Biological and behavioral factors modify urinary arsenic metabolic profiles in a U.S. population

Abstract Background Because some adverse health effects associated with chronic arsenic exposure may be mediated by methylated arsenicals, interindividual variation in capacity to convert inorganic arsenic into mono- and di-methylated metabolites may be an important determinant of risk associated with exposure to this metalloid. Hence, identifying biological and behavioral factors that modify an individual’s capacity to methylate inorganic arsenic could provide insights into critical dose-response relations underlying adverse health effects. Methods A total of 904 older adults (≥45 years old) in Churchill County, Nevada, who chronically used home tap water supplies containing up to 1850 μg of arsenic per liter provided urine and toenail samples for determination of total and speciated arsenic levels. Effects of biological factors (gender, age, body mass index) and behavioral factors (smoking, recent fish or shellfish consumption) on patterns of arsenicals in urine were evaluated with bivariate analyses and multivariate regression models. Results Relative contributions of inorganic, mono-, and di-methylated arsenic to total speciated arsenic in urine were unchanged over the range of concentrations of arsenic in home tap water supplies used by study participants. Gender predicted both absolute and relative amounts of arsenicals in urine. Age predicted levels of inorganic arsenic in urine and body mass index predicted relative levels of mono- and di-methylated arsenic in urine. Smoking predicted both absolute and relative levels of arsenicals in urine. Multivariate regression models were developed for both absolute and relative levels of arsenicals in urine. Concentration of arsenic in home tap water and estimated water consumption were strongly predictive of levels of arsenicals in urine as were smoking, body mass index, and gender. Relative contributions of arsenicals to urinary arsenic were not consistently predicted by concentrations of arsenic in drinking water supplies but were more consistently predicted by gender, body mass index, age, and smoking. Conclusions These findings suggest that analyses of dose-response relations in arsenic-exposed populations should account for biological and behavioral factors that modify levels of inorganic and methylated arsenicals in urine. Evidence of significant effects of these factors on arsenic metabolism may also support mode of action studies in appropriate experimental models

Biological and behavioral factors modify urinary arsenic metabolic profiles in a U.S. population

Abstract Background Because some adverse health effects associated with chronic arsenic exposure may be mediated by methylated arsenicals, interindividual variation in capacity to convert inorganic arsenic into mono- and di-methylated metabolites may be an important determinant of risk associated with exposure to this metalloid. Hence, identifying biological and behavioral factors that modify an individual’s capacity to methylate inorganic arsenic could provide insights into critical dose-response relations underlying adverse health effects. Methods A total of 904 older adults (≥45 years old) in Churchill County, Nevada, who chronically used home tap water supplies containing up to 1850 μg of arsenic per liter provided urine and toenail samples for determination of total and speciated arsenic levels. Effects of biological factors (gender, age, body mass index) and behavioral factors (smoking, recent fish or shellfish consumption) on patterns of arsenicals in urine were evaluated with bivariate analyses and multivariate regression models. Results Relative contributions of inorganic, mono-, and di-methylated arsenic to total speciated arsenic in urine were unchanged over the range of concentrations of arsenic in home tap water supplies used by study participants. Gender predicted both absolute and relative amounts of arsenicals in urine. Age predicted levels of inorganic arsenic in urine and body mass index predicted relative levels of mono- and di-methylated arsenic in urine. Smoking predicted both absolute and relative levels of arsenicals in urine. Multivariate regression models were developed for both absolute and relative levels of arsenicals in urine. Concentration of arsenic in home tap water and estimated water consumption were strongly predictive of levels of arsenicals in urine as were smoking, body mass index, and gender. Relative contributions of arsenicals to urinary arsenic were not consistently predicted by concentrations of arsenic in drinking water supplies but were more consistently predicted by gender, body mass index, age, and smoking. Conclusions These findings suggest that analyses of dose-response relations in arsenic-exposed populations should account for biological and behavioral factors that modify levels of inorganic and methylated arsenicals in urine. Evidence of significant effects of these factors on arsenic metabolism may also support mode of action studies in appropriate experimental models

hsa-miR-20b-5p and hsa-miR-363-3p affect expression of PTEN and BIM tumor suppressor genes and modulate survival of T-ALL cells in vitro

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy arising from T lymphocyte precursors. We have previously shown by miRNA-seq, that miRNAs from the mir-106a-363 cluster are overexpressed in pediatric T-ALL. In silico analysis indicated their potential involvement in the regulation of apoptosis. Here, we aimed to test the hypothesis on the pro-tumorigenic roles of these miRNAs in T-ALL cells in vitro. We demonstrate, for the first time, that hsa-miR-20b-5p and hsa-miR-363-3p from the mir-106a-363 cluster, when upregulated in T-ALL cells in vitro, protect leukemic cells from apoptosis, enhance proliferation, and contribute to growth advantage. We show, using dual luciferase reporter assays, Ago2-RNA immunoprecipitation, RT-qPCR, and Western blots, that the oncogenic effects of these upregulated miRNAs might, at least in part, be mediated by the downregulation of two important tumor suppressor genes, PTEN and BIM, targeted by both miRNAs. Additionally, we demonstrate the cooperative effects of these two miRNAs by simultaneous inhibition of both miRNAs as compared to the inhibition of single miRNAs. We postulate that hsa-miR-20b-5p and hsa-miR-363-3p from the mir-106a-363 cluster might serve as oncomiRs in T-ALL, by contributing to post-transcriptional repression of key tumor suppressors, PTEN and BIM

Metabolism and toxicity of arsenic in human urothelial cells expressing rat arsenic (+3 oxidation state)-methyltransferase

The enzymatic methylation of inorganic As (iAs) is catalyzed by As(+3 oxidation state)-methyltransferase (AS3MT). AS3MT is expressed in rat liver and in human hepatocytes. However, AS3MT is not expressed in UROtsa, human urothelial cells that do not methylate iAs. Thus, UROtsa cells are an ideal null background in which the role of iAs methylation in modulation of toxic and cancer-promoting effects of this metalloid can be examined. A retroviral gene delivery system was used in this study to create a clonal UROtsa cell line (UROtsa/F35) that expresses rat AS3MT. Here, we characterize the metabolism and cytotoxicity of arsenite (iAsIII) and methylated trivalent arsenicals in parental cells and clonal cells expressing AS3MT. In contrast to parental cells, UROtsa/F35 cells effectively methylated iAsIII, yielding methylarsenic (MAs) and dimethylarsenic (DMAs) containing either AsIII or AsV. When exposed to MAsIII, UROtsa/F35 cells produced DMAsIII and DMAsV. MAsIII and DMAsIII were more cytotoxic than iAsIII in UROtsa and UROtsa/F35 cells. The greater cytotoxicity of MAsIII or DMAsIII than of iAsIII was associated with greater cellular uptake and retention of each methylated trivalent arsenical. Notably, UROtsa/F35 cells were more sensitive than parental cells to the cytotoxic effects of iAsIII but were more resistant to cytotoxicity of MAsIII. The increased sensitivity of UROtsa/F35 cells to iAsIII was associated with inhibition of DMAs production and intracellular accumulation of MAs. The resistance of UROtsa/F35 cells to moderate concentrations of MAsIII was linked to its rapid conversion to DMAs and efflux of DMAs. However, concentrations of MAsIII that inhibited DMAs production by UROtsa/F35 cells were equally toxic for parental and clonal cell lines. Thus, the production and accumulation of MAsIII is a key factor contributing to the toxicity of acute iAs exposures in methylating cells

Polychlorinated Biphenyls and Their Hydroxylated Metabolites (OH-PCBs) in Pregnant Women from Eastern Slovakia

OBJECTIVE: Our aim in the present study was to characterize and quantify the levels of polychlorinated biphenyls (PCBs) and specific polychlorobiphenylol (OH-PCB) metabolites in maternal sera from women delivering in eastern Slovakia. DESIGN: During 2002–2004, blood samples were collected from women delivering in two Slovak locations: Michalovce district, where PCBs were formerly manufactured, and Svidnik and Stropkov districts, about 70 km north. PARTICIPANTS: A total of 762 and 341 pregnant women were sampled from Michalovce and Svidnik/Stropkov, respectively, and OH-PCBs were measured in 131 and 31. EVALUATION/MEASUREMENTS: We analyzed PCBs using gas chromatography (GC)/electron capture detection. OH-PCBs and pentachlorophenol (PCP) were determined as methyl derivatives using GC-electron capture negative ionization/mass spectrometry. We characterized distributions in the full cohort using inverse sampling weights. RESULTS: The concentrations of both PCBs and OH-PCB metabolites of Michalovce mothers were about two times higher than those of the Svidnik/Stropkov mothers (p < 0.001). The median weighted maternal serum levels of the sum of PCBs (∑PCBs) were 5.73 ng/g wet weight (Michalovce) and 2.82 ng/g wet weight (Svidnik/Stropkov). The median sum of OH-PCBs (∑OH-PCBs) was 0.55 ng/g wet weight in Michalovce mothers and 0.32 ng/g wet weight in Svidnik/Stropkov mothers. 4-OH-2,2′ ,3,4′ ,5,5′ ,6-Heptachlorobiphenyl (4-OH-CB187) was a primary metabolite, followed by 4-OH-2,2′ ,3,4′ ,5,5′ -hexachlorobiphenyl (4-OH-CB146). Only four PCB congeners—CBs 153, 138, 180, and 170—had higher concentrations than 4-OH-CB187 and 4-OH-CB146 (p < 0.001). The median ratio of the ∑OH-PCBs to the ∑PCBs was 0.10. CONCLUSIONS: Mothers residing in eastern Slovakia are still highly exposed to PCBs, and their body burdens of these pollutants and OH-PCB metabolites may pose a risk for adverse effects on health for themselves and their children

Aktuelle Berichte und Forschungsprojekte

Internationale sprachwissenschaftliche Konferenz "Korpuslinguistik Deutsch-Tschechisch kontrastiv" in Sambachshof und Würzburg, 06.-08. Oktober 2009 (Iva Kratochvílová, Norbert Richard Wolf) "Tschechen und Deutsche im 20. und 21. Jahrhundert. Neue Sichtweisen auf alte Probleme." Deutsch-tschechisches Seminar in Sankelmark, 09.-11. Oktober 2009 (Jarmila Jehličková) Von der Grenze zum Dazwischen. Ein tschechisch-österreichisches Projekt zur Grenze und der Veränderung ihrer Wahrnehmung in Wien, 9.-11. November 2009 und Brünn 7.-10. Dezember 2009 (Michaela Kropik, Katharina Wessely) Bericht über den V. Germanisten-Kongress in Sevilla, 16.-18. Dezember 2009 (Fernando Magallanes) Bericht über die Linguistik-Tage in Freiburg im Breisgau, 02.-04. März 2010 (Martin Lachout) Sprachliches Wissen zwischen Lexikon und Grammatik. Bericht über die 46. Jahrestagung des Instituts für Deutsche Sprache in Mannheim, 09.-11. März 2010 (Veronika Kotůlková) "Mittlerin aus Europas Mitte" – 3. MGV-Kongress in Wien, 08.-10. April 2010 (Manfred Glauniger) "Gedichte und Geschichte – Zur poetischen und politischen Rede in Österreich". Tagung der Franz Werfel-Stipendiaten und –Stipendiatinnen in Wien, 16.–17. April 2010 (Roman Kopřiva) Binationales Kolloquium zur Problematik der Migrationsformen im 20. und 21. Jahrhundert in Geschichte und Kunst in Ústí nad Labem, 22.-24. März 2010 und Linz 04.-07. Mai 2010 (Jarmila Jehličková) Ein "hinternationaler" Schriftsteller aus Böhmen: Dritte internationale Johannes-Urzidil-Konferenz in Ústí nad Labem, 05.-08. Mai 2010 (Vera Schneider) "Wir sind Tschechinnen, wir schreiben Deutsch!" – Öffentliche Gesprächsrunde mit deutschsprachigen Autorinnen in Prag, 13. Mai 2010 (Jenifer Johanna Becker) "Überkreuzungen. Verhandlungen kultureller, ethnischer, religiöser und geschlechtlicher Identitäten in österreichischer Literatur und Kultur." MALCA-Tagung in Wien, 22.-25. Mai 2010 (Daniela Drobna, Katharina Haderer, Natalie Lamprecht, Friedrich Teutsch, Esther Wratschko

Arsenic (+ 3 oxidation state) methyltransferase and the methylation of arsenicals in the invertebrate chordate Ciona intestinalis

Metabolic conversion of inorganic arsenic into methylated products is a multistep process that yields mono-, di-, and trimethylated arsenicals. In recent years, it has become apparent that formation of methylated metabolites of inorganic arsenic is not necessarily a detoxification process. Intermediates and products formed in this pathway may be more reactive and toxic than inorganic arsenic. Like all metabolic pathways, understanding the pathway for arsenic methylation involves identification of each individual step in the process and the characterization of the molecules which participate in each step. Among several arsenic methyltransferases that have been identified, arsenic (+3 oxidation state) methyltransferase is the one best characterized at the genetic and functional levels. This review focuses on phylogenetic relationships in the deuterostomal lineage for this enzyme and on the relation between genotype for arsenic (+3 oxidation state) methyltransferase and phenotype for conversion of inorganic arsenic to methylated metabolites. Two conceptual models for function of arsenic (+3 oxidation state) methyltransferase which posit different roles for cellular reductants in the conversion of inorganic arsenic to methylated metabolites are compared. Although each model accurately represents some aspects of enzyme’s role in the pathway for arsenic methylation, neither model is a fully satisfactory representation of all the steps in this metabolic pathway. Additional information on the structure and function of the enzyme will be needed to develop a more comprehensive model for this pathway

Potentiation of Anticancer Drugs: Effects of Pentoxifylline on Neoplastic Cells

The drug efflux activity of P-glycoprotein (P-gp, a product of the mdr1 gene, ABCB1 member of ABC transporter family) represents a mechanism by which tumor cells escape death induced by chemotherapeutics. In this study, we investigated the mechanisms involved in the effects of pentoxifylline (PTX) on P-gp-mediated multidrug resistance (MDR) in mouse leukemia L1210/VCR cells. Parental sensitive mouse leukemia cells L1210, and multidrug-resistant cells, L1210/VCR, which are characterized by the overexpression of P-gp, were used as experimental models. The cells were exposed to 100 μmol/L PTX in the presence or absence of 1.2 μmol/L vincristine (VCR). Western blot analysis indicated a downregulation of P-gp protein expression when multidrug-resistant L1210/VCR cells were exposed to PTX. The effects of PTX on the sensitization of L1210/VCR cells to VCR correlate with the stimulation of apoptosis detected by Annexin V/propidium iodide apoptosis necrosis kit and proteolytic activation of both caspase-3 and caspase-9 monitored by Western blot analysis. Higher release of matrix metalloproteinases (MMPs), especially MMP-2, which could be attenuated by PTX, was found in L1210/VCR than in L1210 cells by gelatin zymography in electrophoretic gel. Exposure of resistant cells to PTX increased the content of phosphorylated Akt kinase. In contrast, the presence of VCR eliminated the effects of PTX on Akt kinase phosphorylation. Taken together, we conclude that PTX induces the sensitization of multidrug-resistant cells to VCR via downregulation of P-gp, stimulation of apoptosis and reduction of MMPs released from drug-resistant L1210/VCR cells. These facts bring new insights into the mechanisms of PTX action on cancer cells

The Case for Visual Analytics of Arsenic Concentrations in Foods

Arsenic is a naturally occurring toxic metal and its presence in food could be a potential risk to the health of both humans and animals. Prolonged ingestion of arsenic contaminated water may result in manifestations of toxicity in all systems of the body. Visual Analytics is a multidisciplinary field that is defined as the science of analytical reasoning facilitated by interactive visual interfaces. The concentrations of arsenic vary in foods making it impractical and impossible to provide regulatory limit for each food. This review article presents a case for the use of visual analytics approaches to provide comparative assessment of arsenic in various foods. The topics covered include (i) metabolism of arsenic in the human body; (ii) arsenic concentrations in various foods; (ii) factors affecting arsenic uptake in plants; (ii) introduction to visual analytics; and (iv) benefits of visual analytics for comparative assessment of arsenic concentration in foods. Visual analytics can provide an information superstructure of arsenic in various foods to permit insightful comparative risk assessment of the diverse and continually expanding data on arsenic in food groups in the context of country of study or origin, year of study, method of analysis and arsenic species

Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapan and Lagunera Regions in Mexico

Abstract Background Human exposures to inorganic arsenic (iAs) have been linked to an increased risk of diabetes mellitus. Recent laboratory studies showed that methylated trivalent metabolites of iAs may play key roles in the diabetogenic effects of iAs. Our study examined associations between chronic exposure to iAs in drinking water, metabolism of iAs, and prevalence of diabetes in arsenicosis-endemic areas of Mexico. Methods We used fasting blood glucose (FBG), fasting plasma insulin (FPI), oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR) to characterize diabetic individuals. Arsenic levels in drinking water and urine were determined to estimate exposure to iAs. Urinary concentrations of iAs and its trivalent and pentavalent methylated metabolites were measured to assess iAs metabolism. Associations between diabetes and iAs exposure or urinary metabolites of iAs were estimated by logistic regression with adjustment for age, sex, hypertension and obesity. Results The prevalence of diabetes was positively associated with iAs in drinking water (OR 1.13 per 10 ppb, p < 0.01) and with the concentration of dimethylarsinite (DMAsIII) in urine (OR 1.24 per inter-quartile range, p = 0.05). Notably, FPI and HOMA-IR were negatively associated with iAs exposure (β -2.08 and -1.64, respectively, p < 0.01), suggesting that the mechanisms of iAs-induced diabetes differ from those underlying type-2 diabetes, which is typically characterized by insulin resistance. Conclusions Our study confirms a previously reported, but frequently questioned, association between exposure to iAs and diabetes, and is the first to link the risk of diabetes to the production of one of the most toxic metabolites of iAs, DMAsIII