Simulation of fungal-mediated cell death by fumonisin B1 and selection of fumonisin B1-resistant (fbr) Arabidopsis mutants.
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Fumonisin B1 (FB1), a programmed cell death-eliciting toxin produced by the necrotrophic fungal plant pathogen Fusarium moniliforme, was used to simulate pathogen infection in Arabidopsis. Plants infiltrated with 10 microM FB1 and seedlings transferred to agar media containing 1 microM FB1 develop lesions reminiscent of the hypersensitive response, including generation of reactive oxygen intermediates, deposition of phenolic compounds and callose, accumulation of phytoalexin, and expression of pathogenesis-related (PR) genes. Arabidopsis FB1-resistant (fbr) mutants were selected directly by sowing seeds on agar containing 1 microM FB1, on which wild-type seedlings fail to develop. Two mutants chosen for further analyses, fbr1 and fbr2, had altered PR gene expression in response to FB1. fbr1 and fbr2 do not exhibit differential resistance to the avirulent bacterial pathogen Pseudomonas syringae pv maculicola (ES4326) expressing the avirulence gene avrRpt2 but do display enhanced resistance to a virulent isogenic strain that lacks the avirulence gene. Our results demonstrate the utility of FB1 for high-throughput isolation of Arabidopsis defense-related mutants and suggest that pathogen-elicited programmed cell death of host cells may be an important feature of compatible plant-pathogen interactions. (+info)
Effects of human intestinal flora on mutagenicity of and DNA adduct formation from food and environmental mutagens.
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Although the intestinal flora is believed to have a critical role in carcinogenesis, little is known about the role of the human intestinal flora on the effects of mutagens in vivo. The aim of the present study was to address a possible role of the human intestinal flora in carcinogenesis, by exploiting human-flora-associated (HFA) mice. The capacity of human faeces to activate or inactivate 2-amino-3-methyl-3H:-imidazo[4,5-f]quinoline (IQ) and 2-nitrofluorene was determined using the Ames assay. Human faecal suspensions that were active in this regard were then selected and orally inoculated into germfree NMRI mice to generate HFA mice. HFA, germfree, conventionalized and conventional mice were administered IQ, 2-amino-9H:-pyrido[2,3-b]indole (2-amino-alpha-carboline; AAC) and 2-nitrofluorene. The activity of human intestinal flora against mutagens could be transferred into the mice. In comparing germfree mice and mice harbouring an intestinal flora, the presence of a flora was essential for the activities of faeces against mutagens. After administration of IQ and 2-nitrofluorene, DNA adducts were observed in the mice with a flora, while adducts were extremely low or absent in germfree animals. DNA adducts after AAC treatment were higher in germfree mice in some tissues including colon than in mice with bacteria. Differences in DNA adduct formation were also observed between HFA mice and mice with mouse flora in many tissues. These results clearly indicate that the intestinal flora have an active role in DNA adduct formation and that the role is different for the different chemicals to which the animals are exposed. The results also demonstrate that the human intestinal flora have different effects from the mouse flora on DNA adduct formation as well as in vitro metabolic activities against mutagens. Studies using HFA mice could thus provide much-needed information on the role of the human intestinal flora on carcinogenesis in vivo. (+info)
Environmental malignant mesothelioma in southern Anatolia: a study of fifty cases.
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Malignant mesothelioma is a highly aggressive tumor of the serous membranes, which in humans results from exposure to asbestos and asbestiform fibers. Although occupational malignant mesothelioma is still the most common form of this lesion, naturally contaminated soil can play an important role in the development of environmental malignant mesothelioma in some parts of the world. Fifty cases of malignant mesothelioma (MM) from southern Turkey with no occupational history of asbestos exposure were reviewed regarding pathologic and clinical features. A case of hyaline fibrous plaque of the pleura was also included in this series. Histologically the cases were classified as epithelial (36 cases); sarcomatous (7 cases); and biphasic (7 cases). One of the sarcomatous cases was desmoplastic. Ultrastructural examination of the tumor tissue in three cases revealed long-surface microvilli in epithelial cells. Interstitial cells of the lung in one case showed electron-dense asbestos fibers in the cytoplasm. Mineralogical analyses of the lung tissue in three cases of MM and the case of pleural plaque showed high amounts of asbestos fibers most consistent with tremolite and actinolite. The clinical and pathologic features of our cases support that the environmental inhalation of asbestos is still a major health problem in some parts of Turkey. (+info)
Benzene in the environment: an assessment of the potential risks to the health of the population.
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OBJECTIVES: Benzene has long been recognised as a carcinogen and recent concern has centred on the effects of continuous exposure to low concentrations of benzene both occupationally and environmentally. This paper presents an overview of the current knowledge about human exposure to benzene in the United Kingdom population based on recently published data, summarises the known human health effects, and uses this information to provide a risk evaluation for sections of the general United Kingdom population. METHOD: Given the minor contribution that non-inhalation sources make to the overall daily intake of benzene to humans, only exposure from inhalation has been considered when estimating the daily exposure of the general population to benzene. Exposure of adults, children, and infants to benzene has been estimated for different exposure scenarios with time-activity patterns and inhalation and absorption rates in conjunction with measured benzene concentrations for a range of relevant microenvironments. Exposures during refuelling and driving, as well as the contribution of active and passive tobacco smoke, have been considered as part of the characterisation of risk of the general population. RESULTS: Infants (<1 years old), the average child (11 years old), and non-occupationally exposed adults, receive average daily doses in the range of 15-26, 29-50, and 75-522 microg of benzene, respectively, which correspond to average ranges to benzene in air of 3.40-5.76 microg/m(3), 3.37-5.67 microg/m(3), and 3.7-41 microg/m(3) for infants, children, and adults, respectively. Infants and children exposed to environmental tobacco smoke have concentrations of exposure to benzene comparable with those of an adult passive smoker. This is a significant source of exposure as a 1995 United Kingdom survey has shown that 47% of children aged 2-15 years live in households where at least one person smokes. The consequence of exposure to benzene in infants is more significant than for children or adults owing to their lower body weight, resulting in a higher daily intake for infants compared with children or non-smoking adults. A worst case scenario for exposure to benzene in the general population is that of an urban smoker who works adjacent to a busy road for 8 hours/day-for example, a maintenance worker-who can receive a mean daily exposure of about 820 microg (equal to an estimated exposure of 41 microg/m(3)). The major health risk associated with low concentrations of exposure to benzene has been shown to be leukaemia, in particular acute non-lymphocytic leukaemia. The lowest concentration of exposure at which an increased incidence of acute non-lymphocytic leukaemia among occupationally exposed workers has been reliably detected, has been estimated to be in the range of 32-80 mg/m(3). Although some studies have suggested that effects may occur at lower concentrations, clear estimates of risk have not been determined, partly because of the inadequacy of exposure data and the few cases. CONCLUSIONS: Overall the evidence from human studies suggests that any risk of leukaemia at concentrations of exposure in the general population of 3.7-42 microg/m(3)-that is at concentrations three orders of magnitude less than the occupational lowest observed effect level-is likely to be exceedingly small and probably not detectable with current methods. This is also likely to be true for infants and children who may be exposed continuously to concentrations of 3.4-5.7 microg/m(3). As yet there is no evidence to suggest that continuous exposures to these environmental concentrations of benzene manifest as any other adverse health effect. (+info)
Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China.
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Arsenic is an environmental toxicant and a human carcinogen. Epidemiology studies link human arsenic exposure to various diseases and cancers, including liver diseases and hepatocellular carcinoma. However, the molecular mechanisms for arsenic toxicity and carcinogenicity are poorly understood. To better understand these mechanisms, we used the human cancer cDNA expression array to profile aberrant gene expression in arsenic-exposed populations in Guizhou, China. The selected patients had a history of exposure to environmental arsenic for at least 6-10 years, and had arsenic-induced skin lesions and hepatomegaly. Samples were obtained by liver needle biopsy. Histology showed degenerative liver lesions, such as chronic inflammation, vacuolation, and focal necrosis. The University of North Carolina Hospitals provided normal human liver tissues from surgical resection or rejected transplants. Microarray was performed with total RNA from liver samples, and signal intensities were analyzed with AtlasImage software and normalized with 9 housekeeping genes. Means and SEM were calculated for statistical analysis. Approximately 60 genes (10%) were differentially expressed in arsenic-exposed human livers compared to controls. The differentially expressed genes included those involved in cell-cycle regulation, apoptosis, DNA damage response, and intermediate filaments. The observed gene alterations appear to be reflective of hepatic degenerative lesions seen in the arsenic-exposed patients. This array analysis revealed important patterns of aberrant gene expression occurring with arsenic exposure in human livers. Aberrant expressions of several genes were consistent with the results of array analysis of chronic arsenic-exposed mouse livers and chronic arsenic-transformed rat liver cells. Clearly, a variety of gene expression changes may play an integral role in arsenic hepatotoxicity and possibly carcinogenesis. (+info)
Lung cancer in lifetime nonsmoking men - results of a case-control study in Germany.
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Epidemiological studies of lung cancer among nonsmoking men are few. This case-control study was conducted among lifetime nonsmoking men between 1990 and 1996 in Germany to examine lung cancer risk in relation to occupation, environmental tobacco smoke, residential radon, family history of cancer and previous lung disease. A total of 58 male cases with confirmed primary lung cancer and 803 male population controls who had never smoked more than 400 cigarettes in their lifetime were personally interviewed by a standardized questionnaire. In addition, 1-year radon measurements in the living and bedroom of the subjects' last dwelling were carried out. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Having ever worked in a job with known lung carcinogens was associated with a two-fold significantly increased lung cancer risk (OR = 2.2; CI = 1.0-5.0), adjusted for age and region. The linear trend test for lung-cancer risk associated with radon exposure was close to statistical significance, demonstrating an excess relative risk for an increase in exposure of 100 Bq m(-3)of 0.43 (P = 0.052). Nonsignificantly elevated effects of exposure to environmental tobacco smoke in public transportation and in social settings were observed. No associations with a family history of cancer or previous lung diseases were found. Our results indicate that occupational carcinogens and indoor radon may play a role in some lung cancers in nonsmoking men. (+info)
Carcinogen substrate specificity of human COX-1 and COX-2.
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The activation of carcinogenic aromatic and heterocyclic amines and benzo[a]pyrene-7,8-diol to intracellular electrophiles by prostaglandin H synthase (COX) is well documented for ovine sources of this enzyme. Here, the arachidonic acid-dependent activation of substrates by human (h)COX-1 and-2 is examined, utilizing recombinant enzymes. The COX-dependent activation of benzidine (BZ), 4-aminobiphenyl, (+)benzo[a]pyrene-7,8-diol, (+)benzo[a]pyrene-7,8-diol, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), and 4,4'-methylenebis(2-chloroaniline) (MOCA) is assessed by means of COX-catalyzed, covalent DNA binding. The hCOX isozymes activated all substrates tested, activation varied from barely detectable for IQ (0.76 and 1.52 pmol bound/mg DNA for COX-1 and -2, respectively) to a high of 65 and 117 pmol bound/mg DNA for COX-1 and -2, respectively, for the activation of MOCA. BZ, which is an excellent peroxidase substrate, did not exhibit high DNA binding levels in hCOX assays and this phenomenon was found to be due to high levels of binding to protein, which effectively competed with the DNA for binding in the assay. The demonstrated ability of the COX enzymes to activate a variety of environmental and dietary carcinogens indicates a potential role for COX in the activation pathway of aromatic and heterocyclic amines and polycyclic hydrocarbons at extra-hepatic sites during early or late stages of carcinogenesis. (+info)
Risk of cancer in an occupationally exposed cohort with increased level of chromosomal aberrations.
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We used cytogenetic analysis to carry out a cohort study in which the major objective was to test the association between frequency of chromosomal aberrations and subsequent risk of cancer. In spite of the extensive use of the cytogenetic analysis of human peripheral blood lymphocytes in biomonitoring of exposure to various mutagens and carcinogens on an ecologic level, the long-term effects of an increased frequency of chromosomal aberrations in individuals are still uncertain. Few epidemiologic studies have addressed this issue, and a moderate risk of cancer in individuals with an elevated frequency of chromosomal aberrations has been observed. In the present study, we analyzed data on 8,962 cytogenetic tests and 3,973 subjects. We found a significant and strong association between the frequency of chromosomal aberrations and cancer incidence in a group of miners exposed to radon, where a 1% increase in frequency of chromosomal aberrations was followed by a 64% increase in risk of cancer (p < 0.000). In contrast, the collected data are inadequate for a critical evaluation of the association with exposure to other chemicals. (+info)