-ABP in the presence of acetyl-CoA, or incubated with HUC microsomes and N-OH-AABP. These results demonstrate that in the target cells for ABP carcinogenesis in vivo, N-OH-ABP and N-OH-AABP are bioactivated by acyltransferases to reactive arylnitrenium ions that covalently interact at the N2 position of deoxyguanosine in DNA.

Aminobiphenyl Compounds↗
PubMed1990

Mutational specificities of environmental carcinogens in the lacl gene of Escherichia coli. III: The cyclic nitrosamine N-nitrosopyrrolidine is a complex mutagen.

The mutational specificity of the cyclic nitrosamine N-nitrosopyrrolidine (NPYR) was determined through the DNA sequence characterization of 33 lacl-d mutations of Escherichia coli. Base substitution was the predominant class of mutation induced (91%). The majority of these (64%) occurred at GC base pairs, in accordance with the predicted significance of NPYR-derived guanine adducts. In addition, this nitrosamine efficiently produced other kinds of base substitution events as 11 of the 33 mutations occurred at AT base pairs. Deletion, frameshift, and duplication events were also recovered. The complexity of the NPYR mutational spectrum appears to be consistent with the suggestion that this compound acts through both direct and indirect mutational pathways.

Carcinogens, Environmental↗
PubMed1991

Mutational specificities of environmental carcinogens in the lacl gene of Escherichia coli H. V: DNA sequence analysis of mutations in bacteria recovered from the liver of Swiss mice exposed to 1,2-dimethylhydrazine, azoxymethane, and methylazoxymethanolacetate.

The host-mediated assay (HMA) was used to determine the spectra of mutations induced in the lacl gene of Escherichia coli cells recovered from the livers of Swiss mice exposed to the carcinogens 1,2-dimethylhydrazine (SDMH), azoxymethane (AOM), and methylazoxymethanolacetate (MAMA). These spectra were further compared with changes induced by dimethylnitrosamine (DMNA) in the HMA methodology. A total of 177 independent lacl mutations arising in the HMA following exposure to SDMH, AOM, and MAMA were analyzed. Single-base substitutions accounted for 97% of all mutations analyzed. The vast majority of the single-base substitutions consisted of G:C----A:T transitions (94% of all mutations). The remaining mutations consisted of A:T----G:C transitions (3% of all mutations) while non-base substitutions accounted for only 3% of the total mutagenesis. The latter mutations consisted of one frameshift mutation and four lacO deletions. The distribution of G:C----A:T transitions induced by the three chemicals in the first 200 bp of the lacl gene was not random, but rather clustered at sites where a target guanine was flanked at the 5' site by a purine residue.

1,2-Dimethylhydrazine↗
PubMed1981

Environmental carcinogens in the city air and lung cancer incidence.

Possible contribution of polycyclic hydrocarbons, trace metals, and gaseous pollutants to the incidence of lung cancer in the urban populations has been considered, including the role of carcinogens in the cigarette smoke. A long-term plan has been proposed for the epidemiological studies and control of urban lung cancer incidence. A comparative assessment of lung cancer mortality rate for occupational, urban, and rural exposure to levels of benzo(a)pyrene typical of these environments is presented.

Air Pollutants↗
PubMed1983

Effect of environmental carcinogens and other chemicals on murine alpha/beta interferon production.

Mouse embryo fibroblast cultures were pretreated with a variety of chemicals found in the environment. After chemical treatment, polyriboinosinic-polyribocytidylic acid was added to the cultures to induce alpha/beta interferon. Pretreatment of the cell cultures with the chemical carcinogens chloroform and beta-propiolactone severely inhibited the production of alpha/beta interferon, while pretreatment of the cell cultures with their poorly or noncarcinogenic analogs 1,1,1-trichloroethane and gamma-butyrolactone had no effect on interferon induction. Pretreatment of the cell cultures with the possible carcinogen diethylstilbestrol had no effect on alpha/beta interferon induction. Pretreatment of the cells with the poor or noncarcinogens pyrene and ascorbic acid did not effect interferon induction; in fact, treatment with ascorbic acid may have enhanced interferon production. These results augment previous findings that most potent carcinogens can inhibit the induction of alpha/beta interferon.

Animals↗