- الرئيسية
- وقائع المؤتمر
- QScience Proceedings
- وقائع المؤتمر
Sixth International Conference on Environmental Mutagens in Human Populations
- تاريخ المؤتمر: 26-29 Mar 2012
- الموقع: Qatar National Convention Center, Doha, Qatar
- رقم المجلد: 2012
- المنشور: ٠١ مارس ٢٠١٢
21 - 40 of 107 نتائج
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Exposure To Desert Cyanobacteria May Pose A Risk To Human Health
المؤلفون: James MetcalfAbstractStudies on the occurrence of cyanotoxins in desert environments are relatively rare, compared with aquatic environments. Cyanobacteria are, however, important primary-producers in desert environments where they grow rapidly after seasonal rains, stabilizing and fertilizing arid habitats. As cyanobacteria can produce toxins, we tested whether desert cyanobacteria presented a risk to human health.
Cyanobacterial crust coverage was measured using random quadrats, and representative samples of cyanobacterial crust from wadis and sabkha were removed for analysis. Extracts were produced using standard methods and toxins were measured by hplc, uplc, mass spectrometry, elisa and enzyme inhibition assays.
Cyanobacterial crusts were found to cover 80 percent of the state of qatar, and up to 87 percent of the land was covered with cyanobacteria. The neurotoxic amino acids β-n-methylamino-l-alanine (bmaa) and 2,4-diaminobutyric acid (dab) were detected in the crust material. Microcystins were detected at concentrations between 3.8 and 238 ng/g crust, equivalent to between 7 and 40µg/m2. Pcr products for the mycd gene for microcystin biosythesis were detected after amplification of dna from desert crust samples. In addition, the presence of anatoxin-a(s) was inferred by acetylcholine esterase inhibition assay. Based on the concentration of microcystins detected in crust, with reference to previously published inhalation toxicity for microcystins, in combination with the amount of dust potentially inhaled by a person, the dose of microcystins could exceed a tdi value of 3ng/kg/day for an average adult.
The presence of cyanotoxins in desert crusts has important implications for human health and further studies are required to monitor desert dust storms which may contain these crusts. Furthermore, an understanding of the risks of inhaling particles containing cyanotoxins is warranted.
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Susceptibility of Cancer among Tannery Workers Exposed to Chromium
المؤلفون: Amal S HusseinAbstractThere is inadequate evidence about the carcinogenic effect of human exposure to chromium compound. This study aimed to estimate cytogenetic and carcinogenic effects of occupational exposure to chromium in tannery workers, and comparison of the diagnostic value of urinary cytology, nuclear matrix protein (NMP) and Kontron Image Analysis System for the detection of occult bladder cancer. Methodology: The study included 38 tannery workers and 40 unexposed subjects. Cytogenetic analysis was carried out with standard procedures on heparinised venous blood leukocytes. Urine samples were tested for abnormal cells through cytopathological examination and DNA image analysis for any abnormality in the cell life cycle, in addition to NMP, a tumor marker specific for bladder cancer, to detect suspected bladder lesions. Results: Statistical analyses revealed that there was no significant difference in chromosomal aberrations and sister chromatic exchange between tannery workers and their control. But, there were significant differences between the examined groups according to the cytopathological examination of the urine samples and DNA images. In smoking tannery workers, 4C and S phase were significantly higher and 2C was significantly lower compared to those not smoking. There was no significant difference between the two groups according to NMP. The percent of positive NMP in smoking workers was higher compared to non-smokers in both groups. Conclusion: Tannery workers were at high risk for bladder pre-cancerous lesions, but, cytogenetic changes were not approved. Urinary cytology as well as NMP can provide useful excluding information, and can be used in screening for bladder cancer in the population at risk to exclude the presence of the condition, but not as a diagnostic methods.
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Testing the Genotoxicity of Sodium Arsenate in Human Lymphocytes
المؤلفون: Ola Hassan Mohamed El-HabitAbstractSodium arsenite (SA) is a compound with formula NaAsO2. It is the sodium salt of arsenous acid which was tested for its clastogenic effect alone and in combination with gamma rays on the whole blood culture and on isolated lymphocyte culture. The results showed a significant difference in the yield of aberrations induced with respect to the culture time of 48 hours. Whole blood culture showed significant increase in gaps and breaks, whereas isolated lymphocytes culture showed significant inhibition of cell cycle and 75 percent of the lymphocytes were in their first cell cycle at 72 hours. Arsenite showed co-mutagenicity with different doses of gamma rays delivered immediately or few hours after treatment of the culture with SA. The results suggest that SA also is mutagenic at the dose level used and provide support for the indispensability of whole blood culture for evaluation of the in vivo effect of any suspected mutagen. Using isolated lymphocytes appear to have problems leading to extensive cell cycle delay.
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In Vivo Mutagenesis by UVB Irradiation: Detection and the Underlying Mechanisms
المؤلفون: Takehiko NohmiAbstractHuman genome is continuously exposed to endogenous and exogenous genotoxic agents. To evaluate genotoxicity of the agents, we have developed gpt delta mice transgenic gene mutation assay, which allows detection of mutations in vivo in any organ of mice. The mice have been established by microinjection of lambda EG10 phage DNA into fertilized eggs of C57Bl/6J mice. A feature of the transgenic mice assay is incorporation of two selections to detect different types of mutations, i.e., point mutations such as base substitutions and frameshifts by gpt or 6-thioguanine selection and deletion mutations by Spi- (sensitive to P2 interference) selection. The gpt assay effectively detects point mutations induced by a variety of chemical agents that induce DNA adducts while Spi- assay exclusively detects deletions with the molecular sizes from 1 base pair (bp) to several kilo bps (kb). We report that UVB irradiation induces base substitutions and deletions in the epidermis of gpt delta mice and also that p53 suppresses the deletions and complex mutations in vivo. The mice were exposed to UVB at single doses of 0.3, 0.5, 1.0, 1.5 and 2.0 kJ/m2. At four weeks after irradiation, mutations in the epidermis were analyzed. The UVB irradiation induced G:C to A:T mutations at dipyrimidine sites, such as 5’-TC-3’ and 5’-CC-3’. Tandem transitions such as CC to TT were also observed. In addition to point mutations, UVB induced deletions with the size of more than 1 kb. More than half of the large deletions occurred between short homologous sequences from 1 to 6 bps while others had flush ends. The results suggest that the deletions are generated by end-joining of double-strand breaks in DNA. To examine protective roles of p53 against UVB-induced mutagenesis, mutations were measured in the epidermis of UVB-induced p53+/+ and p53-/- gpt delta mice. The mice were exposed to UVB at single doses of 0.5, 1.0 and 2.0 kJ/m2, and the mutant frequencies (MF) were determined in the epidermis 4 weeks after the irradiation. Although UVB enhanced gpt MF more than 10 times over the unirradiated mice, there were no significant differences in gpt MF and the mutation spectra between p53+/+ and p53-/- mice. In contrast, the frequency of Spi- large deletions of more than 1 kb and complex mutations were significantly higher in unirradiated p53-/- mice than in unirradiated p53+/+ mice. These large deletions and complex mutations increased in a UVB-dose-dependent manner in p53+/+ mice, while no increase was observed in p53-/- mice. These results suggest that p53 does not suppress point mutations induced by UVB but suppresses large deletions and complex mutations in vivo.
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Genotoxicity Induced By Nanomaterials
المؤلفون: Yukari TotsukaAbstractNanomaterials are useful for their characteristic properties and are commonly used in various fields. The assessment of genotoxicity and safety of nanomaterials are, therefore, of serious concern. So far, we have examined genotoxic effects of various nanomaterials, including fullerenes, kaolins, multi-wall carbon nanotubes and magnetite, using in vitro and in vivo assay systems. All of these nanomaterials significantly induced micronuclei and enhanced frequency of sister chromatid exchange in cultured mammalian cells. When ICR mice were intratracheally instilled with a single dose (0.2 mg/animal) of these nanomaterials, DNA damage of the lungs analyzed by Comet assay increased about two to three times that of the vehicle control. We also analyzed the formation of DNA adducts related to oxidative stress (8-oxo-2’-deoxyguanosine and heptanone etheno-deoxyribonucleosides) in lungs of mice exposed to nanomaterials using the stable-isotope dilution LC-MS/MS method. These DNA adduct levels were increased in the nanomaterial-treated mice compared with a vehicle control. Moreover, we examined in vivo mutagenicity of nanomaterials using gpt delta transgenic mice intratracheally-instilled with four consecutive doses of 0.2 mg per animal. All nanomaterials increased gpt mutant frequencies in the lungs of gpt delta transgenic mice. Mutation spectra analysis showed transversions were predominant, and among these, the G:C to C:G was commonly increased by these nanomaterials. Based on these observations, it is suggested that oxidative stress and inflammatory responses are probably involved in the genotoxicity induced by nanomaterials. To further clarify the mechanisms of genotoxicity by nanomaterials, comprehensive DNA adduct analysis (DNA adductome) is now being investigated for DNA samples derived from lungs of mice exposed to nanomaterials. On the other hand, the effects of atypical nanomaterials such as difference of surface structure on genotoxicity are not fully elucidated yet. In the present study, we investigated the DNA damaging potency of two types of kaolins by Comet assay, and found out that genotoxicity differs between two types of kaolins. We are now investigating the incorporation rate into mammalian cells, and reactive oxygen species generation of these kaolins.
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Basic Mechanisms in Spontaneous and Induced Mutagenesis
المؤلفون: Robert P FuchsAbstractLiving cells possess a panel of specialized DNA polymerases that deal with the large diversity of DNA lesions that occur in their genomes. How specialized DNA polymerases gain access to the replication intermediate in the vicinity of the lesion is unknown. Using a model system in which a single replication-blocking lesion can be bypassed concurrently by two pathways that leave distinct molecular signatures, we analyzed the complex interplay among replicative and specialized DNA polymerases. In Escherichia coli, the DNA damage response entails several processes such as stalling of the replication fork, activation of the SOS response and induction of dNTP synthesis. Following UV-irradiation, the ribonucleotide reductase (RNR) NrdAB that catalyzes the limiting step in dNTP synthesis, is up-regulated, leading to an increase in dNTP levels. In the present study, we investigate the effect of increased dNTP levels on the process of translesion synthesis (TLS) under DNA damage conditions. We present direct evidence that an elevated dNTP pool level facilitates translesion synthesis (TLS). TLS is a two-step mechanism involving the insertion of a nucleotide opposite the lesion and the subsequent extension steps. Although Pol III, the replicative DNA polymerase, can insert a nucleotide across certain lesion, its proofreading activity usually recognizes the inserted base across the lesion site as a mispair and removes it, thus preventing the subsequent extension steps. Our results suggest that high dNTP levels bolster the polymerase activity of Pol III, in turn reducing its exonuclease activity. The shift in the equilibrium from the exonuclease activity towards the polymerase activity of Pol III favors the production of a key TLS intermediate, ie the intermediate that contains a base inserted across from the lesion site. This intermediate is subsequently elongated by the specialized TLS polymerases. In support of the hypothesis of proofreading activity attenuation of Pol III, we show a robust increase in spontaneous mutagenesis under conditions of elevated dNTP levels referred to as the spontaneous dNTP mutator phenotype.
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Mechanisms of Liver Carcinogenesis: Studies of Co-morbidity Factors Using Animal Models
المؤلفون: Ivan RusynAbstractHepatocellular carcinoma (HCC) is the most common type of primary malignancy in the liver. Main risk factors of HCC are well-defined and include hepatitis B virus (HBV); lifestyle, diet and environmental factors (e.g., alcoholic beverages, aflatoxin B1 (AFB1), and tobacco smoking); and metabolic diseases (e.g., obesity, diabetes and non-alcoholic steatohepatitis). Importantly, the rise in incidence of HCC in the developed countries has been attributed, at least in part, to an increase in hepatitis C virus (HCV) infections and non-alcoholic steatohepatitis, pathological states whose prevalence is growing in the US and Europe. In addition, liver fibrosis and cirrhosis are well known precursor liver disease states for hepatocellular HCC in humans. While animal model studies of HCC have contributed much of the understanding of the molecular events leading to disease initiation, progression and promotion, few publications examined co-morbidity factors that are known to contribute to HCC in humans. This presentation will describe two examples of experimental animal models of HCC where co-morbidity factors (HCV+AFB1, or genotoxic carcinogen diethylnitrosamine+liver fibrosis) were explored. These studies afford an opportunity to examine the molecular mechanisms that are crucial for the synergy between co-morbidity factors.
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Low-Dose Carcinogenicity Studies and Mechanisms
المؤلفون: David DeMariniAbstractOne of the major deficiencies of cancer risk assessments is the lack of low-dose carcinogenicity data. Most assessments require extrapolation from high to low doses, which is subject to various uncertainties. Only four low-dose carcinogenicity studies and five low-dose biomarker/pre-neoplastic studies have been performed. The four carcinogenicity studies involved exposures of 24,192 mice to two acetylaminofluorene, 4,080 rats to nitrosamines (NDMA and NDEA), 40,000 rainbow trout to dibenz[a,l]pyrene, and 20,00 trout to aflatoxin B1. The low-dose biomarker/pre-neoplastic studies involved exposure of 1,145 rats to MeIQx, 2,000 rats each to DEN or DMN, 1,920 rats to PhIP, and 50 rats to potassium bromate. In most cases there was some evidence for a threshold effect for the induction of cancer or biomarkers of cancer. However, absolute proof of a threshold effect for carcinogenicty could not be demonstrated unambiguously by any of the carcinogenicity studies due to the limited number of animals used. The induction of stable DNA adducts was not predictive of tumors in the mouse and trout studies. All of the biomarkers evaluated, including stable DNA adducts, oxidative damage, mutation, and pre-neoplastic foci, exhibited threshold effects, ie, they were not inducible or detectable at the lowest doses tested. Clear proof of a threshold effect for any of the carcinogens tested is lacking. However, the limited data available suggest that these carcinogens may exhibit threshold effects for the induction of carcinogenic biomarkers and cancer. Given the fact that some mutagens clearly show threshold effects and that cancer is a multi-step process, it is possible that carcinogens may also show a threshold effect.
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Environmental Toxicogenomics: How Genomic Technologies are Impacting the Science of Toxicology
المؤلفون: Richard PaulesAbstractDecision-makers in safety assessment of exposures to environmental stressors and health care providers need improved biomarkers of toxic exposures and biomarkers of adverse events that precede the development of overt injury or disease. Two toxicogenomic studies will be presented that demonstrate the utility of genomic approaches for developing potential biomarkers of toxicity for both nephrotoxicity and hepatotoxicity. The use of calcineurin inhibitor (CI) immunosuppressants has revolutionized the clinical practice of organ transplantation. However, chronic nephrotoxicity limits their long-term utility. In order to understand the pathophysiology that underlies the development of CI-associated nephrotoxicity and to develop CI-specific biomarkers of toxicity, rats were dosed with cyclosporine A (CsA) or FK506, or rapamycin, and gene expression profiling was performed on RNA isolated from kidneys 24 hours after one, seven, 14 or 28 daily doses. A gene expression signature was identified that was correlated with CI-specific kidney damage and responded with an earlier onset than the more general kidney injury biomarkers Kim-1 and Clusterin, and is CI-specific. We have been interested in gene expression patterns derived from peripheral blood cells as they would provide useful early indicators of acute toxicity. With respect to hepatotoxicity, the case of acetaminophen (APAP) intoxication is particularly important, as this is the leading cause of liver failure in the United States. We generated a blood gene expression data set from rats exposed to APAP to train genomic classifiers of toxicity. Prediction accuracy was tested on a blinded, independent rat blood test data set and ranged from 88.9% to 95.8%. Genomic markers outperformed predictions based on traditional clinical parameters. We are currently testing the hypothesis that gene expression data from peripheral blood cells can provide valuable information about hepatotoxicity to humans, well before liver damage is detected by classical parameters. Our results support the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage.
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Genetic, Genomic and Proteomic Approaches to Identify Arsenic Susceptibility and Carcinogenicity
المؤلفون: Ashok Kumar GiriAbstractIn West Bengal, India, more that 26 million people are exposed to arsenic through drinking water. However, only less than 15% to 20% of them show arsenic-induced skin lesions. Hence it is assumed that genetic variations might play an important role in arsenic-induced toxicity and carcinogenicity. Major genetic, genomic and proteomic approaches have been made to find out the cause of arsenic susceptibility. For this reason, the Chromosomal Aberrations (CA), Comet assay and challenge assay were performed and single nucleotide polymorphisms (SNPs) studies were carried out for a number of genes that may involve the different pathways in arsenic metabolism and detoxification SNPs of p53 gene, PNP, ERCC2 and XRCC3 genes were also analyses. Attempts have also been made to identify the different proteins in the plasma of the individuals exposed to arsenic that may be responsible for arsenic susceptibility. Individuals with p53 codon 72 Arg/Arg genotype are overrepresented, indicating that this genotype is more susceptible to arsenic-induced toxicity. Lys/Lys genotype in the ERCC2 polymorphism was almost five fold overrepresented in the arsenic-induced hyperkeratosis skin lesions group when compared to the group with no skin lesions. In each of these cases, individuals with risk genotype were found to have significantly higher genetic damage, functionally validating our associations. In case of XRCC3 T241M polymorphism, presence of at least one M allele (M/M or T/M) was protective toward development of arsenic-induced skin lesions, and also toward arsenic-related peripheral neuropathy and conjunctivitis. A significant correlation was observed between protective genotype and decreased frequencies of chromosomal aberrations. Results of DNA repair studies through Challenge and Comet assay show that the individuals with arsenic-induced skin lesions have suboptimal DNA repair capacity and are hence inefficient in combating the DNA damage induced by chronic arsenic exposure. Thus the above results indicate that the suboptimal DNA repair and genetic variations are responsible for arsenic induced toxicity and carcinogenicity. Attempts were made to identify the proteins that are differentially expressed in the arsenic unexposed and arsenic exposed skin symptomatic and asymptomatic individuals through iTraq. A number of proteins were found to be differentially expressed between exposed individuals with and without arsenic-induced skin lesions and might thus play a critical role in arsenic susceptibility.
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Genomic Approach for Understanding the Mutagenic and Carcinogenic Mechanisms of Heavy Metal Nickel in terms of Gene-environment Interaction.
المؤلفون: Young R SeoAbstractNickel is a toxic metal that causes mutagenesis and promotes carcinogenesis. Its toxicological properties are partially related to the generation of reactive oxygen species (ROS) that can induce DNA damage and mutation. It also interfere redox-sensitive transcription factors, particularly p53 and hypoxia-inducible factor 1 (HIF-1), which might lead to genomic expression change. Nuclear factor erythroid-2 related factor 2 (Nrf2) is a redox factor which is responsible for control of oxidation/reduction status and consequent cytoprotection against environmental toxicants. First, we confirmed the protective effect of the Nrf2 gene under oxidative stress and DNA damage induced by 20uM nickel at sub-lethal doses in terms of gene-environment interactions. Here, we attempted to identify potential nickel and Nrf2-responsive targets and the relevant pathway via microarray, qRT-PCR, and pathway analysis. Under nickel exposure conditions, we detected significantly higher amounts of DNA damage via a comet assay, in addition to increased intracellular ROS generation, in Nrf2 lacking cells in comparison to Nrf2 wild-type cells. Additionally, gene expression data were analyzed via microarray assays for the selection of Nrf2-responsive genes under nickel treatment. In particular, altered expressions of 10 genes (CAV1, FOSL2, MICA, PIM2, RUNX1, SLC7A6, APLP1, CLSPN, PCAF, and PRAME) were verified by qRT-PCR. These genes functioned principally in a variety of biological processes, including oxidative stress response, DNA repair, necrosis, and cell survival. These findings indicate that Nrf2 is an important factor that performs a protective role in the suppression of oxidative stress-induced DNA damage by environmental nickel exposure. Furthermore, we describe the potential biomarkers regarded as molecular targets for Nrf2-related cellular protection against nickel exposure.
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Proteomic Profiling of Lung Cancer Specific Plasma Proteins: Novel Diagnostic Strategy for Environmentally Exposed Male Lung Cancer Patients
المؤلفون: Rita SinghAbstractLung carcinomas are highly heterogeneous malignancies and the patient survival rate for lung cancer is very low. This is due to the lack of diagnostic markers for lung cancer and for predicting response or monitoring recurrence after treatments of the lung carcinomas. Human blood plasma proteomics has become one of most preferred method for cancer biomarker discovery. In this study, we used plasma for the detection of lung cancer-specific proteomic biomarker pattern by one-dimensional SDS- Polyacrylamide Gel Electrophoresis followed by nLC-MS/MS. Panels of low molecular weight proteins were found to be lung cancer specific or were not found in the parallel samples from ovarian and breast cancer plasma. To reveal the interactions of identified proteins we analyzed them by I2D - Interologous interaction software. Out of 30 identified proteins, 10 showed association with albumin. Albumin is the most abundant protein in plasma and serum and protects the smaller proteins and peptides from renal clearance. On integrating bioinformatics data with published literature 50% of identified proteins were found to be albumin associated. A list of proteins was identified such as apolipoprotein, transthyretin, haptoglobin alpha, haemoglobin, alpha-1 acid glycoprotein, zinc-alpha-2-glycoproteins known to be associated with lung cancer. To assess the potential usefulness of the identified proteomic pattern for diagnostic purpose, we raised the antibodies to the lung cancer specific proteins. Western blot analysis of lung, ovarian and breast cancer plasma samples with the lung cancer specific antibodies confirmed our findings on the specificity of the proteomic pattern to lung cancer. Validation of the lung cancer specific proteomic pattern would have significant implications for the early detection and diagnosis of lung cancer and better management of high risk patients.
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Inactivation of the Putative Tumour Suppressor Gene DOK1 by Epigenetic Modifications in Human Cancers
المؤلفون: Bakary SyllaAbstractEpigenetics investigates heritable changes in gene expression that occur without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation and histone modifications, can change genome function under exogenous influence. Results obtained from animal models indicate that in utero, or early-life environmental exposures, produce effects that can be inherited transgenerationally and are accompanied by epigenetic alterations. The search for human equivalents of the epigenetic mechanisms identified in animal models is in progress. I will present evidence from human environmental studies indicating that epigenetic alterations may mediate effects caused by exposure to environmental toxicants. In these investigations, we have shown that air pollution exposure is associated with altered methylation of human repetitive elements or genes. In recent preliminary studies, we have shown alterations of histone modifications in subjects exposed to metal-rich airborne particles. I will present original data demonstrating that altered DNA methylation in blood and other tissues is associated with environmentally induced disease, such as cardiovascular disease and asthma. On the basis of current evidence, I will propose possible models for the interplay between air pollution exposure and the human epigenome.
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Epigenetic Effects of Early Environmental Exposures on Whole Genomes and Repetitive Elements
المؤلفون: Christopher FaulkAbstractIncreasing evidence suggests that environmental exposures during in utero development impact adult health through epigenetic modifications of the genome. High production-volume chemicals such as bisphenol A (BPA), and known toxins including lead (Pb), are ubiquitous in the environment and may contribute to disease susceptibility through epigenetic mechanisms. Developmental and adult exposure to environmentally relevant levels of BPA has been shown to affect both global and gene-specific DNA methylation patterns. Preliminary studies also indicate that Pb exhibits epigenetic effects that may contribute to its known neurotoxic and obesogenic activities. During early embryogenesis, epigenetic marks, including DNA methylation, are reset at specific times in both rodents and humans. Utilizing the viable yellow agouti (Avy) mouse as a biosensor, we assess the impact of BPA and Pb on the DNA methylation status of the genome by examining coat color shifts, whole genome methylation, and repetitive element methylation. Since repetitive elements comprise nearly half of the human genome and contribute to disease when reactivated, the suppressive methylation of these elements during development is crucial to human health outcomes. Previously, only a handful of repetitive elements were known to be epigenetically variable; here we describe additional novel and environmentally responsive epigenetic elements. To illustrate the long-term biological dysregulation caused by BPA and Pb, we survey the epigenomic changes on repetitive elements and the whole genome induced by developmental exposure in mice as well as humans. The characterization of epialleles in the mouse, the most widely used model for human health, is crucial for the identification of human epialleles and the development of epigenetic therapies for the prevention and treatment of human disease throughout the life course.
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Correlation Among Epigenetic, Environmental and Genetic Factors in Colorectal Carcinoma and Alzheimer's Disease
المؤلفون: Lucia MiglioreAbstractIt has been postulated that dietary components, in conjunction with the presence of susceptibility genes, can influence the epigenome, altering genetic expression and potentially modifying colorectal cancer (CRC) as well as Alzheimer’s disease (AD) risk. The aim of two ongoing projects is to investigate the interaction of dietary components (folate levels) with genetic susceptibility (polymorphisms of genes involved in the folate metabolic pathway) in influencing the methylation levels of genes critical for colon cancer or for neurodegeneration. We are currently analyzing the methylation status of CRC related genes including RASSF1A, MGMT, APC, hMLH1, and CDKN2A in the DNA obtained from epithelial cancerous cells isolated from either early or late stage CRC tissues through immuno-magnetic method, in order to evaluate the association between methylation and clinicopathological features. Promoter methylation profiles are evaluated by means of Methylation-Sensitive High-Resolution Melting (MS-HRM) technique. Results on a subgroup of 30 CRC patients suggest that APC is the most frequently methylated gene in our cohort, and all the other genes are found to be methylated in approximately 20-25% of the cases. Several CRC patients had elevated plasma Hcy levels (above the normal range), consistent with a condition of impaired one-carbon metabolism. We also screened blood DNA from 20 late-onset AD patients, 20 healthy controls and 20 individuals with Mild Cognitive Impairment (MCI) for CpG methylation analyses in the promoter of the β-secretase gene (BACE1). Our epigenetic analysis revealed that the BACE1 gene might be subject to epigenetic regulation due to methylation/demethylation processes of different CpG islands. The outcomes of these studies comprise more knowledge of predisposing conditions (diet, genetic variants) to develop colon cancer or neurodegeneration with the possibility to undergo a primary prevention, moreover to get information on epigenetic biomarkers associated with susceptible individuals, easily detectable and useful to design a precocious diagnostic tool.
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Serum Organochlorines Pesticides Level, Cyp1a1, Cyp1b1 Genetic Polymorphism and Risk of Breast Cancer
المؤلفون: Fatima Abu Baker Hamad Ahamed El HagAbstractThe aim of this study was to find the relationship between the Organochlorine and PCBs pesticides residues and female breast cancer, together with the related genetic polymorphisms, biochemical parameters and anthropometric measurements in Sudanese female breast cancer patients attending the Wad-Madina teaching hospital, Gezira State, Sudan. The prospective study was performed on 200 female breast cancer patients (of ages ranging between 25-80 years). 100 healthy persons of a range of ages and from different community areas were chosen to form a control group. The Organochlorine and PCBs pesticides residues were measured in serum and adipose tissues. We used Gas chromatographs, Thermoquest-Trace GC with 63Ni selective Electron- Capture Detector with advanced software and Nucon-GC-5765 series equipped with Nitrogen Phosphorus Detector. The genetic polymorphisms was determined the Cytochrome P- 450 (CYP1A1) in the blood and tissues. The DNA extraction by QIAamp DNA Mini Kits .PCR Technique was used for laboratory genetic analysis by using Genotypes Restriction Enzymes Length Polymorphisms (RFLP). Anthropometrics measurements were determined by weight, height and body mass index (BMI). A questionnaire was completed in order to obtain information regarding: sociodemographic characteristics, obstetric and gynaecological variables and nutritional information. The risk of breast cancer increased among women with higher serum concentrations of any Organochlorine: o, p’-DDT, p, p’-DDT, p, p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, beta-hexachlorocyclohexane, trans-nonachlor, cis-nonachlor, oxychlordane, mirex, or PCBs. The high serum levels of PCBs were associated with a decreased risk of breast cancer; CYP1A1 polymorphisms were more frequent in younger patients and in patients with high level Organochlorine pesticides. Organochlorine pesticide residues may increase the risk of breast cancer in females, particularly in premenopausal women in Sudan. CYP1A1 polymorphisms probably predispose to an earlier onset of breast cancer and might be associated with a higher Organochlorine pesticides level, but further studies on a much larger group are required to substantiate our findings.
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Cytogenetic Biomarkers, DNA Repair Efficiency and Susceptibility to Gentoxic Exposure of Lymphocytes from Persons Exposed to Low and High Doses of Iodine –131.
المؤلفون: Antonina Cebulska-WasilewskaAbstractIn case of any accidental mass exposure and particularly in cases of radiation contamination, there is a need to estimate possible effects in a short time. The best known, gold standard, accurate and associated to cancer risk increase proofed measurement of absorbed dose via classic cytogenetics is unfortunately laborious and time consuming. The aim of our human monitoring studies performed on subjects from various cities and countries was to investigate if exposures to genotoxic agents, environmental, occupational, diagnostic or therapeutic can cause a detectable increase risk. Exposures to ionizing radiation, pesticides, mercury ions, benzene related compounds have significantly elevated levels of cytogenetic damage. The 25 years follow up studies revealed significantly increased risk of cancer in the group of subjects characterized by the highest levels of the detected chromosomal damage. Results of DNA repair competence assay, with a use of challenging dose of X-rays and the detection of induced DNA damage by the SCGE assay, have correlated to levels of induced chromosome damage detected by classic and FISH cytogenetic methods. Results from studies on the influence of occupational exposure to environmental PAHs, on the efficiency of the radiation induced DNA damage’s repair, have shown a strong variability between donors and significant decrease of the DNA repair efficiency in exposed subjects, that was strongly differentiated between groups stratified first according to various genotypes for genes, encoding enzymes involved in the process of bio-transformation (CYP1A1(Ile/Val), GSTM1, NAT2) or DNA repair (EPHX4 or XRCC1)1 and then to levels of exposures. Results of our studies in various groups of (prostate or colon cancers or thyroid diseases) patients have also shown the higher levels of chromosome aberrations frequencies and associated significant reduction of cellular DNA repair efficacy in comparison to healthy subjects groups. Thyroid patients were examined first after low diagnostic 131 one, and another time five weeks after medical treatments with higher doses. Strong inter individual variability was observed. Preliminary study of polymorphisms XRCC1 and XRCC3 genes encoding enzymes involved in the repair process, confirmed strong influence of genes of the DNA damage induced by IR and stepped up levels of biomarkers, the predictor of cancer risk. Our results demonstrate also that the DNA repair competence biomarker (RCB), fast and inexpensive, can reliably detects an influence of ontogenetic or exogenous factors on biological effects, which via alteration of the DNA repair processes can rise levels of chromosome aberrations and result in increased health risk. That knowledge might be key factor in stratification of the population at risk, or in predicting beneficial range for high dose therapeutic procedures.
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Research Strategies to Advance Our Understanding Early Life Exposures to Improve Child Health and Reduce Disease Burden.
المؤلفون: William SukAbstractThe environment is a fundamental determinant of human health. Targeting the best scientific research to environmental problems, wherever they arise, can lead to breakthroughs in our understanding that can be of great benefit to all. Environmental factors cause or influence an array of conditions that lead to illness and death among mothers and children, populations at greatest risk for premature death and illness. Exposures during pregnancy can influence maternal conditions during pregnancy, such as: asthma, anemia, and infectious disease susceptibility, and result in adverse pregnancy outcomes, such as: miscarriage, intra- uterine growth retardation, prematurity. These exposures can also adversely affect long-term health outcomes for the offspring, leading to chronic diseases. Developmental-stage specific exposures and windows of susceptibility are critically important since the effects of any given exposure are determined largely by the time in the developmental and maturational process when exposure occurs. Therefore, it is important to gain a better understanding of developmental toxicology: the effect of in utero exposures that may cause permanent functional changes that result in increased susceptibility to disease/dysfunction later in the life span. There is evidence that some environmental agents, especially those with endocrine agonist or antagonist activity, may alter developmental programming via alteration in gene expression or gene imprinting resulting in functional deficits that become apparent later in life. It is essential to translate research findings and knowledge into information, resources, and/or tools used by public health and medical professionals, and by the public to improve overall health and well-being. This can be accomplished by launching a globally strategic series of networks to enhance collaborations and communications between and amongst environmental health investigators, integrating investigator-initiated research, establishing and maintaining partnerships, and developing community-based primary-care and health services for vulnerable populations. The objective is fundamental: to translate the basic discoveries that prevents disease and improves health..
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Recent Findings from the Health Effects of Arsenic Longitudinal Study in Bangladesh
المؤلفون: Joseph H GrazianoAbstractThe Health Effects of Arsenic Longitudinal Study (HEALS), a large multidisciplinary prospective cohort study in Araihazar, Bangladesh, was established in 2000 to evaluate the effects of a wide range of arsenic (As) exposures on various health outcomes, including premalignant and malignant skin lesions, total mortality, and children’s neuropsychological development (1). In this presentation, some important recent findings will be presented. Approximately 12,000 adults, aged 18-75, were recruited for the study; their well water As concentrations ranged from 0.1 to 864 ug/L. Since 2000, each participant has been evaluated roughly every other year. A total of 7.31, 9.95 and 2.03% of the participants completing 4 years of active follow-up reported having a chronic cough, breathing problem or blood in their sputum, respectively, as assessed by trained physicians. We found a dose-response relationship between As exposure and clinical symptoms of respiratory diseases (2). The mechanism of this effect, also reported in other countries, is not known. In particular, these adverse respiratory effects of As were clearly evident in the low to moderate dose range. We have also studied the association between As exposure and total mortality. 407 deaths were ascertained between October 2000 and February 2009. Multivariate adjusted hazard ratios for all-cause mortality in a comparison of arsenic at concentrations of 10•1–50•0 μg/L, 50•1–150•0 μg/L, and 150•1–864•0 μg/L with at least 10•0 μg/L in well water were 1•34 (95% CI 0•99–1•82), 1•09 (0•81–1•47), and 1•68 (1•26–2•23), respectively (3). Deaths due to diseases of circulatory system accounted for 43% of total mortality in the population. The mortality rate for cardiovascular disease was 214.3 per 100 000 person years in people drinking water containing <12.0 μg/L arsenic, compared with 271.1 per 100 000 person years in people drinking water with ≥12.0 μg/L arsenic. There was a dose-response relation between exposure to arsenic in well water assessed at baseline and mortality from ischaemic heart disease and other heart disease (4). The children of HEALS participants have been involved in several cross-sectional studies that examined the relationships between As exposure and several neuropsychological outcomes. We have observed dose-dependent deficits in intelligence in 8- to 11-year-old children (5, 6) and in 6-year-old children (7). More recently, we have also investigated the associations of water As and water manganese (Mn) with motor function in 304 children in Bangladesh, aged 8 to 11 years. In addition to water, we measured As and Mn concentrations in blood, urine and toenails. We assessed motor function with the Bruininks-Oseretsky Test (BOT-2), which can be summarized with a total score of overall motor proficiency (TMC) or in four subscales: fine manual control (FMC), manual co-ordination (MC), body co-ordination (BC) and strength and agility (SA). After adjustment for covariates, water As (but not Mn) levels were associated with decreases in FMC, BC and TMC; similar findings were observed when we used urinary or blood As as the exposure measure (8). Collectively, the findings from the HEALS study and a growing body of basic science and population-based evidence indicate the urgent need to provide As-free drinking water to the many affected populations around the world.
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Impact of Air Pollution on Health of Children – Czech Experience
المؤلفون: Radim J SramAbstractThe Ostrava region in northern Moravia (Silesia) is the most polluted region in the Czech Republic by carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) as benzo[a]pyrene (B[a]P), especially by the steel industry. In the most polluted part of Ostrava City, Bartovice (OB), in the year 2008 was B[a]P 9.3±14.4 ng/ m3 vs control district of Prachatice (PRA) in the southern Bohemia, where B[a]P was 1.0±1.3 ng/ m3. We studied a group of 200 children living in OB (100 asthmatic and 100 healthy, aged eight-15 years) and a control group of 200 children living in PRA(100 asthmatic and 100 healthy, aged eight-15 years). As biomarkers of oxidative damage were followed 8-oxodG in urine, lipid peroxidation and protein oxidation in plasma, as biomarkers of effect gene expression profiles in lymphocytes using Illumina HumanHT-12 BeadChip and genetic polymorphisms in 768 SNPs by Illumina GoldenGate Assay. Oxidative damage by 8-oxodG was significantly higher in OB vs PRA (OR=2.27, P<0.001, 95%CI 1.40-3.70). Gene expression profiles significantly differ between OB and PRA. Comparing asthmatic vs control children, we observed nine deregulated genes in Ostrava and 17 deregulated genes in Prachatice. These changed genes are specific for each locality and asthma. Microarray results were verified by qPCR, five genes selected for Ostrava, another five for Prachatice. The verification confirmed previous results. In the asthmatic children from Ostrava were upregulated genes HPG2, AHSP and DEFA4. In the asthmatic children from Prachatice were upregulated genes SIGLEC8, CCL23, CLC and CACNG6. Gene expression profiles of asthma children seem to be specific and different in two regions. We detected also SNPs specific for the asthma children in OB. Results indicate that higher exposure to c-PAHs may induce non-allergic form of asthma bronchiale in children. We also studied the effect of exposure to B[a]P to DNA adducts, micronuclei and transcriptome in pregnancies from Prague and Ceske Budejovice. Exposure to B[a]P was three months before delivery 1.9±0.5 ng/m3 vs 3.2±0.2 ng/m3. Samples obtained from 35 mothers from Prague and 52 mothers from Ceske Budejovice were analyzed. All subjects were nonsmokers. DNA adducts were determined by 32P-postlabeling. Total DNA adducts were in cord blood 0.98±0.89 vs 1.40±1.31/108 nucleotides (p<0.001), in placentas 1.15±1.06 vs 1.94±1.80/108 nucleotides (p<0.001) from Prague and Ceske Budejovice, respectively. The frequencies of micronuclei (MN) determined by automated image analysis as MN per 1000 binucleated cells were 2.17±1.32 3.82±2.43 (p<0.001) for newborns from Prague and Ceske Budejovice, respectively. Using microarrays we assayed gene expression profiles in peripheral blood and placentas of the mothers, and in cord blood of their newborns. Comparative analysis of the profiles between the areas indicated that the pregnancies from Ceske Budejovice showed up-regulation of genes whose activity is associated with exposure to genotoxic compounds (eg, genes for xenobiotic enzymes, compensation of oxidative stress and inflammatory factors). This finding corresponded with the increased level of DNA adducts as well as micronuslei detected in the cord blood from Ceske Budejovice.
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