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Sample records for genes urinary arsenic

  1. Polymorphisms in cell cycle regulatory genes, urinary arsenic profile and urothelial carcinoma

    SciTech Connect

    Chung, C.-J.; Huang, C.-J.; Pu, Y.-S.; Su, C.-T.; Huang, Y.-K.; Chen, Y.-T.; Hsueh, Y.-M.

    2008-10-15

    Introduction: Polymorphisms in p53, p21 and CCND1 could regulate the progression of the cell cycle and might increase the susceptibility to inorganic arsenic-related cancer risk. The goal of our study was to evaluate the roles of cell cycle regulatory gene polymorphisms in the carcinogenesis of arsenic-related urothelial carcinoma (UC). Methods: A hospital-based case-controlled study was conducted to explore the relationships among the urinary arsenic profile, 8-hydroxydeoxyguanosine (8-OHdG) levels, p53 codon 72, p21 codon 31 and CCND1 G870A polymorphisms and UC risk. The urinary arsenic profile was determined using high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). 8-OHdG levels were measured by high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymerase (PCR-RFLP). Results: Subjects carrying the p21 Arg/Arg genotype had an increased UC risk (age and gender adjusted OR = 1.53; 95% CI, 1.02-2.29). However, there was no association of p53 or CCND1 polymorphisms with UC risk. Significant effects were observed in terms of a combination of the three gene polymorphisms and a cumulative exposure of cigarette smoking, along with the urinary arsenic profile on the UC risk. The higher total arsenic concentration, monomethylarsonic acid percentage (MMA%) and lower dimethylarsinic acid percentage (DMA%), possessed greater gene variant numbers, had a higher UC risk and revealed significant dose-response relationships. However, effects of urinary 8-OHdG levels combined with three gene polymorphisms did not seem to be important for UC risk. Conclusions: The results showed that the variant genotype of p21 might be a predictor of inorganic arsenic-related UC risk.

  2. Hypomethylation of inflammatory genes (COX2, EGR1, and SOCS3) and increased urinary 8-nitroguanine in arsenic-exposed newborns and children.

    PubMed

    Phookphan, Preeyaphan; Navasumrit, Panida; Waraprasit, Somchamai; Promvijit, Jeerawan; Chaisatra, Krittinee; Ngaotepprutaram, Thitirat; Ruchirawat, Mathuros

    2017-02-01

    Early-life exposure to arsenic increases risk of developing a variety of non-malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic-exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p<0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p<0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10-100μM) and long-term low doses (0.5-1μM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p<0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Binational Arsenic Exposure Survey: Methodology and Estimated Arsenic Intake from Drinking Water and Urinary Arsenic Concentrations

    PubMed Central

    Roberge, Jason; O’Rourke, Mary Kay; Meza-Montenegro, Maria Mercedes; Gutiérrez-Millán, Luis Enrique; Burgess, Jefferey L.; Harris, Robin B.

    2012-01-01

    The Binational Arsenic Exposure Survey (BAsES) was designed to evaluate probable arsenic exposures in selected areas of southern Arizona and northern Mexico, two regions with known elevated levels of arsenic in groundwater reserves. This paper describes the methodology of BAsES and the relationship between estimated arsenic intake from beverages and arsenic output in urine. Households from eight communities were selected for their varying groundwater arsenic concentrations in Arizona, USA and Sonora, Mexico. Adults responded to questionnaires and provided dietary information. A first morning urine void and water from all household drinking sources were collected. Associations between urinary arsenic concentration (total, organic, inorganic) and estimated level of arsenic consumed from water and other beverages were evaluated through crude associations and by random effects models. Median estimated total arsenic intake from beverages among participants from Arizona communities ranged from 1.7 to 14.1 µg/day compared to 0.6 to 3.4 µg/day among those from Mexico communities. In contrast, median urinary inorganic arsenic concentrations were greatest among participants from Hermosillo, Mexico (6.2 µg/L) whereas a high of 2.0 µg/L was found among participants from Ajo, Arizona. Estimated arsenic intake from drinking water was associated with urinary total arsenic concentration (p < 0.001), urinary inorganic arsenic concentration (p < 0.001), and urinary sum of species (p < 0.001). Urinary arsenic concentrations increased between 7% and 12% for each one percent increase in arsenic consumed from drinking water. Variability in arsenic intake from beverages and urinary arsenic output yielded counter intuitive results. Estimated intake of arsenic from all beverages was greatest among Arizonans yet participants in Mexico had higher urinary total and inorganic arsenic concentrations. Other contributors to urinary arsenic concentrations should be evaluated. PMID:22690182

  4. Binational arsenic exposure survey: methodology and estimated arsenic intake from drinking water and urinary arsenic concentrations.

    PubMed

    Roberge, Jason; O'Rourke, Mary Kay; Meza-Montenegro, Maria Mercedes; Gutiérrez-Millán, Luis Enrique; Burgess, Jefferey L; Harris, Robin B

    2012-04-01

    The Binational Arsenic Exposure Survey (BAsES) was designed to evaluate probable arsenic exposures in selected areas of southern Arizona and northern Mexico, two regions with known elevated levels of arsenic in groundwater reserves. This paper describes the methodology of BAsES and the relationship between estimated arsenic intake from beverages and arsenic output in urine. Households from eight communities were selected for their varying groundwater arsenic concentrations in Arizona, USA and Sonora, Mexico. Adults responded to questionnaires and provided dietary information. A first morning urine void and water from all household drinking sources were collected. Associations between urinary arsenic concentration (total, organic, inorganic) and estimated level of arsenic consumed from water and other beverages were evaluated through crude associations and by random effects models. Median estimated total arsenic intake from beverages among participants from Arizona communities ranged from 1.7 to 14.1 µg/day compared to 0.6 to 3.4 µg/day among those from Mexico communities. In contrast, median urinary inorganic arsenic concentrations were greatest among participants from Hermosillo, Mexico (6.2 µg/L) whereas a high of 2.0 µg/L was found among participants from Ajo, Arizona. Estimated arsenic intake from drinking water was associated with urinary total arsenic concentration (p < 0.001), urinary inorganic arsenic concentration (p < 0.001), and urinary sum of species (p < 0.001). Urinary arsenic concentrations increased between 7% and 12% for each one percent increase in arsenic consumed from drinking water. Variability in arsenic intake from beverages and urinary arsenic output yielded counter intuitive results. Estimated intake of arsenic from all beverages was greatest among Arizonans yet participants in Mexico had higher urinary total and inorganic arsenic concentrations. Other contributors to urinary arsenic concentrations should be evaluated.

  5. INFLUENCE OF DIETARY ARSENIC ON URINARY ARSENIC METABOLITE EXCRETION

    EPA Science Inventory

    Influence of Dietary Arsenic on Urinary Arsenic Metabolite Excretion

    Cara L. Carty, M.S., Edward E. Hudgens, B.Sc., Rebecca L. Calderon, Ph.D., M.S.P.H., Richard Kwok, M.S.P.H., Epidemiology and Biomarkers Branch/HSD, NHEERL/US EPA; David J. Thomas, Ph.D., Pharmacokinetics...

  6. INFLUENCE OF DIETARY ARSENIC ON URINARY ARSENIC METABOLITE EXCRETION

    EPA Science Inventory

    Influence of Dietary Arsenic on Urinary Arsenic Metabolite Excretion

    Cara L. Carty, M.S., Edward E. Hudgens, B.Sc., Rebecca L. Calderon, Ph.D., M.S.P.H., Richard Kwok, M.S.P.H., Epidemiology and Biomarkers Branch/HSD, NHEERL/US EPA; David J. Thomas, Ph.D., Pharmacokinetics...

  7. Renin–angiotensin–aldosterone system related gene polymorphisms and urinary total arsenic is related to chronic kidney disease

    SciTech Connect

    Chen, Wei-Jen; Huang, Ya-Li; Shiue, Horng-Sheng; Chen, Tzen-Wen; Lin, Yuh-Feng; Huang, Chao-Yuan; Lin, Ying-Chin; Han, Bor-Cheng; Hsueh, Yu-Mei

    2014-09-01

    A recent study demonstrated that an increased risk of chronic kidney disease (CKD) was associated with high urinary total arsenic levels. However, whether genomic instability is related to CKD remains unclear. An association between CKD and genetic polymorphisms of regulation enzymes of the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AT1R), and aldosterone synthase (CYP11B2) has not been shown. The aim of the present study was to investigate the relationship between arsenic, genetic polymorphisms of RAAS enzymes and CKD. A total of 233 patients and 449 age- and gender-matched controls were recruited from the Taipei Medical University Hospital, Taipei Municipal Wan Fang Hospital and the Shin Kong Wu Ho-Su Memorial Hospital. Concentrations of urinary arsenic were determined by a high-performance liquid chromatography-linked hydride generator, and atomic absorption spectrometry. Polymorphisms of ACE(I/D), AGT(A[− 20]C), (T174M), (M235T), AT1R(A1166C) and CYP11B2(C[− 344]T) were examined by polymerase chain reaction and restriction fragment length polymorphism. Subjects carrying the CYP11B2 TT genotype had a higher odds ratio (OR), 1.39 (0.96–2.01), of CKD; while those with the AGT(A[− 20]C) CC genotype had an inverse OR of CKD (0.20 (0.05–0.81)), and a high-risk genotype was defined as A/A + A/C for AGT(A[− 20C]) and T/T for CYP11B2(C[− 344]T). The trend test showed a higher OR for CKD in patients who had either high urinary total arsenic levels or carried the high-risk genotype, or both, compared to patients with low urinary total arsenic levels, who carried the low-risk genotype, and could also be affected by the hypertension or diabetes status. - Highlights: • AGT(− 20 C) and CYP11B2(− 344 T) genotypes were significantly associated with CKD. • Combined effect of high-risk genotypes and high urinary total arsenic on OR of CKD. • Combined

  8. Profile of urinary arsenic metabolites during pregnancy.

    PubMed

    Hopenhayn, Claudia; Huang, Bin; Christian, Jay; Peralta, Cecilia; Ferreccio, Catterina; Atallah, Raja; Kalman, David

    2003-12-01

    Chronic exposure to inorganic arsenic (In-As) from drinking water is associated with different health effects, including skin, lung, bladder, and kidney cancer as well as vascular and possibly reproductive effects. In-As is metabolized through the process of methylation, resulting in the production and excretion of methylated species, mainly monomethylarsenate (MMA) and dimethylarsenate (DMA). Because a large percentage of the dose is excreted in urine, the distribution of urinary In-As, MMA, and DMA is considered a useful indicator of methylation patterns in human populations. Several factors affect these patterns, including sex and exposure level. In this study, we investigated the profile of urinary In-As, MMA, and DMA of pregnant women. Periodic urine samples were collected from early to late pregnancy among 29 pregnant women living in Antofagasta, Chile, who drank tap water containing 40 micro g/L In-As. The total urinary arsenic across four sampling periods increased with increasing weeks of gestation, from an initial mean value of 36.1 to a final value of 54.3 micro g/L. This increase was mainly due to an increase in DMA, resulting in lower percentages of In-As and MMA and a higher percentage of DMA. Our findings indicate that among women exposed to moderate arsenic from drinking water during pregnancy, changes occur in the pattern of urinary arsenic excretion and metabolite distribution. The toxicologic significance of this is not clear, given recent evidence suggesting that intermediate methylated species may be highly toxic. Nevertheless, this study suggests that arsenic metabolism changes throughout the course of pregnancy, which in turn may have toxicologic effects on the developing fetus. Key words: arsenic, arsenic metabolism, arsenic methylation, Chile, pregnancy, urinary arsenic.

  9. Profile of urinary arsenic metabolites during pregnancy.

    PubMed Central

    Hopenhayn, Claudia; Huang, Bin; Christian, Jay; Peralta, Cecilia; Ferreccio, Catterina; Atallah, Raja; Kalman, David

    2003-01-01

    Chronic exposure to inorganic arsenic (In-As) from drinking water is associated with different health effects, including skin, lung, bladder, and kidney cancer as well as vascular and possibly reproductive effects. In-As is metabolized through the process of methylation, resulting in the production and excretion of methylated species, mainly monomethylarsenate (MMA) and dimethylarsenate (DMA). Because a large percentage of the dose is excreted in urine, the distribution of urinary In-As, MMA, and DMA is considered a useful indicator of methylation patterns in human populations. Several factors affect these patterns, including sex and exposure level. In this study, we investigated the profile of urinary In-As, MMA, and DMA of pregnant women. Periodic urine samples were collected from early to late pregnancy among 29 pregnant women living in Antofagasta, Chile, who drank tap water containing 40 micro g/L In-As. The total urinary arsenic across four sampling periods increased with increasing weeks of gestation, from an initial mean value of 36.1 to a final value of 54.3 micro g/L. This increase was mainly due to an increase in DMA, resulting in lower percentages of In-As and MMA and a higher percentage of DMA. Our findings indicate that among women exposed to moderate arsenic from drinking water during pregnancy, changes occur in the pattern of urinary arsenic excretion and metabolite distribution. The toxicologic significance of this is not clear, given recent evidence suggesting that intermediate methylated species may be highly toxic. Nevertheless, this study suggests that arsenic metabolism changes throughout the course of pregnancy, which in turn may have toxicologic effects on the developing fetus. Key words: arsenic, arsenic metabolism, arsenic methylation, Chile, pregnancy, urinary arsenic. PMID:14644662

  10. Urinary excretion of arsenic following rice consumption.

    PubMed

    Meharg, A A; Williams, P N; Deacon, C M; Norton, G J; Hossain, M; Louhing, D; Marwa, E; Lawgalwi, Y; Taggart, M; Cascio, C; Haris, P

    2014-11-01

    Patterns of arsenic excretion were followed in a cohort (n = 6) eating a defined rice diet, 300 g per day d.wt. where arsenic speciation was characterized in cooked rice, following a period of abstinence from rice, and other high arsenic containing foods. A control group who did not consume rice were also monitored. The rice consumed in the study contained inorganic arsenic and dimethylarsinic acid (DMA) at a ratio of 1:1, yet the urine speciation was dominated by DMA (90%). At steady state (rice consumption/urinary excretion) ∼40% of rice derived arsenic was excreted via urine. By monitoring of each urine pass throughout the day it was observed that there was considerable variation (up to 13-fold) for an individual's total arsenic urine content, and that there was a time dependent variation in urinary total arsenic content. This calls into question the robustness of routinely used first pass/spot check urine sampling for arsenic analysis.

  11. Arsenic methylation, urinary arsenic metabolites and human diseases: current perspective.

    PubMed

    Tseng, Chin-Hsiao

    2007-01-01

    Arsenic can cause cancerous and non-cancerous human diseases. Inorganic arsenic from drinking water is the most common source of human exposure. Pentavalent arsenate can be reduced to trivalent arsenite in the blood, which is taken up mainly in the liver and metabolized by a sequence of reduction and oxidative methylation. A proportion of the inorganic arsenicals together with methylated metabolites are excreted in urine. Analyses of the urinary arsenic profile can give a hint to the methylation capacity of exposed individuals. All studies evaluating the association between urinary arsenic profiles and human diseases nowadays measure mainly the inorganic arsenate and arsenite and the two organic forms of methylated metabolites: the pentavalent form of monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV). A review of the current literature suggests that reduced methylation capacity with increased MMAV percentage, decreased DMAV percentage, or decreased DMAV/MMAV is associated with skin lesions, skin cancer, bladder cancer, peripheral vascular disease, muscle cramps and structural chromosome aberrations in peripheral lymphocytes obtained from exposed subjects. The detection of the recently identified more toxic trivalent forms of methylated metabolites in urine awaits further confirmation.

  12. Developmentally Restricted Genetic Determinants of Human Arsenic Metabolism: Association between Urinary Methylated Arsenic and CYT19 Polymorphisms in Children

    PubMed Central

    Meza, Maria Mercedes; Yu, Lizhi; Rodriguez, Yelitza Y.; Guild, Mischa; Thompson, David; Gandolfi, A. Jay; Klimecki, Walter T.

    2005-01-01

    We report the results of a screen for genetic association with urinary arsenic metabolite levels in three arsenic metabolism candidate genes, PNP, GSTO, and CYT19, in 135 arsenic-exposed subjects from the Yaqui Valley in Sonora, Mexico, who were exposed to drinking water concentrations ranging from 5.5 to 43.3 ppb. We chose 23 polymorphic sites to test in the arsenic-exposed population. Initial phenotypes evaluated included the ratio of urinary inorganic arsenic(III) to inorganic arsenic(V) and the ratio of urinary dimethylarsenic(V) to monomethylarsenic(V) (D:M). In the initial association screening, three polymorphic sites in the CYT19 gene were significantly associated with D:M ratios in the total population. Subsequent analysis of this association revealed that the association signal for the entire population was actually caused by an extremely strong association in only the children (7–11 years of age) between CYT19 genotype and D:M levels. With children removed from the analysis, no significant genetic association was observed in adults (18–79 years). The existence of a strong, developmentally regulated genetic association between CYT19 and arsenic metabolism carries import for both arsenic pharmacogenetics and arsenic toxicology, as well as for public health and governmental regulatory officials. PMID:15929903

  13. Correlation of Breastmilk Arsenic With Maternal, Infant Urinary Arsenic and Drinking Water Arsenic in an Arsenic Affected Area of Bangladesh

    NASA Astrophysics Data System (ADS)

    Alauddin, M.; Islam, M. R.; Milton, A. H.; Alauddin, S. T.; Mouly, T.; Behri, E.; Ayesha, A.; Akter, S.; Islam, M. M.

    2016-12-01

    About 97% of population in Bangladesh depend on groundwater as the principle source of drinking water and this water is highly contaminated with inorganic arsenic. Consumption of arsenic contaminated drinking water by pregnant women raises the prospect of early life exposure to inorganic arsenic for newborn which may be lead to adverse health effect in later life. This work was carried out in parts of Gopalganj district in Bangladesh, a region affected by arsenic contamination in groundwater. The objective of the work was to assess potential early life exposure to arsenic for infants through breastfeeding by mothers who were drinking water with arsenic levels ranging from 100 to 300 µg/l. A cohort of 30 mother-baby pairs were selected for the current study. Breastmilk samples from mothers, urine samples from each pair of subjects at 1, 6 and 9 month age of infant were collected and total arsenic were determined in these samples. In addition speciation of urinary arsenic and metabolites were carried out in 12 mother-baby pairs. Median level for breastmilk arsenic were 0.50 µg/l. Urinary arsenic of infants did not correlate with breastmilk arsenic with progressing age of infants. Maternal and infant urinary total arsenic at 1 month age of infant showed some positive correlation (r = 0.39). In infant urine major metabolite were dimethyl arsenic acid (DMA) (approximately 70%) indicating good methylating capacity for infants at 1 and 6 months of age. In conclusion, infants were not exposed to arsenic through breastfeeding even though mothers were exposed to significant levels of arsenic through drinking water.

  14. Effects of biological and behavioral factors on urinary arsenic ...

    EPA Pesticide Factsheets

    Abstract In older men and women who were long-term residents of Churchill County, Nevada, we examined the relation between arsenic exposure from home tap water and urinary levels of inorganic arsenic and its methylated metabolites. Over a wide exposure range (up to 1850 ug of arsenic per liter), urinary concentrations of inorganic, monomethylated, and dimethylated arsenicals strongly correlated with home tap water arsenic concentrations. However, percentages of summed urinary concentrations of inorganic, monomethylated, and dimethylated arsenicals accounted for by each arsenical species were unaffected by arsenic concentration in home tap water, suggesting thc1t capacity for formation and excretion of methylated metabolites was not exceeded. Biological factors (gender, age, body mass index, and genotype) and a behavioral factor (smoking) influenced absolute and relative levels of arsenicals in urine. A multivariate regression model showed that both biological and behavioral factors were significant predictors of absolute and relative concentrations of inorganic arsenic and its methylated metabolites in urine. These findings suggest that analyses of dose-response relations in arsenic-exposed populations should account for these biological and behavioral factors. Furthermore, evidence of significant effects of these factors on arsenic metabolism may support mode of action studies in appropriate experimental models. Running title- Methylated arsenicals as urinary b

  15. Urinary arsenic metabolites of subjects exposed to elevated arsenic present in coal in Shaanxi Province, China.

    PubMed

    Gao, Jianwei; Yu, Jiangping; Yang, Linsheng

    2011-06-01

    In contrast to arsenic (As) poisoning caused by naturally occurring inorganic arsenic-contaminated water consumption, coal arsenic poisoning (CAP) induced by elevated arsenic exposure from coal combustion has rarely been reported. In this study, the concentrations and distributions of urinary arsenic metabolites in 57 volunteers (36 subjects with skin lesions and 21 subjects without skin lesions), who had been exposed to elevated levels of arsenic present in coal in Changshapu village in the south of Shaanxi Province (China), were reported. The urinary arsenic species, including inorganic arsenic (iAs) [arsenite (iAsIII) and arsenate (iAsV)], monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), were determined by high-performance liquid chromatography (HPLC) combined with inductively coupled plasma mass spectroscopy (ICP-MS). The relative distributions of arsenic species, the primary methylation index (PMI=MMAV/iAs) and the secondary methylation index (SMI=DMAV/MMAV) were calculated to assess the metabolism of arsenic. Subjects with skin lesions had a higher concentration of urinary arsenic and a lower arsenic methylation capability than subjects without skin lesions. Women had a significantly higher methylation capability of arsenic than men, as defined by a higher percent DMAV and SMI in urine among women, which was the one possible interpretation of women with a higher concentration of urinary arsenic but lower susceptibility to skin lesions. The findings suggested that not only the dose of arsenic exposure but also the arsenic methylation capability have an impact on the individual susceptibility to skin lesions induced by coal arsenic exposure.

  16. Urinary Arsenic Metabolites of Subjects Exposed to Elevated Arsenic Present in Coal in Shaanxi Province, China

    PubMed Central

    Gao, Jianwei; Yu, Jiangping; Yang, Linsheng

    2011-01-01

    In contrast to arsenic (As) poisoning caused by naturally occurring inorganic arsenic-contaminated water consumption, coal arsenic poisoning (CAP) induced by elevated arsenic exposure from coal combustion has rarely been reported. In this study, the concentrations and distributions of urinary arsenic metabolites in 57 volunteers (36 subjects with skin lesions and 21 subjects without skin lesions), who had been exposed to elevated levels of arsenic present in coal in Changshapu village in the south of Shaanxi Province (China), were reported. The urinary arsenic species, including inorganic arsenic (iAs) [arsenite (iAsIII) and arsenate (iAsV)], monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), were determined by high-performance liquid chromatography (HPLC) combined with inductively coupled plasma mass spectroscopy (ICP-MS). The relative distributions of arsenic species, the primary methylation index (PMI = MMAV/iAs) and the secondary methylation index (SMI = DMAV/MMAV) were calculated to assess the metabolism of arsenic. Subjects with skin lesions had a higher concentration of urinary arsenic and a lower arsenic methylation capability than subjects without skin lesions. Women had a significantly higher methylation capability of arsenic than men, as defined by a higher percent DMAV and SMI in urine among women, which was the one possible interpretation of women with a higher concentration of urinary arsenic but lower susceptibility to skin lesions. The findings suggested that not only the dose of arsenic exposure but also the arsenic methylation capability have an impact on the individual susceptibility to skin lesions induced by coal arsenic exposure. PMID:21776214

  17. Evaluation of urinary speciated arsenic in NHANES: Issues in interpretation in the context of potential inorganic arsenic exposure

    EPA Science Inventory

    Urinary dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) are among the commonly used biomarkers for inorganic arsenic (iAs) exposure, but may also arise from seafood consumption and organoarsenical pesticide applications. We examined speciated urinary arsenic data from...

  18. Evaluation of urinary speciated arsenic in NHANES: Issues in interpretation in the context of potential inorganic arsenic exposure

    EPA Science Inventory

    Urinary dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) are among the commonly used biomarkers for inorganic arsenic (iAs) exposure, but may also arise from seafood consumption and organoarsenical pesticide applications. We examined speciated urinary arsenic data from...

  19. The effect of variable environmental arsenic contamination on urinary concentrations of arsenic species

    SciTech Connect

    Kalman, D.A.; Hughes, J.; van Belle, G.; Mottet, N.K.; Polissar, L. ); Bolgiano, D. ); Coble, K. )

    1990-11-01

    Urinary arsenic species have been determined for approximately 3,000 urine samples obtained from residents of a community surrounding an arsenic-emitting copper smelter. Levels of inorganic, monomethylated and dimethylated arsenic species ranged from less than 1 {mu}g/L (the instrumental detection limit) to 180 {mu}g/L seen for dimethyl arsenic. Comparison of a subsample of this population that had the least environmental contamination with the subsample having highest environmental arsenic concentrations showed small but statistically significant differences in urinary arsenic levels for all species except dimethylated arsenic. However, for children under 7 years of age living in areas with increased environmental arsenic contamination, there was a larger and equally significant increase in all urinary species. This effect was more pronounced and was observed as a weaker effect in the next higher age group (7-13 years of age). Reported consumption of seafood also was significantly related to increased urinary dimethyl arsenic, but changes in distribution among the urinary arsenic species detected was not a sensitive indicator of recent seafood consumption.

  20. Association between GSTO2 polymorphism and the urinary arsenic profile in copper industry workers.

    PubMed

    Paiva, Leiliane; Hernández, Alba; Martínez, Valeria; Creus, Amadeu; Quinteros, Domingo; Marcos, Ricardo

    2010-07-01

    Two members of the recently identified Omega class glutathione S-transferase enzymes (GSTO1 and GSTO2) have been proposed to play a role in the response to arsenic exposure. Therefore, polymorphisms in these genes could be related with variations in the arsenic excretion profile and, consequently, with the individual response to chronic exposure. Exons and flanking regions of GSTO2 gene have been screened in two different ethnic groups (20 Europeans and 20 Chilean Indians), and the urinary arsenic patterns and the GSTO2 Asn142Asp polymorphism have been investigated in 207 copper mine workers occupationally exposed to arsenic. Three polymorphisms of GSTO2 already described were detected in Europeans and Chilean Indians, although with significant different allele frequencies. The genotyping for the Asn142Asp polymorphism revealed that almost no significant association exists between this change and the arsenic excretion profile. However, 142Asp change seems to be correlated with an increase in DMA excretion after age and total urinary arsenic adjustment (OR=3.61; P=0.05). Altogether, our findings indicate that ethnical differences should be taken into account for correlation studies between GST Omega polymorphisms and arsenic susceptibility, and that the 142Asp allozyme could modulate arsenic biotransformation and thereby arsenic toxicity.

  1. GSTO and AS3MT genetic polymorphisms and differences in urinary arsenic concentrations among residents in Bangladesh

    PubMed Central

    Rodrigues, Ema G.; Kile, Molly; Hoffman, Elaine; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Hsueh, Yumei; Christiani, David C.

    2012-01-01

    We determined whether single nucleotide polymorphisms (SNPs) in the glutathione S-transferase omega (GSTO) and arsenic(III)methyltransferase (AS3MT) genes were associated with concentrations of urinary arsenic metabolites among 900 individualswithout skin lesions in Bangladesh. Four SNPs were assessed in these genes. A pathway analysis evaluated the association between urinary arsenic metabolites and SNPs. GSTO1 rs4925 homozygous wild type was significantly associated with higher monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) urinary concentrations, whereas wild type AS3MT rs11191439 had significantly lower levels of AsIII and MMA. Genetic polymorphisms GSTO and As3MT modify arsenic metabolism as evidenced by altered urinary arsenic excretion. PMID:22339537

  2. Urinary Arsenic and Insulin Resistance in US Adolescents

    PubMed Central

    Peng, Qing; Harlow, Siobán D.; Park, Sung Kyun

    2015-01-01

    Chronic arsenic exposure has been associated with increased diabetes risk in adults. Insulin resistance (IR) has been proposed as a mechanism of arsenic-related diabetes. Although limited evidence in adults found no association between arsenic and IR, the association in adolescents is largely unknown. We examined the association between urinary arsenic and insulin resistance in US adolescents. Eight hundred thirty five adolescents aged 12-19 years, with complete data on urinary arsenic (total arsenic, inorganic arsenic and dimethylarsenic acid (DMA)), fasting glucose, insulin and key covariates were identified from the National Health and Nutrition Examination Survey (NHANES) cycles 2003/2004 through 2009/2010. Generalized additive mixed models accounting for intra-cluster correlation arising from the complex survey design were used to estimate the association between the updated Homeostasis Model Assessment (HOMA2)-IR and each type of arsenic. After adjusting for potential confounders, including urinary creatinine, sociodemographic factors, BMI, waist circumference, and arsenobetaine, arsenic exposure was not associated with HOMA2-IR. Interquartile range increases in total arsenic, inorganic arsenic and DMA were associated with 1.5% (95% CI: -2.0, 5.2), 1.1% (95% CI: -1.5, 3.8) and 0.25% (95% CI: -2.3, 2.9) increases in HOMA2-IR, respectively. In conclusion, despite arsenic's association with diabetes in adults and potential role in insulin resistance, our findings do not support the hypothesis that arsenic exposure at levels common in the US contributes to insulin resistance in adolescents. Whether higher doses and longer exposure duration are required for appreciable influence on insulin resistance, or that arsenic does not act through insulin resistance to induce diabetes needs further investigation.1 PMID:25845984

  3. Urinary arsenic and insulin resistance in US adolescents.

    PubMed

    Peng, Qing; Harlow, Siobán D; Park, Sung Kyun

    2015-06-01

    Chronic arsenic exposure has been associated with increased diabetes risk in adults. Insulin resistance (IR) has been proposed as a mechanism of arsenic-related diabetes. Although limited evidence in adults found no association between arsenic and IR, the association in adolescents is largely unknown. We examined the association between urinary arsenic and insulin resistance in US adolescents. Eight hundred thirty five adolescents aged 12-19 years, with complete data on urinary arsenic (total arsenic, inorganic arsenic and dimethylarsenic acid (DMA)), fasting glucose, insulin and key covariates were identified from the National Health and Nutrition Examination Survey (NHANES) cycles 2003/2004 through 2009/2010. Generalized additive mixed models accounting for intra-cluster correlation arising from the complex survey design were used to estimate the association between the updated Homeostasis Model Assessment (HOMA2)-IR and each type of arsenic. After adjusting for potential confounders, including urinary creatinine, sociodemographic factors, BMI, waist circumference, and arsenobetaine, arsenic exposure was not associated with HOMA2-IR. Interquartile range increases in total arsenic, inorganic arsenic and DMA were associated with 1.5% (95% CI: -2.0, 5.2), 1.1% (95% CI: -1.5, 3.8) and 0.25% (95% CI: -2.3, 2.9) increases in HOMA2-IR, respectively. In conclusion, despite arsenic's association with diabetes in adults and potential role in insulin resistance, our findings do not support the hypothesis that arsenic exposure at levels common in the US contributes to insulin resistance in adolescents. Whether higher doses and longer exposure duration are required for appreciable influence on insulin resistance, or that arsenic does not act through insulin resistance to induce diabetes needs further investigation.

  4. Urinary arsenic profile affects the risk of urothelial carcinoma even at low arsenic exposure

    SciTech Connect

    Pu, Y.-S.; Yang, S.-M.; Huang, Y.-K.; Chung, C.-J.; Huang, Steven K.; Chiu, Allen Wen-Hsiang; Yang, M.-H.; Chen, C.-J.; Hsueh, Y.-M. . E-mail: ymhsueh@tmu.edu.tw

    2007-01-15

    Arsenic exposure is associated with an increased risk of urothelial carcinoma (UC). To explore the association between individual risk and urinary arsenic profile in subjects without evident exposure, 177 UC cases and 313 age-matched controls were recruited between September 2002 and May 2004 for a case-control study. Urinary arsenic species including the following three categories, inorganic arsenic (As{sup III} + As{sup V}), monomethylarsonic acid (MMA{sup V}) and dimethylarsinic acid (DMA{sup V}), were determined with high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Arsenic methylation profile was assessed by percentages of various arsenic species in the sum of the three categories measured. The primary methylation index (PMI) was defined as the ratio between MMA{sup V} and inorganic arsenic. Secondary methylation index (SMI) was determined as the ratio between DMA{sup V} and MMA{sup V}. Smoking is associated with a significant risk of UC in a dose-dependent manner. After multivariate adjustment, UC cases had a significantly higher sum of all the urinary species measured, higher percent MMA{sup V}, lower percent DMA{sup V}, higher PMI and lower SMI values compared with controls. Smoking interacts with the urinary arsenic profile in modifying the UC risk. Differential carcinogenic effects of the urinary arsenic profile, however, were seen more prominently in non-smokers than in smokers, suggesting that smoking is not the only major environmental source of arsenic contamination since the UC risk differs in non-smokers. Subjects who have an unfavorable urinary arsenic profile have an increased UC risk even at low exposure levels.

  5. DETERMINATION OF URINARY TRIVALENT ARSENICALS (MMASIII AND DMASIII) IN INDIVIDUALS CHRONICALLY EXPOSED TO ARSENIC

    EPA Science Inventory

    DETERMINATION OF URINARY TRIVALENT ARSENICALS (MMAsIII and DMAsIII) IN INDIVIDUALS CHRONICALLY EXPOSED TO ARSENIC.
    L. M. Del Razo1, M. Styblo2, W. R. Cullen3, and D.J. Thomas4.
    1Toxicology Section, Cinvestav-IPN, Mexico, D.F., 2Univ. North Carolina, Chapel Hill, NC; 3Uni...

  6. Rice consumption and urinary concentrations of arsenic in US adults.

    PubMed

    Wei, Yudan; Zhu, Jianmin; Nguyen, An

    2014-01-01

    Exposure to inorganic arsenic in the general population occurs mainly from drinking water and food sources. This study examined the association between rice consumption and urinary concentrations of arsenic in US adults, aged 20-85 years, in the 2003-2006 National Health and Nutrition Examination Survey. Significantly higher geometric means of creatinine-corrected urinary concentrations of total arsenic (TAs) and dimethylarsinic acid (DMA) were found in participants who consumed rice more than twice per week, compared to the reference group. Multivariate logistic regression analysis revealed a statistically significant association between rice consumption and urinary concentrations of TAs [odds ratio (OR) = 1.51 (1.08, 2.09)] and DMA [OR = 2.24 (1.57, 3.21)] after adjustment for demographic variables, seafood intake (the main source of organic arsenic), and source of drinking water. Furthermore, significant variations in rice consumption and urinary concentrations of arsenic were observed in different racial groups. This study demonstrated that rice consumption contributed to inorganic arsenic exposure in US adults.

  7. Exposure to inorganic arsenic in drinking water and total urinary arsenic concentration in a Chilean population.

    PubMed

    Caceres, Dante D; Pino, Paulina; Montesinos, Nestor; Atalah, Eduardo; Amigo, Hugo; Loomis, Dana

    2005-06-01

    The relationship of inorganic arsenic exposure through drinking water and total urinary arsenic excretion in a nonoccupationally exposed population was evaluated in a cross-sectional study in three mayor cities of Chile (Antofagasta, Santiago, and Temuco). A total of 756 individuals in three population strata (elderly, students, and workers) provided first morning void urine specimens the day after exposure and food surveys were administered. Arsenic intake from drinking water was estimated from analysis of tap water samples, plus 24-h dietary recall and food frequency questionnaires. Multilevel analysis was used to evaluate the effects of the age group and city factors adjusted by predictor variables. Arsenic levels in drinking water and urine were significantly higher in Antofagasta compared with the other cities. City-and individual-level factors, 12% and 88%, respectively, accounted for the variability in urinary arsenic concentration. The main predictors of urinary arsenic concentration were total arsenic consumption through water and age. These findings indicate that arsenic concentration in drinking water continues to be the principal contributing factor to exposure to inorganic arsenic in the Chilean population.

  8. Correlation of arsenic exposure through drinking groundwater and urinary arsenic excretion among adults in Pakistan.

    PubMed

    Ahmed, Mubashir; Fatmi, Zafar; Ali, Arif

    2014-01-01

    Long-term exposure to arsenic has been associated with manifestation of skin lesions (melanosis/keratosis) and increased risk of internal cancers (lung/bladder). The objective of the study described here was to determine the relationship between exposure of arsenic through drinking groundwater and urinary arsenic excretion among adults > or =15 years of age living in Khairpur district, Pakistan. Total arsenic was determined in drinking groundwater and in spot urine samples of 465 randomly selected individuals through hydride generation-atomic absorption spectrometry. Spearman's rank correlation coefficient was calculated between arsenic in drinking groundwater and arsenic excreted in urine. The median arsenic concentration in drinking water was 2.1 microg/L (range: 0.1-350), and in urine was 28.5 microg/L (range: 0.1-848). Positive correlation was found between total arsenic in drinking water and in urine (r = .52, p < .01). Urinary arsenic may be used as a biomarker of arsenic exposure through drinking water.

  9. Influence of MRP1 G1666A and GSTP1 Ile105Val genetic variants on the urinary and blood arsenic levels of Turkish smelter workers.

    PubMed

    Kaya-Akyüzlü, Dilek; Kayaaltı, Zeliha; Söylemezoğlu, Tülin

    2016-04-01

    To understand the cellular mechanisms responsible for arsenic metabolism and transport pathways plays a fundamental role in order to prevent the arsenic-induced toxicity. The effect of MRP1 G1666A and GSTP1 Ile105Val polymorphisms on blood and urinary arsenic levels were determined in 95 Turkish smelter workers. Blood and urinary arsenic concentrations were measured by GF-AAS with Zeeman correction and gene polymorphisms were investigated by PCR-RFLP method. The mean blood and urinary arsenic levels were 21.60±12.28μg/L and 5.58±4.37μg/L, respectively. A significant association between MRP1 1666A allele and urinary arsenic levels was found (p=0.001). GSTP1 Ile105Val polymorphism was detected not to be associated with either blood or urinary arsenic levels (p=0.384, p=0.440, respectively). Significant association was also detected between MRP1A(-)/GSTP1Val(-) genotypes and urinary arsenic levels (p=0.001). This study suggested that MRP1 G1666A alone and, also, combined with GSTP1 Ile105Val were associated with inter-individual variations in urinary arsenic levels, but not with blood arsenic levels.

  10. Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals

    PubMed Central

    Gao, Jianjun; Roy, Shantanu; Tong, Lin; Argos, Maria; Jasmine, Farzana; Rahaman, Ronald; Rakibuz-Zaman, Muhammad; Parvez, Faruque; Ahmed, Alauddin; Hore, Samar K; Sarwar, Golam; Slavkovich, Vesna; Yunus, Mohammad; Rahman, Mahfuzar; Baron, John A.; Graziano, Joseph H.; Ahsan, Habibul; Pierce, Brandon L.

    2014-01-01

    Background Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. Methods We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1,799 individuals. Association between arsenic exposure and a qPCR-based telomere length was assessed among 167 individuals. Results Urinary arsenic was possitively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P < 0.00035, Bonferroni correction threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction = 0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). Discussion Our findings suggest that arsenic’s carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes. PMID:25460668

  11. Risk factors for increased urinary inorganic arsenic concentrations from low arsenic concentrations in drinking water.

    PubMed

    Hinwood, Andrea L; Sim, Malcolm R; Jolley, Damien; de Klerk, Nick; Bastone, Elisa B; Gerostamoulos, Jim; Drummer, Olaf H

    2003-09-01

    A large number of drinking water supplies worldwide have greater than 50 microg l(- 1) inorganic arsenic in drinking water, and there is increasing pressure to reduce concentrations. Few studies have specifically considered low concentrations of arsenic in water supplies and the significance of other factors which may contribute to increased exposure. This study aimed to investigate risk factors for increased urinary inorganic arsenic concentrations, in a population exposed to 10 - 100 microg l(- 1) of arsenic in drinking water, as well as a control population with lower arsenic concentrations in their drinking water. Inorganic arsenic in urine was used as the measure of exposure. The median drinking water arsenic concentration in the exposed population was 43.8 microg l(- 1) (16.0 - 73 microg l(- 1)) and less than the analytical limit of detection of 1 microg l(- 1) (urinary inorganic arsenic concentration for the exposed group was 4.24 microg l(- 1) (rangeurinary inorganic arsenic concentrations with factors such as age, season and drinking water consumption important risk factors. These results show that concentrations of arsenic in drinking water, even at lower concentrations, make an important contribution to exposure. Further work is required to define the potential for absorption at these lower levels.

  12. Urinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic exposure

    SciTech Connect

    Huang, Chao-Yuan; Su, Chien-Tien; Chung, Chi-Jung; Pu, Yeong-Shiau; Chu, Jan-Show; Yang, Hsiu-Yuan; Wu, Chia-Chang; Hsueh, Yu-Mei

    2012-08-01

    8-Hydroxydeoxyguanosine (8-OHdG) is one of the most reliable and abundant markers of DNA damage. The study was designed to explore the relationship between urinary 8-OHdG and renal cell carcinoma (RCC) and to investigate whether individuals with a high level of 8-OHdG would have a modified odds ratio (OR) of arsenic-related RCC. This case–control study was conducted with 132 RCC patients and 245 age- and sex-matched controls from a hospital-based pool between November 2006 and May 2009. Pathological verification of RCC was completed by image-guided biopsy or surgical resection of renal tumors. Urinary 8-OHdG levels were determined using liquid chromatography with tandem mass spectrometry (LC–MS/MS). Concentrations of urinary arsenic species, including inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Level of urinary 8-OHdG was significantly associated with the OR of RCC in a dose–response relationship after multivariate adjustment. Urinary 8-OHdG was significantly related to urinary total arsenic. The greatest OR (3.50) was seen in the individuals with high urinary 8-OHdG and high urinary total arsenic. A trend test indicated that the OR of RCC was increased with one of these factors and was further increased with both (p = 0.002). In conclusion, higher urinary 8-OHdG was a strong predictor of the RCC. High levels of 8-OHdG combined with urinary total arsenic might be indicative of arsenic-induced RCC. -- Highlights: ► Urinary 8-OHdG was significantly related to urinary total arsenic. ► Higher urinary 8-OHdG was a strong predictor of RCC risk. ► Urinary 8-OHdG may modify arsenic related RCC risk.

  13. Urinary arsenic species, toenail arsenic, and arsenic intake estimates in a Michigan population with low levels of arsenic in drinking water.

    PubMed

    Rivera-Núñez, Zorimar; Meliker, Jaymie R; Meeker, John D; Slotnick, Melissa J; Nriagu, Jerome O

    2012-01-01

    The large disparity between arsenic concentrations in drinking water and urine remains unexplained. This study aims to evaluate predictors of urinary arsenic in a population exposed to low concentrations (≤50 μg/l) of arsenic in drinking water. Urine and drinking water samples were collected from a subsample (n=343) of a population enrolled in a bladder cancer case-control study in southeastern Michigan. Total arsenic in water and arsenic species in urine were determined using ICP-MS: arsenobetaine (AsB), arsenite (As[III]), arsenate (As[V]), methylarsenic acid (MMA[V]), and dimethylarsenic acid (DMA[V]). The sum of As[III], As[V], MMA[V], and DMA[V] was denoted as SumAs. Dietary information was obtained through a self-reported food intake questionnaire. Log(10)-transformed drinking water arsenic concentration at home was a significant (P<0.0001) predictor of SumAs (R(2)=0.18). Associations improved (R(2)=0.29, P<0.0001) when individuals with less than 1 μg/l of arsenic in drinking water were removed and further improved when analyses were applied to individuals who consumed amounts of home drinking water above the median volume (R(2)=0.40, P<0.0001). A separate analysis indicated that AsB and DMA[V] were significantly correlated with fish and shellfish consumption, which may suggest that seafood intake influences DMA[V] excretion. The Spearman correlation between arsenic concentration in toenails and SumAs was 0.36 and between arsenic concentration in toenails and arsenic concentration in water was 0.42. Results show that arsenic exposure from drinking water consumption is an important determinant of urinary arsenic concentrations, even in a population exposed to relatively low levels of arsenic in drinking water, and suggest that seafood intake may influence urinary DMA[V] concentrations.

  14. Comparative genomic hybridization study of arsenic-exposed and non-arsenic-exposed urinary transitional cell carcinoma

    SciTech Connect

    Hsu, L.-I; Chiu, Allen W.; Pu, Y.-S.; Wang, Y.-H.; Huan, Steven K.; Hsiao, C.-H.; Hsieh, F.-I; Chen, C.-J.

    2008-03-01

    To compare the differences in DNA aberrations between arsenic-exposed and non-arsenic-exposed transitional cell carcinoma (TCC), we analyzed 19 arsenic-exposed and 29 non-arsenic-exposed urinary TCCs from Chi-Mei Hospital using comparative genomic hybridization. DNA aberrations were detected in 42 TCCs including 19 arsenic-exposed and 23 non-arsenic-exposed TCCs. Arsenic-exposed TCCs had more changes than unexposed TCCs (mean {+-} SD, 6.6 {+-} 2.9 vs. 2.9 {+-} 2.2). Arsenic exposure was significantly associated with the number of DNA aberrations after adjustment for tumor stage, tumor grade and cigarette smoking in multiple regression analysis. The most frequent DNA gains, which were strikingly different between arsenic-exposed and non-arsenic-exposed TCCs, included those at 1p, 4p, 4q and 8q. A much higher frequency of DNA losses in arsenic-exposed TCCs compared with non-arsenic-exposed TCCs was observed in 10q, 11p and 17p. Chromosomal loss in 17p13 was associated not only with arsenic exposure, but also with tumor stage and grade. The p53 immunohistochemistry staining showed that chromosome 17p13 loss was associated with either p53 no expression (25%) or p53 overexpression (75%). The findings suggest that long-term arsenic exposure may increase the chromosome abnormality in TCC, and 17p loss plays an important role in arsenic-induced urinary carcinogenesis.

  15. Dietary B vitamin intakes and urinary total arsenic concentration in the Health Effects of Arsenic Longitudinal Study (HEALS) cohort, Bangladesh

    PubMed Central

    Argos, Maria; Rathouz, Paul J.; Pierce, Brandon L.; Kalra, Tara; Parvez, Faruque; Slavkovich, Vesna; Ahmed, Alauddin; Chen, Yu

    2012-01-01

    Purpose The objective of this analysis was to evaluate the effects of dietary B vitamin intakes on creatinine-adjusted urinary total arsenic concentration among individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS) cohort in Araihazar, Bangladesh. Arsenic exposure is a major public health problem in Bangladesh, where nearly 77 million people have been chronically exposed to arsenic through the consumption of naturally contaminated groundwater. Dietary factors influencing the metabolism of ingested arsenic may potentially be important modifiers of the health effects of arsenic in this population. Methods Daily average B vitamin intakes from a validated food frequency questionnaire and laboratory data on drinking water and urinary arsenic concentrations among 9,833 HEALS cohort participants were utilized. Statistical analyses were conducted using generalized estimating equations incorporating knotted spline linear regression. Results Increasing dietary intakes of thiamin, niacin, pantothenic acid, and pyridoxine were found to significantly increase urinary total arsenic excretion, adjusted for daily arsenic intake from drinking water and other potential confounders. Conclusions These results suggest that higher intakes of certain B vitamins may enhance the excretion of arsenic from the body. This study offers new insights into modifiable dietary factors that relate to arsenic excretion and thus provides potential avenues for the prevention of arsenic-related health effects. PMID:20386915

  16. Urinary arsenic speciation and its correlation with 8-OHdG in Chinese residents exposed to arsenic through coal burning

    SciTech Connect

    Li, X.; Pi, J.B.; Li, B.; Xu, Y.Y.; Jin, Y.P.; Sun, G.F.

    2008-10-15

    In contrast to arsenicosis caused by consumption of water contaminated by naturally occurring inorganic arsenic, human exposure to this metalloid through coal burning has been rarely reported. In this study, arsenic speciation and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in urine were determined in the Chinese residents exposed to arsenic through coal burning in Guizhou, China, an epidemic area of chronic arsenic poisoning caused by coal burning. The urinary concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and total arsenic (tAs) of high-arsenic exposed subjects were significantly higher than those of low-arsenic exposed residents. A biomarker of oxidative DNA damage, urinary 8-OHdG level was significantly higher in high-arsenic exposed subjects than that of low exposed. Significant positive correlations were found between 8-OHdG levels and concentrations of iAs, MMA, DMA and tAs, respectively. In addition, a significant negative correlation was observed between 8-OHdG levels and the secondary methylation ratio (DMA/(MMA + DMA)). The results suggest that chronic arsenic exposure through burning coal rich in arsenic is associated with oxidative DNA damages, and that secondary methylation capacity is potentially related to the susceptibility of individuals to oxidative DNA damage induced by arsenic exposure through coal burning in domestic living.

  17. Developmental and genetic modulation of arsenic biotransformation: A gene by environment interaction?

    SciTech Connect

    Meza, Mercedes; Gandolfi, A. Jay; Klimecki, Walter T.

    2007-08-01

    The complexity of arsenic toxicology has confounded the identification of specific pathways of disease causation. One focal point of arsenic research is aimed at fully characterizing arsenic biotransformation in humans, a process that appears to be quite variable, producing a mixture of several arsenic species with greatly differing toxic potencies. In an effort to characterize genetic determinants of variability in arsenic biotransformation, a genetic association study of 135 subjects in western Sonora, Mexico was performed by testing 23 polymorphic sites in three arsenic biotransformation candidate genes. One gene, arsenic 3 methyltransferase (AS3MT), was strongly associated with the ratio of urinary dimethylarsinic acid to monomethylarsonic acid (D/M) in children (7-11 years) but not in adults (18-79 years). Subsequent analyses revealed that the high D/M values associated with variant AS3MT alleles were primarily due to lower levels of monomethylarsonic acid as percent of total urinary arsenic (%MMA5). In light of several reports of arsenic-induced disease being associated with relatively high %MMA5 levels, these findings raise the possibility that variant AS3MT individuals may suffer less risk from arsenic exposure than non-variant individuals. These analyses also provide evidence that, in this population, regardless of AS3MT variant status, children tend to have lower %MMA5 values than adults, suggesting that the global developmental regulation of arsenic biotransformation may interact with genetic variants in metabolic genes to result in novel genetic effects such as those in this report.

  18. Airborne arsenic and urinary excretion of arsenic metabolites during boiler cleaning operations in a Slovak coal-fired power plant.

    PubMed Central

    Yager, J W; Hicks, J B; Fabianova, E

    1997-01-01

    Little information is available on the relationship between occupational exposure to inorganic arsenic in coal fly ash and urinary excretion of arsenic metabolites. This study ws undertaken in a coal-fired power plant in Slovakia during a routine maintenance outage. Arsenic was measured in the breathing zone of workers during 5 consecutive workdays, and urine samples were obtained for analysis of arsenic metabolites--inorganic arsenic (Asi), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)--prior to the start of each shift. Results from a small number of cascade impactor air samples indicated that approximately 90% of total particle mass and arsenic was present in particle size fractions >/= 3.5 micron. The 8-hr time-weighted average (TWA) mean arsenic air concentration was 48.3 microg/m3 (range 0.17-375.2) and the mean sum of urinary arsenic (SigmaAs) metabolites was 16.9 microg As/g creatinine (range 2.6-50.8). For an 8-hr TWA of 10 microg/m3 arsenic from coal fly ash, the predicted mean concentration of the SigmaAs urinary metabolites was 13.2 microg As/G creatinine [95% confidence interval (CI), 10.1-16.3). Comparisons with previously published studies of exposure to arsenic trioxide vapors and dusts in copper smelters suggest that bioavailability of arsenic from airborne coal fly ash (as indicated by urinary excretion) is about one-third that seen in smelters and similar settings. Arsenic compound characteristics, matrix composition, and particle size distribution probably play major roles in determining actual uptake of airborne arsenic. Images Figure 1. A Figure 1. B Figure 2. PMID:9347899

  19. Airborne arsenic and urinary excretion of arsenic metabolites during boiler cleaning operations in a Slovak coal-fired power plant.

    PubMed

    Yager, J W; Hicks, J B; Fabianova, E

    1997-08-01

    Little information is available on the relationship between occupational exposure to inorganic arsenic in coal fly ash and urinary excretion of arsenic metabolites. This study ws undertaken in a coal-fired power plant in Slovakia during a routine maintenance outage. Arsenic was measured in the breathing zone of workers during 5 consecutive workdays, and urine samples were obtained for analysis of arsenic metabolites--inorganic arsenic (Asi), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)--prior to the start of each shift. Results from a small number of cascade impactor air samples indicated that approximately 90% of total particle mass and arsenic was present in particle size fractions >/= 3.5 micron. The 8-hr time-weighted average (TWA) mean arsenic air concentration was 48.3 microg/m3 (range 0.17-375.2) and the mean sum of urinary arsenic (SigmaAs) metabolites was 16.9 microg As/g creatinine (range 2.6-50.8). For an 8-hr TWA of 10 microg/m3 arsenic from coal fly ash, the predicted mean concentration of the SigmaAs urinary metabolites was 13.2 microg As/G creatinine [95% confidence interval (CI), 10.1-16.3). Comparisons with previously published studies of exposure to arsenic trioxide vapors and dusts in copper smelters suggest that bioavailability of arsenic from airborne coal fly ash (as indicated by urinary excretion) is about one-third that seen in smelters and similar settings. Arsenic compound characteristics, matrix composition, and particle size distribution probably play major roles in determining actual uptake of airborne arsenic.

  20. Metabolites of arsenic and increased DNA damage of p53 gene in arsenic plant workers

    SciTech Connect

    Wen Weihua; Wen Jinghua; Lu Lin; Liu Hua; Yang Jun; Cheng Huirong; Che Wangjun; Li Liang; Zhang Guanbei

    2011-07-01

    Recent studies have shown that monomethylarsonous acid is more cytotoxic and genotoxic than arsenate and arsenite, which may attribute to the increased levels of reactive oxygen species. In this study, we used hydride generation-atomic absorption spectrometry to determine three arsenic species in urine of workers who had been working in arsenic plants,and calculated primary and secondary methylation indexes. The damages of exon 5, 6, 8 of p53 gene were determined by the method developed by Sikorsky, et al. Results show that the concentrations of each urinary arsenic species,and damage indexes of exon 5 and 8 of p53 gene in the exposed population were significantly higher, but SMI was significantly lower than in the control group. The closely positive correlation between the damage index of exon 5 and PMI,MMA, DMA were found, but there was closely negative correlation between the damage index of exon 5 and SMI. Those findings suggested that DNA damage of exon 5 and 8 of p53 gene existed in the population occupationally exposed to arsenic. For exon 5, the important factors may include the model of arsenic metabolic transformation, the concentrations of MMA and DMA, and the MMA may be of great importance. - Research Highlights: > In our study, the mean SMI for workers came from arsenic plants is 4.06, so they may be in danger. > There are more MMA, there are more damage of exon 5 of p53 gene. > MMA and damage of exon 5 of p53 gene may be useful biomarkers to assess adverse health effects caused by arsenic.

  1. The impact of a rice based diet on urinary arsenic.

    PubMed

    Cascio, Claudia; Raab, Andrea; Jenkins, Richard O; Feldmann, Joerg; Meharg, Andrew A; Haris, Parvez I

    2011-02-01

    Rice is elevated in arsenic (As) compared to other staple grains. The Bangladeshi community living in the United Kingdom (UK) has a ca. 30-fold higher consumption of rice than white Caucasians. In order to assess the impact of this difference in rice consumption, urinary arsenicals of 49 volunteers in the UK (Bangladeshi n = 37; white Caucasians n = 12) were monitored along with dietary habits. Total urinary arsenic (As(t)) and speciation analysis for dimethylarsinic acid (DMA), monomethylarsonic acid (MA) and inorganic arsenic (iAs) was conducted. Although no significant difference was found for As(t) (median: Bangladeshis 28.4 µg L(-1)) and white Caucasians (20.6 µg L(-1)), the sum of medians of DMA, MA and iAs for the Bangladeshi group was found to be over 3-fold higher (17.9 µg L(-1)) than for the Caucasians (3.50 µg L(-1)). Urinary DMA was significantly higher (p < 0.001) in the UK Bangladeshis (median: 16.9 µg DMA L(-1)) than in the white Caucasians (3.16 µg DMA L(-1)) as well as iAs (p < 0.001) with a median of 0.630 µg iAs L(-1) for Bangladeshi and 0.250 µg iAs L(-1) for Caucasians. Cationic compounds were significantly lower in the Bangladeshis (2.93 µg L(-1)) than in Caucasians (14.9 µg L(-1)). The higher DMA and iAs levels in the Bangladeshis are mainly the result of higher rice consumption: arsenic is speciated in rice as both iAs and DMA, and iAs can be metabolized, through MA, to DMA by humans. This study shows that a higher dietary intake of DMA alters the DMA/MA ratio in urine. Consequently, DMA/MA ratio as an indication of methylation capacity in populations consuming large quantities of rice should be applied with caution since variation in the quantity and type of rice eaten may alter this ratio.

  2. Relation of dietary inorganic arsenic exposure and urinary inorganic arsenic metabolites excretion in Japanese subjects.

    PubMed

    Oguri, Tomoko; Yoshinaga, Jun; Suzuki, Yayoi; Tao, Hiroaki; Nakazato, Tetsuya

    2017-06-03

    Inorganic arsenic (InAs) is a ubiquitous metalloid that has been shown to exert multiple adverse health outcomes. Urinary InAs and its metabolite concentration has been used as a biomarker of arsenic (As) exposure in some epidemiological studies, however, quantitative relationship between daily InAs exposure and urinary InAs metabolites concentration has not been well characterized. We collected a set of 24-h duplicated diet and spot urine sample of the next morning of diet sampling from 20 male and 19 female subjects in Japan from August 2011 to October 2012. Concentrations of As species in duplicated diet and urine samples were determined by using liquid chromatography-ICP mass spectrometry with a hydride generation system. Sum of the concentrations of urinary InAs and methylarsonic acid (MMA) was used as a measure of InAs exposure. Daily dietary InAs exposure was estimated to be 0.087 µg kg(-1) day(-1) (Geometric mean, GM), and GM of urinary InAs+MMA concentrations was 3.5 ng mL(-1). Analysis of covariance did not find gender-difference in regression coefficients as significant (P > 0.05). Regression equation Log 10 [urinary InAs+MMA concentration] = 0.570× Log 10 [dietary InAs exposure level per body weight] + 1.15 was obtained for whole data set. This equation would be valuable in converting urinary InAs concentration to daily InAs exposure, which will be important information in risk assessment.

  3. Urinary arsenic profiles reveal exposures to inorganic arsenic from private drinking water supplies in Cornwall, UK

    NASA Astrophysics Data System (ADS)

    Middleton, D. R. S.; Watts, M. J.; Hamilton, E. M.; Ander, E. L.; Close, R. M.; Exley, K. S.; Crabbe, H.; Leonardi, G. S.; Fletcher, T.; Polya, D. A.

    2016-05-01

    Private water supplies (PWS) in Cornwall, South West England exceeded the current WHO guidance value and UK prescribed concentration or value (PCV) for arsenic of 10 μg/L in 5% of properties surveyed (n = 497). In this follow-up study, the first of its kind in the UK, volunteers (n = 207) from 127 households who used their PWS for drinking, provided urine and drinking water samples for total As determination by inductively coupled plasma mass spectrometry (ICP-MS) and urinary As speciation by high performance liquid chromatography ICP-MS (HPLC-ICP-MS). Arsenic concentrations exceeding 10 μg/L were found in the PWS of 10% of the volunteers. Unadjusted total urinary As concentrations were poorly correlated (Spearman’s ρ = 0.36 (P < 0.001)) with PWS As largely due to the use of spot urine samples and the dominance of arsenobetaine (AB) from seafood sources. However, the osmolality adjusted sum, U-AsIMM, of urinary inorganic As species, arsenite (AsIII) and arsenate (AsV), and their metabolites, methylarsonate (MA) and dimethylarsinate (DMA), was found to strongly correlate (Spearman’s ρ: 0.62 (P < 0.001)) with PWS As, indicating private water supplies as the dominant source of inorganic As exposure in the study population of PWS users.

  4. Urinary arsenic profiles reveal exposures to inorganic arsenic from private drinking water supplies in Cornwall, UK

    PubMed Central

    Middleton, D. R. S.; Watts, M. J.; Hamilton, E. M.; Ander, E. L.; Close, R. M.; Exley, K. S.; Crabbe, H.; Leonardi, G. S.; Fletcher, T.; Polya, D. A.

    2016-01-01

    Private water supplies (PWS) in Cornwall, South West England exceeded the current WHO guidance value and UK prescribed concentration or value (PCV) for arsenic of 10 μg/L in 5% of properties surveyed (n = 497). In this follow-up study, the first of its kind in the UK, volunteers (n = 207) from 127 households who used their PWS for drinking, provided urine and drinking water samples for total As determination by inductively coupled plasma mass spectrometry (ICP-MS) and urinary As speciation by high performance liquid chromatography ICP-MS (HPLC-ICP-MS). Arsenic concentrations exceeding 10 μg/L were found in the PWS of 10% of the volunteers. Unadjusted total urinary As concentrations were poorly correlated (Spearman’s ρ = 0.36 (P < 0.001)) with PWS As largely due to the use of spot urine samples and the dominance of arsenobetaine (AB) from seafood sources. However, the osmolality adjusted sum, U-AsIMM, of urinary inorganic As species, arsenite (AsIII) and arsenate (AsV), and their metabolites, methylarsonate (MA) and dimethylarsinate (DMA), was found to strongly correlate (Spearman’s ρ: 0.62 (P < 0.001)) with PWS As, indicating private water supplies as the dominant source of inorganic As exposure in the study population of PWS users. PMID:27156998

  5. Arsenic drinking water exposure and urinary excretion among adults in the Yaqui Valley, Sonora, Mexico.

    PubMed

    Meza, Maria Mercedes; Kopplin, Michael J; Burgess, Jefferey L; Gandolfi, A Jay

    2004-10-01

    The objective of this study was to determine arsenic exposure via drinking water and to characterize urinary arsenic excretion among adults in the Yaqui Valley, Sonora, Mexico. A cross-sectional study was conducted from July 2001 to May 2002. Study subjects were from the Yaqui Valley, Sonora, Mexico, residents of four towns with different arsenic concentrations in their drinking water. Arsenic exposure was estimated through water intake over 24 h. Arsenic excretion was assessed in the first morning void urine. Total arsenic concentrations and their species arsenate (As V), arsenite (As III), monomethyl arsenic (MMA), and dimethyl arsenic (DMA) were determined by HPLC/ICP-MS. The town of Esperanza with the highest arsenic concentration in water had the highest daily mean intake of arsenic through drinking water, the mean value was 65.5 microg/day. Positive correlation between total arsenic intake by drinking water/day and the total arsenic concentration in urine (r = 0.50, P < 0.001) was found. Arsenic excreted in urine ranged from 18.9 to 93.8 microg/L. The people from Esperanza had the highest geometric mean value of arsenic in urine, 65.1 microg/L, and it was statistically significantly different from those of the other towns (P < 0.005). DMA was the major arsenic species in urine (47.7-67.1%), followed by inorganic arsenic (16.4-25.4%), and MMA (7.5-15%). In comparison with other reports the DMA and MMA distribution was low, 47.7-55.6% and 7.5-9.7%, respectively, in the urine from the Yaqui Valley population (except the town of Cocorit). The difference in the proportion of urinary arsenic metabolites in those towns may be due to genetic polymorphisms in the As methylating enzymes of these populations.

  6. COMPARISON OF THE URINARY METABOLITES OF RATS, MICE, AND HUMANS AFTER ORAL ARSENIC EXPOSURE FOCUSING ON THIOARSENICALS

    EPA Science Inventory

    Urinary metabolites of arsenic are useful as biomarkers of exposure because ingested arsenic is excreted primarily in urine1. Complete urinary arsenic speciation can provide insight into possible metabolic pathways as well as potential exposure sources. The pattern of excreted me...

  7. COMPARISON OF THE URINARY METABOLITES OF RATS, MICE, AND HUMANS AFTER ORAL ARSENIC EXPOSURE FOCUSING ON THIOARSENICALS

    EPA Science Inventory

    Urinary metabolites of arsenic are useful as biomarkers of exposure because ingested arsenic is excreted primarily in urine1. Complete urinary arsenic speciation can provide insight into possible metabolic pathways as well as potential exposure sources. The pattern of excreted me...

  8. Reduction in urinary arsenic levels in response to arsenic mitigation efforts in Araihazar, Bangladesh.

    PubMed

    Chen, Yu; van Geen, Alexander; Graziano, Joseph H; Pfaff, Alexander; Madajewicz, Malgosia; Parvez, Faruque; Hussain, A Z M Iftekhar; Slavkovich, Vesna; Islam, Tariqul; Ahsan, Habibul

    2007-06-01

    There is a need to identify and evaluate an effective mitigation program for arsenic exposure from drinking water in Bangladesh. We evaluated the effectiveness of a multifaceted mitigation program to reduce As exposure among 11,746 individuals in a prospective cohort study initiated in 2000 in Araihazar, Bangladesh, by interviewing participants and measuring changes in urinary As levels. The interventions included a) person-to-person reporting of well test results and health education; b) well labeling and village-level health education; and c) installations of 50 deep, low-As community wells in villages with the highest As exposure. Two years after these interventions, 58% of the 6,512 participants with unsafe wells (As >/=50 microg) at baseline had responded by switching to other wells. Well labeling and village-level health education was positively related to switching to safe wells (As < 50 mug/L) among participants with unsafe wells [rate ratio (RR) = 1.84; 95% confidence interval (CI), 1.60-2.11] and inversely related to any well switching among those with safe wells (RR = 0.80; 95% CI, 0.66-0.98). The urinary As level in participants who switched to a well identified as safe (< 50 microg As/L) dropped from an average of 375 microg As/g creatinine to 200 microg As/g creatinine, a 46% reduction toward the average urinary As content of 136 microg As/g creatinine for participants that used safe wells throughout. Urinary As reduction was positively related to educational attainment, body mass index, never-smoking, absence of skin lesions, and time since switching (p for trend < 0.05). Our study shows that testing of wells and informing households of the consequences of As exposure, combined with installation of deep community wells where most needed, can effectively address the continuing public health emergency from arsenic in drinking water in Bangladesh.

  9. Urinary Trivalent Methylated Arsenic Species in a Population Chronically Exposed to Inorganic Arsenic

    PubMed Central

    Valenzuela, Olga L.; Borja-Aburto, Victor H.; Garcia-Vargas, Gonzalo G.; Cruz-Gonzalez, Martha B.; Garcia-Montalvo, Eliud A.; Calderon-Aranda, Emma S.; Del Razo, Luz M.

    2005-01-01

    Chronic exposure to inorganic arsenic (iAs) has been associated with increased risk of various forms of cancer and of noncancerous diseases. Metabolic conversions of iAs that yield highly toxic and genotoxic methylarsonite (MAsIII) and dimethylarsinite (DMAsIII) may play a significant role in determining the extent and character of toxic and cancer-promoting effects of iAs exposure. In this study we examined the relationship between urinary profiles of MAsIII and DMAsIII and skin lesion markers of iAs toxicity in individuals exposed to iAs in drinking water. The study subjects were recruited among the residents of an endemic region of central Mexico. Drinking-water reservoirs in this region are heavily contaminated with iAs. Previous studies carried out in the local populations have found an increased incidence of pathologies, primarily skin lesions, that are characteristic of arseniasis. The goal of this study was to investigate the urinary profiles for the trivalent and pentavalent As metabolites in both high- and low-iAs–exposed subjects. Notably, methylated trivalent arsenicals were detected in 98% of analyzed urine samples. On average, the major metabolite, DMAsIII, represented 49% of total urinary As, followed by DMAsV (23.7%), iAsV (8.6%), iAsIII (8.5%), MAsIII (7.4%), and MAsV (2.8%). More important, the average MAsIII concentration was significantly higher in the urine of exposed individuals with skin lesions compared with those who drank iAs-contaminated water but had no skin lesions. These data suggest that urinary levels of MAsIII, the most toxic species among identified metabolites of iAs, may serve as an indicator to identify individuals with increased susceptibility to toxic and cancer-promoting effects of arseniasis. PMID:15743710

  10. Urinary trivalent methylated arsenic species in a population chronically exposed to inorganic arsenic.

    PubMed

    Valenzuela, Olga L; Borja-Aburto, Victor H; Garcia-Vargas, Gonzalo G; Cruz-Gonzalez, Martha B; Garcia-Montalvo, Eliud A; Calderon-Aranda, Emma S; Del Razo, Luz M

    2005-03-01

    Chronic exposure to inorganic arsenic (iAs) has been associated with increased risk of various forms of cancer and of noncancerous diseases. Metabolic conversions of iAs that yield highly toxic and genotoxic methylarsonite (MAsIII) and dimethylarsinite (DMAsIII) may play a significant role in determining the extent and character of toxic and cancer-promoting effects of iAs exposure. In this study we examined the relationship between urinary profiles of MAsIII and DMAsIII and skin lesion markers of iAs toxicity in individuals exposed to iAs in drinking water. The study subjects were recruited among the residents of an endemic region of central Mexico. Drinking-water reservoirs in this region are heavily contaminated with iAs. Previous studies carried out in the local populations have found an increased incidence of pathologies, primarily skin lesions, that are characteristic of arseniasis. The goal of this study was to investigate the urinary profiles for the trivalent and pentavalent As metabolites in both high- and low-iAs-exposed subjects. Notably, methylated trivalent arsenicals were detected in 98% of analyzed urine samples. On average, the major metabolite, DMAsIII, represented 49% of total urinary As, followed by DMAsV (23.7%), iAsV (8.6%), iAsIII (8.5%), MAsIII (7.4%), and MAsV (2.8%). More important, the average MAsIII concentration was significantly higher in the urine of exposed individuals with skin lesions compared with those who drank iAs-contaminated water but had no skin lesions. These data suggest that urinary levels of MAsIII, the most toxic species among identified metabolites of iAs, may serve as an indicator to identify individuals with increased susceptibility to toxic and cancer-promoting effects of arseniasis.

  11. Urinary arsenic levels influenced by abandoned mine tailings in the Southernmost Baja California Peninsula, Mexico.

    PubMed

    Colín-Torres, Carlos G; Murillo-Jiménez, Janette M; Del Razo, Luz M; Sánchez-Peña, Luz C; Becerra-Rueda, Oscar F; Marmolejo-Rodríguez, Ana J

    2014-10-01

    Gold has been mined at San Antonio-El Triunfo, (Baja California Sur, Mexico) since the 18th century. This area has approximately 5,700 inhabitants living in the San Juan de Los Planes and El Carrizal hydrographic basins, close to more than 100 abandoned mining sites containing tailings contaminated with potentially toxic elements such as arsenic. To evaluate the arsenic exposure of humans living in the surrounding areas, urinary arsenic species, such as inorganic arsenic (iAs) and the metabolites mono-methylated (MMA) and di-methylated arsenic acids (DMA), were evaluated in 275 residents (18-84 years of age). Arsenic species in urine were analyzed by hydride generation-cryotrapping-atomic absorption spectrometry, which excludes the non-toxic forms of arsenic such as those found in seafood. Urinary samples contained a total arsenic concentration (sum of arsenical species) which ranged from 1.3 to 398.7 ng mL(-1), indicating 33% of the inhabitants exceeded the biological exposition index (BEI = 35 ng mL(-1)), the permissible limit for occupational exposure. The mean relative urinary arsenic species were 9, 11 and 80% for iAs, MMA and DMA, respectively, in the Los Planes basin, and 17, 10 and 73%, respectively, in the El Carrizal basin. These data indicated that environmental intervention is required to address potential health issues in this area.

  12. Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion.

    PubMed

    Gao, Shuang; Duan, Xiaoxu; Wang, Xin; Dong, Dandan; Liu, Dan; Li, Xin; Sun, Guifan; Li, Bing

    2013-09-01

    Oxidative stress is one of the major mechanisms implicated in inorganic arsenic poisoning. Curcumin is a natural phenolic compound with impressive antioxidant properties. What's more, curcumin is recently proved to exert its chemopreventive effects partly through the activation of nuclear factor (erythroid-2 related) factor 2 (Nrf2) and its antioxidant and phase II detoxifying enzymes. In vivo, we investigated the protective effects of curcumin against arsenic-induced hepatotoxicity and oxidative injuries. Our results showed that arsenic-induced elevation of serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) activities, augmentation of hepatic malonaldehyde (MDA), as well as the reduction of blood and hepatic glutathione (GSH) levels, were all consistently relieved by curcumin. We also observed the involvement of curcumin in promoting arsenic methylation and urinary elimination in vivo. Furthermore, both the hepatic Nrf2 protein and two typically recognized Nrf2 downstream genes, NADP(H) quinine oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), were consistently up-regulated in curcumin-treated mice. Our study confirmed the antagonistic roles of curcumin to counteract inorganic arsenic-induced hepatic toxicity in vivo, and suggested that the potent Nrf2 activation capability might be valuable for the protective effects of curcumin against arsenic intoxication. This provides a potential useful chemopreventive dietary component for human populations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Urinary 8-hydroxydeoxyguanosine and urothelial carcinoma risk in low arsenic exposure area

    SciTech Connect

    Chung, C.-J.; Huang, C.-J.; Pu, Y.-S.; Su, C.-T.; Huang, Y.-K.; Chen, Y.-T.; Hsueh, Y.-M.

    2008-01-01

    Arsenic is a well-documented human carcinogen and is known to cause oxidative stress in cultured cells and animals. A hospital-based case-control study was conducted to evaluate the relationship among the levels of urinary 8-hydroxydeoxyguanosine (8-OHdG), the arsenic profile, and urothelial carcinoma (UC). Urinary 8-OHdG was measured by using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. The urinary species of inorganic arsenic and their metabolites were analyzed by high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). This study showed that the mean urinary concentration of total arsenics was significantly higher, at 37.67 {+-} 2.98 {mu}g/g creatinine, for UC patients than for healthy controls of 21.10 {+-} 0.79 {mu}g/g creatinine (p < 0.01). Urinary 8-OHdG levels correlated with urinary total arsenic concentrations (r = 0.19, p < 0.01). There were significantly higher 8-OHdG levels, of 7.48 {+-} 0.97 ng/mg creatinine in UC patients, compared to healthy controls of 5.95 {+-} 0.21 ng/mg creatinine. Furthermore, female UC patients had higher 8-OHdG levels of 9.22 {+-} 0.75 than those of males at 5.76 {+-} 0.25 ng/mg creatinine (p < 0.01). Multiple linear regression analyses revealed that high urinary 8-OHdG levels were associated with increased total arsenic concentrations, inorganic arsenite, monomethylarsonic acid (MMA), and dimethylarsenate (DMA) as well as the primary methylation index (PMI) even after adjusting for age, gender, and UC status. The results suggest that oxidative DNA damage was associated with arsenic exposure, even at low urinary level of arsenic.

  14. Environmental Arsenic Exposure and Urinary 8-OHdG in Arizona and Sonora.

    PubMed

    Burgess, Jefferey L; Meza, María M; Josyula, Arun B; Poplin, Gerald S; Kopplin, Michael J; McClellen, Hannah E; Stürup, Stefan; Lantz, R Clark

    2007-01-01

    Although at high levels arsenic exposure is associated with increased cancer incidence, information on the health effects of lower exposure levels is limited. The objective of this study was to determine whether arsenic at concentrations below 40 microg/L in drinking water is associated with increased urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of DNA oxidative damage and repair. Urine samples were collected from 73 nonsmoking adults residing in two communities in Arizona (mean tap water arsenic (microg/L) 4.0 +/- 2.3 and 20.3 +/- 3.7), and 51 subjects in four communities in Sonora, Mexico (mean tap water arsenic (microg/L) ranging from 4.8 +/- 0.1 to 33.3 +/- 0.6). Although urinary arsenic concentration increased with higher exposure in tap water, urinary 8-OHdG concentration did not differ by community within Arizona or Sonora, and was not associated with urinary arsenic concentration. At the exposure levels evaluated in this study, drinking water arsenic was not associated with increased DNA oxidation as measured by urinary 8-OHdG.

  15. Biological and behavioral modifiers of urinary arsenic metabolic profiles in a U.S. population

    EPA Science Inventory

    Biological and behavioral modifiers of urinary arsenic metabolic profiles in a U.S. population David J. Thomas – ISTD, NHEERL Edward F. Hudgens – EHPD, NHEERL John Rogers - Westat Relations between intensity of arsenic exposure from home tap water and levels of inorganic As ...

  16. Biological and behavioral modifiers of urinary arsenic metabolic profiles in a U.S. population

    EPA Science Inventory

    Biological and behavioral modifiers of urinary arsenic metabolic profiles in a U.S. population David J. Thomas – ISTD, NHEERL Edward F. Hudgens – EHPD, NHEERL John Rogers - Westat Relations between intensity of arsenic exposure from home tap water and levels of inorganic As ...

  17. Urinary porphyrins as biomarkers for arsenic exposure among susceptible populations in Guizhou Province, China

    SciTech Connect

    Ng, J.C.; Wang, J.P.; Zheng, B.S.; Zhai, C.; Maddalena, R.; Liu, F.; Moore, M.R.

    2005-08-07

    Coal from some areas in Guizhou Province contains elevated levels of arsenic. This has caused arsenicosis in individuals who use arsenic-contaminated coal for the purposes of heating, cooking and drying of food in poorly ventilated dwellings. The population at risk has been estimated to be approximately 200,000 people. We analyzed the porphyrin excretion profile using a HPLC method in urine samples collected from 113 villagers who lived in Xing Ren district, a coal-borne arsenicosis endemic area and from 30 villagers from Xing Yi where arsenicosis is not prevalent. Urinary porphyrins were higher in the arsenic exposed group than those in the control group. The correlation between urinary arsenic and porphyrin concentrations demonstrated the effect of arsenic on heme biosynthesis resulting in increased porphyrin excretion. Both uroporphyrin and coproporphyrin III showed significant increases in the excretion profile of the younger age ({lt} 20 years) arsenic-exposed group, suggesting that porphyrins could be used as early warning biomarkers of chronic arsenic exposure in humans. Greater increases of urinary arsenic and porphyrins in women, children and older age groups who spend much of their time indoors suggest that they might be at a higher risk. Whether elevated porphyrins could predict adverse health effects associated with both cancer and non-cancer end-points in chronically arsenic-exposed populations need further investigation.

  18. Urinary arsenic speciation profile in ethnic group of the Atacama desert (Chile) exposed to variable arsenic levels in drinking water.

    PubMed

    Yáñez, Jorge; Mansilla, Héctor D; Santander, I Paola; Fierro, Vladimir; Cornejo, Lorena; Barnes, Ramón M; Amarasiriwardena, Dulasiri

    2015-01-01

    Ethnic groups from the Atacama Desert (known as Atacameños) have been exposed to natural arsenic pollution for over 5000 years. This work presents an integral study that characterizes arsenic species in water used for human consumption. It also describes the metabolism and arsenic elimination through urine in a chronically exposed population in northern Chile. In this region, water contained total arsenic concentrations up to 1250 μg L(-1), which was almost exclusively As(V). It is also important that this water was ingested directly from natural water sources without any treatment. The ingested arsenic was extensively methylated. In urine 93% of the arsenic was found as methylated arsenic species, such as monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. The original ingested inorganic species [As(V)], represent less than 1% of the total urinary arsenic. Methylation activity among individuals can be assessed by measuring primary [inorganic As/methylated As] and secondary methylation [MMA/DMA] indexes. Both methylation indexes were 0.06, indicating a high biological converting capability of As(V) into MMA and then MMA into DMA, compared with the control population and other arsenic exposed populations previously reported.

  19. Environmental arsenic exposure and DNA methylation of the tumor suppressor gene p16 and the DNA repair gene MLH1: effect of arsenic metabolism and genotype.

    PubMed

    Hossain, Mohammad Bakhtiar; Vahter, Marie; Concha, Gabriela; Broberg, Karin

    2012-11-01

    Arsenic is carcinogenic, possibly partly through epigenetic mechanisms. We evaluated the effects of arsenic exposure and metabolism on DNA methylation. Arsenic exposure and methylation efficiency in 202 women in the Argentinean Andes were assessed from concentrations of arsenic metabolites in urine (inorganic arsenic, methylarsonic acid [MMA], and dimethylarsinic acid [DMA]), measured by HPLC-ICPMS. Methylation of CpGs of the tumor suppressor gene p16, the DNA repair gene MLH1, and the repetitive elements LINE1 was measured by PCR pyrosequencing of blood DNA. Genotyping (N = 172) for AS3MT was performed using Sequenom™, and gene expression (N = 90) using Illumina DirectHyb HumanHT-12 v3.0. Median arsenic concentration in urine was 230 μg L(-1) (range 10.1-1251). In linear regression analysis, log(2)-transformed urinary arsenic concentrations were positively associated with methylation of p16 (β = 0.14, P = 0.0028) and MLH1 (β = 0.28, P = 0.0011), but not with LINE1. Arsenic concentrations were of borderline significance negatively correlated with expression of p16 (r(s) = -0.20; P = 0.066)), but not with MLH1. The fraction of inorganic arsenic was positively (β = 0.026; P = 0.010) and DMA was negatively (β = -0.017, P = 0.043) associated with p16 methylation with no effect of MMA. Carriers of the slow-metabolizing AS3MT haplotype were associated with more p16 methylation (P = 0.022). Arsenic exposure was correlated with increased methylation, in blood, of genes encoding enzymes that suppress carcinogenesis, and the arsenic metabolism efficiency modified the degree of epigenetic alterations.

  20. Urinary arsenic species concentration in residents living near abandoned metal mines in South Korea.

    PubMed

    Chung, Jin-Yong; Kim, Byoung-Gwon; Lee, Byung-Kook; Moon, Jai-Dong; Sakong, Joon; Jeon, Man Joong; Park, Jung-Duck; Choi, Byung-Sun; Kim, Nam-Soo; Yu, Seung-Do; Seo, Jung-Wook; Ye, Byeong-Jin; Lim, Hyoun-Ju; Hong, Young-Seoub

    2016-01-01

    Arsenic is a carcinogenic heavy metal that has a species-dependent health effects and abandoned metal mines are a source of significant arsenic exposure. Therefore, the aims of this study were to analyze urinary arsenic species and their concentration in residents living near abandoned metal mines and to monitor the environmental health effects of abandoned metal mines in Korea. This study was performed in 2014 to assess urinary arsenic excretion patterns of residents living near abandoned metal mines in South Korea. Demographic data such as gender, age, mine working history, period of residency, dietary patterns, smoking and alcohol use, and type of potable water consumed were obtaining using a questionnaire. Informed consent was also obtained from all study subjects (n = 119). Urinary arsenic species were quantified using high performance liquid chromatography (HPLC) and inductively coupled plasma mass spectrometry (ICP/MS). The geometric mean of urinary arsenic (sum of dimethylarsinic acid, monomethylarsonic acid, As(3+), and As(5+)) concentration was determined to be 131.98 μg/L (geometric mean; 95% CI, 116.72-149.23) while urinary inorganic arsenic (As(3+) and As(5+)) concentration was 0.81 μg/L (95% CI, 0.53-1.23). 66.3% (n = 79) and 21.8% (n = 26) of these samples exceeded ATSDR reference values for urinary arsenic (>100 μg/L) and inorganic arsenic (>10 μg/L), respectively. Mean urinary arsenic concentrations (geometric mean, GM) were higher in women then in men, and increased with age. Of the five regions evaluated, while four regions had inorganic arsenic concentrations less than 0.40 μg/L, one region showed a significantly higher concentration (GM 15.48 μg/L; 95% CI, 7.51-31.91) which investigates further studies to identify etiological factors. We propose that the observed elevation in urinary arsenic concentration in residents living near abandoned metal mines may be due to environmental contamination from the abandoned metal

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

    PubMed

    Hudgens, Edward E; Drobna, Zuzana; He, Bin; Le, X C; Styblo, Miroslav; Rogers, John; Thomas, David J

    2016-05-26

    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. 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. 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

  2. Reduction in Urinary Arsenic Levels in Response to Arsenic Mitigation Efforts in Araihazar, Bangladesh

    PubMed Central

    Chen, Yu; van Geen, Alexander; Graziano, Joseph H.; Pfaff, Alexander; Madajewicz, Malgosia; Parvez, Faruque; Hussain, A.Z.M. Iftekhar; Slavkovich, Vesna; Islam, Tariqul; Ahsan, Habibul

    2007-01-01

    Background There is a need to identify and evaluate an effective mitigation program for arsenic exposure from drinking water in Bangladesh. Objective We evaluated the effectiveness of a multifaceted mitigation program to reduce As exposure among 11,746 individuals in a prospective cohort study initiated in 2000 in Araihazar, Bangladesh, by interviewing participants and measuring changes in urinary As levels. Methods The interventions included a) person-to-person reporting of well test results and health education; b) well labeling and village-level health education; and c) installations of 50 deep, low-As community wells in villages with the highest As exposure. Results Two years after these interventions, 58% of the 6,512 participants with unsafe wells (As ≥50 μg) at baseline had responded by switching to other wells. Well labeling and village-level health education was positively related to switching to safe wells (As < 50 μg/L) among participants with unsafe wells [rate ratio (RR) = 1.84; 95% confidence interval (CI), 1.60–2.11] and inversely related to any well switching among those with safe wells (RR = 0.80; 95% CI, 0.66–0.98). The urinary As level in participants who switched to a well identified as safe (< 50 μg As/L) dropped from an average of 375 μg As/g creatinine to 200 μg As/g creatinine, a 46% reduction toward the average urinary As content of 136 μg As/g creatinine for participants that used safe wells throughout. Urinary As reduction was positively related to educational attainment, body mass index, never-smoking, absence of skin lesions, and time since switching (p for trend < 0.05). Conclusions Our study shows that testing of wells and informing households of the consequences of As exposure, combined with installation of deep community wells where most needed, can effectively address the continuing public health emergency from arsenic in drinking water in Bangladesh. PMID:17589600

  3. Use of human metabolic studies and urinary arsenic speciation is assessing arsenic exposure

    SciTech Connect

    Johnson, L.R.; Farmer, J.G. Univ. of Edinburgh )

    1991-01-01

    The use of hair and nail analyses to assess human exposure to the trace metalloid arsenic (As) is hindered by the possibility of external contamination. Even though urine represents the major excretory route, its use as an indicator of exposure is limited when no distinction is made between the nontoxic organoarsenical (arsenobetaine) excreted following the consumption of seafood and the toxic inorganic forms of As and related metabolites. The development of analytical techniques capable of separating the different chemical species of As in urine have shown that the ingestion of inorganic As (AsV or AsIII) by animals and man triggers an in vivo reduction/methylation process resulting in excretion of the less toxic species, monomethylarsonic acid (MMAA) and dimethylarsinic acid (DMAA). This paper establishes the uptake, bio-transformation and elimination patterns reflected in urinary As following carefully controlled experimental exposure.

  4. Urinary arsenic metabolism in a Western Chinese population exposed to high-dose inorganic arsenic in drinking water: Influence of ethnicity and genetic polymorphisms

    SciTech Connect

    Fu, Songbo; Wu, Jie; Li, Yuanyuan; Liu, Yan; Gao, Yanhui; Yao, Feifei; Qiu, Chuanying; Song, Li; Wu, Yu; Liao, Yongjian; Sun, Dianjun

    2014-01-01

    To investigate the differences in urinary arsenic metabolism patterns of individuals exposed to a high concentration of inorganic arsenic (iAs) in drinking water, an epidemiological investigation was conducted with 155 individuals living in a village where the arsenic concentration in the drinking water was 969 μg/L. Blood and urine samples were collected from 66 individuals including 51 cases with skin lesions and 15 controls without skin lesions. The results showed that monomethylated arsenic (MMA), the percentage of MMA (%MMA) and the ratio of MMA to iAs (MMA/iAs) were significantly increased in patients with skin lesions as compared to controls, while dimethylated arsenic (DMA), the percentage of DMA (%DMA) and the ratio of DMA to MMA (DMA/MMA) were significantly reduced. The percent DMA of individuals with the Ala/Asp genotype of glutathione S-transferase omega 1 (GSTO1) was significantly lower than those with Ala/Ala. The percent MMA of individuals with the A2B/A2B genotype of arsenic (+ 3 oxidation state) methyltransferase (AS3MT) was significantly lower than those with AB/A2B. The iAs and total arsenic (tAs) content in the urine of a Tibetan population were significantly higher than that of Han and Hui ethnicities, whereas MMA/iAs was significantly lower than that of Han and Hui ethnicities. Our results showed that when exposed to the same arsenic environment, different individuals exhibited different urinary arsenic metabolism patterns. Gender and ethnicity affect these differences and above polymorphisms may be effectors too. - Highlights: • We first survey a village with high iAs content in the drinking water (969 μg/L). • 90 villagers suffered typical skin lesions with a morbidity rate of 58%. • Cases exhibited higher %MMA and MMA/iAs, and lower %DMA and DMA/MMA than controls. • Gender and ethnicity affect the differences of iAs methylation metabolism levels. • GSTO1 and AS3MT gene polymorphisms may be factors too.

  5. Occurrence of trivalent monomethyl arsenic and other urinary arsenic species in a highly exposed juvenile population in Bangladesh.

    PubMed

    Kalman, David A; Dills, Russell L; Steinmaus, Craig; Yunus, Md; Khan, Al Fazal; Prodhan, Md Mofijuddin; Yuan, Yan; Smith, Allan H

    2014-01-01

    Following reports of high cytotoxicity and mutagenicity of monomethyl arsonous acid (MMA(III)) and early reports of urinary MMA(III) in arsenic-exposed individuals, MMA(III) has often been included in population studies. Use of urinary MMA(III) as an indicator of exposure and/or health risk is challenged by inconsistent results from field studies and stability studies, which indicate potential artifacts. We measured urinary arsenic species in children chronically exposed to arsenic in drinking water, using collection, storage, and analysis methods shown to conserve MMA(III). MMA(III) was easily oxidized in sample storage and processing, but recoveries of 80% or better in spiked urine samples were achieved. Attempts to preserve the distribution of MMA between trivalent and pentavalent forms using complexing agents were unsuccessful and MMA(III) spiked into treated urine samples actually showed lower stability than in untreated samples. In 643 urine samples from a highly exposed population from the Matlab district in Bangladesh stored for 3-6 months at ≤-70 °C, MMA(III) was detected in 41 samples, with an estimated median value of 0.3 μg/l, and levels of MMA(III) above 1 μg/l in only two samples. The low urinary concentrations in highly exposed individuals and known difficulties in preserving sample oxidation state indicate that urinary MMA(III) is not suitable for use as an epidemiological biomarker.

  6. Measured versus modeled dietary arsenic and relation to urinary arsenic excretion and total exposure

    PubMed Central

    Kurzius-Spencer, Margaret; O’Rourke, Mary Kay; Hsu, Chiu-Hsieh; Hartz, Vern; Harris, Robin B.; Burgess, Jefferey L.

    2014-01-01

    Chronic exposure to arsenic (As) in food and water is a significant public health problem. Person-specific aggregate exposure is difficult to collect, and modeling based on limited food As residue databases is of uncertain reliability. Two, cross-sectional, population exposure studies—the National Human Exposure Assessment Survey (NHEXAS)-Arizona and the Arizona Border Survey (ABS)— had a total of 252 subjects with diet, water, and urinary As data. Total As was measured in 24-hour duplicate diet samples and modeled using 24-hour diet diaries in conjunction with several published food surveys of As. Two-stage regression was used to assess the effects of dietary As on urinary total As (uAs): 1) generalized linear mixed models of uAs above versus below the limit of detection (LOD); and 2) restricted models limited to those subjects with uAs > LOD, using bootstrap sampling and mixed models adjusted for age, sex, BMI, ethnicity, current smoking, and As intake from drinking and cooking water. In restricted models, measured and modeled estimates were significant predictors of uAs. Modeled dietary As based on Total Diet Study mean residues greatly underestimated dietary intake. In households with tap water As ≤ 10 ppb, over 93% of total As exposure was attributable to diet. PMID:23321855

  7. A COMPARISON OF URINARY ARSENIC SPECIATION VIA DIRECT NEBULIZATION AND ON-LINE PHOTOOXIDATION-HYDRIDE GENERATION WITH DETECTION BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY

    EPA Science Inventory

    Arsenic speciation continues to be important in assessing human and environmental exposure risk. Urinary arsenic analysis provides information on recent arsenic exposure. In this study, two sample introduction pathways: direct nebulization (DN) and hydride generation (HG) were ut...

  8. A COMPARISON OF URINARY ARSENIC SPECIATION VIA DIRECT NEBULIZATION AND ON-LINE PHOTOOXIDATION-HYDRIDE GENERATION WITH DETECTION BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY

    EPA Science Inventory

    Arsenic speciation continues to be important in assessing human and environmental exposure risk. Urinary arsenic analysis provides information on recent arsenic exposure. In this study, two sample introduction pathways: direct nebulization (DN) and hydride generation (HG) were ut...

  9. Association of Children’s Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media

    PubMed Central

    Beamer, Paloma I.; Klimecki, Walter T.; Loh, Miranda; Van Horne, Yoshira Ornelas; Sugeng, Anastasia J.; Lothrop, Nathan; Billheimer, Dean; Guerra, Stefano; Lantz, Robert Clark; Canales, Robert A.; Martinez, Fernando D.

    2016-01-01

    Arsenic exposure has been associated with decreased club cell secretory protein (CC16) levels in adults. Further, both arsenic exposure and decreased levels of CC16 in childhood have been associated with decreased adult lung function. Our objective was to determine if urinary CC16 levels in children are associated with arsenic concentrations in environmental media collected from their homes. Yard soil, house dust, and tap water were taken from 34 homes. Urine and toenail samples were collected from 68 children. All concentrations were natural log-transformed prior to data analysis. There were associations between urinary CC16 and arsenic concentration in soil (b = −0.43, p = 0.001, R2 = 0.08), water (b = −0.22, p = 0.07, R2 = 0.03), house dust (b = −0.37, p = 0.07, R2 = 0.04), and dust loading (b = −0.21, p = 0.04, R2 = 0.04). In multiple analyses, only the concentration of arsenic in soil was associated with urinary CC16 levels (b = −0.42, p = 0.02, R2 = 0.14 (full model)) after accounting for other factors. The association between urinary CC16 and soil arsenic may suggest that localized arsenic exposure in the lungs could damage the airway epithelium and predispose children for diminished lung function. Future work to assess this possible mechanism should examine potential associations between airborne arsenic exposures, CC16 levels, lung function, and other possible confounders in children in arsenic-impacted communities. PMID:27223295

  10. Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood.

    PubMed

    Ameer, Syeda Shegufta; Engström, Karin; Hossain, Mohammad Bakhtiar; Concha, Gabriela; Vahter, Marie; Broberg, Karin

    2017-04-15

    Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N=80 women) and DNA methylation (N=93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. U-As concentrations, ranging 10-1251μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Urinary and Dietary Analysis of 18,470 Bangladeshis Reveal a Correlation of Rice Consumption with Arsenic Exposure and Toxicity

    PubMed Central

    Melkonian, Stephanie; Argos, Maria; Hall, Megan N.; Chen, Yu; Parvez, Faruque; Pierce, Brandon; Cao, Hongyuan; Aschebrook-Kilfoy, Briseis; Ahmed, Alauddin; Islam, Tariqul; Slavcovich, Vesna; Gamble, Mary; Haris, Parvez I.; Graziano, Joseph H.; Ahsan, Habibul

    2013-01-01

    Background We utilized data from the Health Effects of Arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh, to evaluate the association of steamed rice consumption with urinary total arsenic concentration and arsenical skin lesions in the overall study cohort (N=18,470) and in a subset with available urinary arsenic metabolite data (N=4,517). Methods General linear models with standardized beta coefficients were used to estimate associations between steamed rice consumption and urinary total arsenic concentration and urinary arsenic metabolites. Logistic regression models were used to estimate prevalence odds ratios (ORs) and their 95% confidence intervals (CIs) for the associations between rice intake and prevalent skin lesions at baseline. Discrete time hazard models were used to estimate discrete time (HRs) ratios and their 95% CIs for the associations between rice intake and incident skin lesions. Results Steamed rice consumption was positively associated with creatinine-adjusted urinary total arsenic (β=0.041, 95% CI: 0.032-0.051) and urinary total arsenic with statistical adjustment for creatinine in the model (β=0.043, 95% CI: 0.032-0.053). Additionally, we observed a significant trend in skin lesion prevalence (P-trend=0.007) and a moderate trend in skin lesion incidence (P-trend=0.07) associated with increased intake of steamed rice. Conclusions This study suggests that rice intake may be a source of arsenic exposure beyond drinking water. PMID:24260455

  12. Urinary metabolomics revealed arsenic exposure related to metabolic alterations in general Chinese pregnant women.

    PubMed

    Li, Han; Wang, Mu; Liang, Qiande; Jin, Shuna; Sun, Xiaojie; Jiang, Yangqian; Pan, Xingyun; Zhou, Yanqiu; Peng, Yang; Zhang, Bin; Zhou, Aifen; Zhang, Yiming; Chen, Zhong; Cao, Jiangxia; Zhang, Hongling; Xia, Wei; Zheng, Tongzhang; Cai, Zongwei; Li, Yuanyuan; Xu, Shunqing

    2017-01-06

    Arsenic exposure is considered a major environmental threat to human health. It is already known that high-level arsenic exposure has adverse effects on human health. Since the pregnant women are known to be more susceptible to some chemical exposures than ordinary people, the understanding regarding the health effects of low-level arsenic exposure on pregnant women is critical and remains unclear. The aim of this study is to investigate the urinary metabolic changes of pregnant women exposed to low-dose arsenic, and to identify biomarkers from metabolomics analysis. Urine samples of 246 pregnant women were collected in the first trimester of pregnancy and were divided into three groups based on the tertile distribution of urinary arsenic concentrations which were determined using inductively coupled plasma mass spectrometry (ICP-MS). Changes in the metabolite profile were measured using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS). Arsenic- related metabolic biomarkers were investigated by comparing the samples of the first and third tertiles of arsenic exposure classifications using a partial least-squares discriminant model (PLS-DA). Nine urine potential biomarkers were putatively identified, including LysoPC (14:0), glutathione, 18-carboxy-dinor-LTE4, 20-COOH-LTE4, cystathionine ketimin, 1-(beta-d-ribofuranosyl)-1,4-dihydronicotinamide, thiocysteine, p-cresol glucuronide and vanillactic acid. The obtained results showed that environmental arsenic exposure, even at low levels, could cause metabolite alterations in pregnant women which might be associated with adverse health outcomes. This is the first report on metabolic changes in pregnant women for arsenic exposure. The findings may be valuable for the arsenic risk assessment for pregnant women. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Association of urinary monomethylated arsenic concentration and risk of hypertension: a cross-sectional study from arsenic contaminated areas in northwestern China

    PubMed Central

    2013-01-01

    Background Although some studies mainly from Taiwan, Bangladesh and the United States, have suggested a consistent dose–response increase in the prevalence of hypertension with increasing arsenic exposure, the association between chronic environmental arsenic exposure and the risk of hypertension is still inconclusive. Most of the studies discussed the association from the point of view of arsenic concentration in drinking water or cumulative arsenic exposure (CAE), few involved arsenic speciation into the discussion. In this cross-sectional study, we evaluated the potential association between environmental arsenic exposure through drinking water and the prevalence of hypertension by analyzing not only CAE but also urinary arsenic speciation, and provided data on arsenic exposure and hypertension from mainland of China. Methods A cross-sectional study was conducted in one of the arsenic contaminated areas in the northwest of China. Among a total of 1005 residents who voluntarily participated in the study, 604 of eligible subjects were confirmed and interviewed door to door. Standing height, body weight, and blood pressure were measured. First void urine was collected and measured for the concentration of urinary arsenic speciation. CAE was calculated in a subpopulation of 360 subjects with detailed water consumption history. The association between urinary arsenic speciation, CAE and the risk of hypertension were analyzed by multiple logistic regressions. Results We found that the levels of urinary arsenic species of inorganic arsenic (iAs), monomethylated arsenic (MMA), dimethylated arsenic (DMA) and total arsenic (tAs) were significantly correlated with systolic or pulse blood pressure. A positive relationship was found between the highest tertile of CAE and hypertension in a dose-dependent manner. Subjects with higher concentration of urinary MMA or lower percentage of DMA tended to be liable to suffer from hypertension. A significant increasing trend of the

  14. Association of urinary monomethylated arsenic concentration and risk of hypertension: a cross-sectional study from arsenic contaminated areas in northwestern China.

    PubMed

    Li, Xin; Li, Bing; Xi, Shuhua; Zheng, Quanmei; Wang, Da; Sun, Guifan

    2013-04-21

    Although some studies mainly from Taiwan, Bangladesh and the United States, have suggested a consistent dose-response increase in the prevalence of hypertension with increasing arsenic exposure, the association between chronic environmental arsenic exposure and the risk of hypertension is still inconclusive. Most of the studies discussed the association from the point of view of arsenic concentration in drinking water or cumulative arsenic exposure (CAE), few involved arsenic speciation into the discussion. In this cross-sectional study, we evaluated the potential association between environmental arsenic exposure through drinking water and the prevalence of hypertension by analyzing not only CAE but also urinary arsenic speciation, and provided data on arsenic exposure and hypertension from mainland of China. A cross-sectional study was conducted in one of the arsenic contaminated areas in the northwest of China. Among a total of 1005 residents who voluntarily participated in the study, 604 of eligible subjects were confirmed and interviewed door to door. Standing height, body weight, and blood pressure were measured. First void urine was collected and measured for the concentration of urinary arsenic speciation. CAE was calculated in a subpopulation of 360 subjects with detailed water consumption history. The association between urinary arsenic speciation, CAE and the risk of hypertension were analyzed by multiple logistic regressions. We found that the levels of urinary arsenic species of inorganic arsenic (iAs), monomethylated arsenic (MMA), dimethylated arsenic (DMA) and total arsenic (tAs) were significantly correlated with systolic or pulse blood pressure. A positive relationship was found between the highest tertile of CAE and hypertension in a dose-dependent manner. Subjects with higher concentration of urinary MMA or lower percentage of DMA tended to be liable to suffer from hypertension. A significant increasing trend of the risk of hypertension with

  15. Levels of plasma selenium and urinary total arsenic interact to affect the risk for prostate cancer.

    PubMed

    Hsueh, Yu-Mei; Su, Chien-Tien; Shiue, Horng-Sheng; Chen, Wei-Jen; Pu, Yeong-Shiau; Lin, Ying-Chin; Tsai, Cheng-Shiuan; Huang, Chao-Yuan

    2017-09-01

    This study investigated whether plasma selenium levels modified the risk for prostate cancer (PC) related to arsenic exposure. We conducted a case-control study that included 318 PC patients and 318 age-matched, healthy control subjects. Urinary arsenic profiles were examined using HPLC-HG-AAS and plasma selenium levels were measured by ICP-MS. We found that plasma selenium levels displayed a significant dose-dependent inverse association with PC. The odds ratio (OR) and 95% confidence interval (CI) for PC was 0.07 (0.04-0.13) among participants with a plasma selenium level >28.06 μg/dL vs. ≤19.13 μg/dL. A multivariate analysis showed that participants with a urinary total arsenic concentration >29.28 μg/L had a significantly higher OR (1.75, 1.06-2.89) for PC than participants with ≤29.89 μg/L. The combined presence of a low plasma selenium level and a high urinary total arsenic concentration exponentially increased the OR for PC, and additively interacted with PSA at levels ≥20 ng/mL. This is the first epidemiological study to examine the combined effects of plasma selenium and urinary total arsenic levels on the OR for PC. Our data suggest a low plasma selenium level coupled with a high urinary total arsenic concentration creates a significant risk for aggressive PC. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Differences in urinary arsenic metabolites between diabetic and non-diabetic subjects in Bangladesh.

    PubMed

    Nizam, Saika; Kato, Masashi; Yatsuya, Hiroshi; Khalequzzaman, Md; Ohnuma, Shoko; Naito, Hisao; Nakajima, Tamie

    2013-03-12

    Ingestion of inorganic arsenic (iAs) is considered to be related to the development of diabetes mellitus. In order to clarify the possible differences in the metabolism in diabetics, we measured urinary iAs metabolites in diabetic cases and non-diabetic control subjects in Faridpur, an arsenic-contaminated area in Bangladesh. Physician-diagnosed type 2 diabetic cases (140 persons) and non-diabetic controls (180 persons) were recruited. Drinking water and spot urine samples were collected. Mean concentrations of total arsenic in drinking water did not differ between cases (85.1 μg/L) and controls (85.8 μg/L). The percentage of urinary iAs (iAs%) was significantly lower in cases (8.6%) than in controls (10.4%), while that of dimethylarsinic acid (DMA%) was higher in cases (82.6%) than in controls (79.9%). This may have been due to the higher secondary methylation index (SMI) in the former (11.6) rather than the latter (10.0). Adjusting for matching factors (sex and unions), and the additional other covariates (age and water arsenic) significantly attenuated the differences in iAs%, SMI, and DMA%, respectively, though the difference in monomethylarsonic acid% was newly significant in the latter adjustment. Our study did not suggest any significant differences in urinary arsenic metabolites between diabetic and non-diabetic subjects.

  17. Differences in Urinary Arsenic Metabolites between Diabetic and Non-Diabetic Subjects in Bangladesh

    PubMed Central

    Nizam, Saika; Kato, Masashi; Yatsuya, Hiroshi; Khalequzzaman, Md.; Ohnuma, Shoko; Naito, Hisao; Nakajima, Tamie

    2013-01-01

    Ingestion of inorganic arsenic (iAs) is considered to be related to the development of diabetes mellitus. In order to clarify the possible differences in the metabolism in diabetics, we measured urinary iAs metabolites in diabetic cases and non-diabetic control subjects in Faridpur, an arsenic-contaminated area in Bangladesh. Physician-diagnosed type 2 diabetic cases (140 persons) and non-diabetic controls (180 persons) were recruited. Drinking water and spot urine samples were collected. Mean concentrations of total arsenic in drinking water did not differ between cases (85.1 μg/L) and controls (85.8 μg/L). The percentage of urinary iAs (iAs%) was significantly lower in cases (8.6%) than in controls (10.4%), while that of dimethylarsinic acid (DMA%) was higher in cases (82.6%) than in controls (79.9%). This may have been due to the higher secondary methylation index (SMI) in the former (11.6) rather than the latter (10.0). Adjusting for matching factors (sex and unions), and the additional other covariates (age and water arsenic) significantly attenuated the differences in iAs%, SMI, and DMA%, respectively, though the difference in monomethylarsonic acid% was newly significant in the latter adjustment. Our study did not suggest any significant differences in urinary arsenic metabolites between diabetic and non-diabetic subjects. PMID:23481591

  18. Increased damage of exon 5 of p53 gene in workers from an arsenic plant.

    PubMed

    Wen, Weihua; Che, Wangjun; Lu, Lin; Yang, Jun; Gao, Xufang; Wen, Jinghua; Heng, Zhengchang; Cao, Shuqiao; Cheng, Huirong

    2008-08-25

    Mutagenesis is a multistage process. Substitution mutations can be induced by base modified through alteration of pairing property. Mutations of exon 5 and 8 of p53 gene have been found in most arsenicosis patients with precarcinomas and carcinomas, but never in arsenicosis individuals without precarcinomas and carcinomas. This study investigates whether base modification exists in exon 5 and 8 of p53 gene, and explores the dose-effect relationship between damage of exon 5 of p53 gene and urinary arsenic. Concentrations of urinary 8-hydroxydeoxyguanine (8-OHdG) are analyzed to identify the occurrence of DNA damage. The real-time PCR developed by Sikorsky et al. is applied to detect base modification in exon 5 and 8 of p53 gene for apparently healthy participants. Our results show that the mean total arsenic concentrations of two exposed groups from an arsenic plant are significantly elevated compared with the control group, and the damage level of exon 5 of the high-exposed group is significantly higher than that of the control group, but which does not happen in exon 8. The closely correlation between the damage index of exon 5 and urinary organic arsenic concentration are found. Concentration of 8-OHdG of the high-exposed group is significantly higher than that of the control group. These results imply that base modification in exon 5 of p53 gene can be induced by arsenic. In addition, our study suggests that the damage level of exon 5 is a useful biomarker to assess adverse health effect levels caused by chronic exposure to arsenic.

  19. Relation of polymorphism of arsenic metabolism genes to arsenic methylation capacity and developmental delay in preschool children in Taiwan.

    PubMed

    Hsieh, Ru-Lan; Su, Chien-Tien; Shiue, Horng-Sheng; Chen, Wei-Jen; Huang, Shiau-Rung; Lin, Ying-Chin; Lin, Ming-I; Mu, Shu-Chi; Chen, Ray-Jade; Hsueh, Yu-Mei

    2017-04-15

    Inefficient arsenic methylation capacity has been associated with developmental delay in children. The present study was designed to explore whether polymorphisms and haplotypes of arsenic methyltransferase (AS3MT), glutathione-S-transferase omegas (GSTOs), and purine nucleoside phosphorylase (PNP) affect arsenic methylation capacity and developmental delay. A case-control study was conducted from August 2010 to March 2014. All participants were recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. In total, 179 children with developmental delay and 88 children without delay were recruited. Urinary arsenic species, including arsenite (As(III)), arsenate (As(V)), monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V)) were measured using a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphisms of AS3MT, GSTO, and PNP were performed using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Polymorphisms of AS3MT genes were found to affect susceptibility to developmental delay in children, but GSTO and PNP polymorphisms were not. Participants with AS3MT rs3740392 A/G+G/G genotype, compared with AS3MT rs3740392 A/A genotype, had a significantly lower secondary methylation index. This may result in an increased OR for developmental delay. Participants with the AS3MT high-risk haplotype had a significantly higher OR than those with AS3MT low-risk haplotypes [OR and 95% CI, 1.59 (1.08-2.34)]. This is the first study to show a joint dose-response effect of this AS3MT high-risk haplotype and inefficient arsenic methylation capacity on developmental delay. Our data provide evidence that AS3MT genes are related to developmental delay and may partially influence arsenic methylation capacity. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Arsenic levels in the groundwater of Korea and the urinary excretion among contaminated area.

    PubMed

    Park, Jung-Duck; Choi, Seong-Jin; Choi, Byung-Sun; Lee, Choong-Ryeol; Kim, Heon; Kim, Yong-Dae; Park, Kyung-Soo; Lee, Young-Jo; Kang, Seojin; Lim, Kyung-Min; Chung, Jin-Ho

    2016-09-01

    Drinking water is a main source of human exposure to arsenic. Hence, the determination of arsenic in groundwater is essential to assess its impact on public health. Here, we report arsenic levels in the groundwater of 722 sites covering all six major provinces of Korea. Water was sampled in two occasions (summer, 722 sites and winter, 636 sites) and the arsenic levels were measured with highly sensitive inductively coupled plasma-mass spectrometry method (limit of detection, 0.1 μg/l) to encompass the current drinking water standard (<10 μg/l). Seasonal variation was negligible, but the geographical difference was prominent. Total arsenic in groundwater ranged from 0.1 to 48.4 μg/l. A 88.0-89.0% of sites were <2.0 μg/l and the remaining ones generally did not exceed 10 μg/l (6.4-7.0%, 2.0-4.9 μg/l; 2.4-3.0%, 5.0-9.9 μg/l). However, some areas (1.0-9.2%) exhibited >10 μg/l. Notably, urinary arsenic excretion of people around these regions was markedly higher compared with non-contaminated areas (<5 μg/l) (79.7±5.2 μg/g (N=122) vs 68.4±5.4 μg/g (N=65) creatinine, P=0.052). All stratified analysis also revealed higher urinary excretion, where a statistically significant difference was noted for non-smokers (85.9±12.7 vs 54.0±6.3, P=0.030), suggesting that arsenic-contaminated groundwater may contribute to its systemic exposure.

  1. Effects of arsenic exposure among semiconductor workers: a cautionary note on urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine.

    PubMed

    Hu, Chiung-Wen; Pan, Chih-Hong; Huang, Yeou-Lih; Wu, Ming-Tsang; Chang, Louis W; Wang, Chien-Jen; Chao, Mu-Rong

    2006-04-01

    Arsenic is a notorious environmental toxicant and was found to cause oxidative stress in cultured cells and animals. However, little work has been done in human studies, especially for the population occupationally exposed to arsenic. In order to investigate the effect of occupational exposure to arsenic in oxidative stress, we measured urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) from 90 semiconductor workers including 50 exposed and 40 nonexposed subjects. A highly sensitive and specific isotope dilution LC-MS/MS method was used for quantification of 8-oxodGuo. The levels of inorganic arsenic (iAs3+, iAs5+), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in urine were determined by high-performance liquid chromatography-flow injection atomic absorption spectrometry (HPLC-FIAAS). Results showed that the mean urinary concentrations of total arsenic and 8-oxodGuo were significantly higher for exposed workers compared with the nonexposed workers. In addition, elevated urinary 8-oxodGuo concentrations of exposed workers were correlated with urinary levels of MMA (r = 0.44, P < 0.005) and the extent of primary methylation (the ratio of MMA to inorganic arsenic) (r = 0.40, P < 0.005). These findings suggested that occupational exposure to arsenic could result in the induction of oxidative stress. The presence and/or formation of MMA could play an important role in arsenic-involved injuries.

  2. Effects of biological and behavioral factors on urinary arsenic metabolic profiles in a U.S. population

    EPA Science Inventory

    Abstract In older men and women who were long-term residents of Churchill County, Nevada, we examined the relation between arsenic exposure from home tap water and urinary levels of inorganic arsenic and its methylated metabolites. Over a wide exposure range (up to 1850 ug of ars...

  3. A biological indicator of inorganic arsenic exposure using the sum of urinary inorganic arsenic and monomethylarsonic acid concentrations

    PubMed Central

    Hata, Akihisa; Kurosawa, Hidetoshi; Endo, Yoko; Yamanaka, Kenzo; Fujitani, Noboru; Endo, Ginji

    2016-01-01

    Objectives: The sum of urinary inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) concentrations is used for the biological monitoring of occupational iAs exposure. Although DMA is a major metabolite of iAs, it is an inadequate index because high DMA levels are present in urine after seafood consumption. We estimated the urinary iAs+MMA concentration corresponding to iAs exposure. Methods: We used data from two arsenic speciation analyses of urine samples from 330 Bangladeshi with oral iAs exposure and 172 Japanese workers without occupational iAs exposure using high-performance liquid chromatography with inductively coupled plasma mass spectrometry. Results: iAs, MMA, and DMA, but not arsenobetaine (AsBe), were detected in the urine of the Bangladeshi subjects. The correlation between iAs+MMA+DMA and iAs+MMA was obtained as log (iAs+MMA) = 1.038 log (iAs+MMA+DMA) -0.658. Using the regression formula, the iAs+MMA value was calculated as 2.15 and 7.5 μg As/l, corresponding to 3 and 10 μg As/m3 of exposures, respectively. In the urine of the Japanese workers, arsenic was mostly excreted as AsBe. We used the 95th percentile of iAs+MMA (12.6 μg As/l) as the background value. The sum of the calculated and background values can be used as a biological indicator of iAs exposure. Conclusion: We propose 14.8 and 20.1 μg As/l of urinary iAs+MMA as the biological indicators of 3 and 10 μg As/m3 iAs exposure, respectively. PMID:27010090

  4. DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic.

    PubMed

    Gonzalez-Cortes, Tania; Recio-Vega, Rogelio; Lantz, Robert Clark; Chau, Binh T

    2017-08-15

    Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases. Copyright © 2017. Published by Elsevier Inc.

  5. Association Between Variants in Arsenic (+3 Oxidation State) Methyltranserase (AS3MT) and Urinary Metabolites of Inorganic Arsenic: Role of Exposure Level.

    PubMed

    Xu, Xiaofan; Drobná, Zuzana; Voruganti, V Saroja; Barron, Keri; González-Horta, Carmen; Sánchez-Ramírez, Blanca; Ballinas-Casarrubias, Lourdes; Cerón, Roberto Hernández; Morales, Damián Viniegra; Terrazas, Francisco A Baeza; Ishida, María C; Gutiérrez-Torres, Daniela S; Saunders, R Jesse; Crandell, Jamie; Fry, Rebecca C; Loomis, Dana; García-Vargas, Gonzalo G; Del Razo, Luz M; Stýblo, Miroslav; Mendez, Michelle A

    2016-09-01

    Variants in AS3MT, the gene encoding arsenic (+3 oxidation state) methyltranserase, have been shown to influence patterns of inorganic arsenic (iAs) metabolism. Several studies have suggested that capacity to metabolize iAs may vary depending on levels of iAs exposure. However, it is not known whether the influence of variants in AS3MT on iAs metabolism also vary by level of exposure. We investigated, in a population of Mexican adults exposed to drinking water As, whether associations between 7 candidate variants in AS3MT and urinary iAs metabolites were consistent with prior studies, and whether these associations varied depending on the level of exposure. Overall, associations between urinary iAs metabolites and AS3MT variants were consistent with the literature. Referent genotypes, defined as the genotype previously associated with a higher percentage of urinary dimethylated As (DMAs%), were associated with significant increases in the DMAs% and ratio of DMAs to monomethylated As (MAs), and significant reductions in MAs% and iAs%. For 3 variants, associations between genotypes and iAs metabolism were significantly stronger among subjects exposed to water As >50 versus ≤50 ppb (water As X genotype interaction P < .05). In contrast, for 1 variant (rs17881215), associations were significantly stronger at exposures ≤50 ppb. Results suggest that iAs exposure may influence the extent to which several AS3MT variants affect iAs metabolism. The variants most strongly associated with iAs metabolism-and perhaps with susceptibility to iAs-associated disease-may vary in settings with exposure level. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. A Pathway-based Analysis of Urinary Arsenic Metabolites and Skin Lesions

    PubMed Central

    Kile, Molly L.; Hoffman, Elaine; Rodrigues, Ema G.; Breton, Carrie V.; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Hsueh, Yu-Mei; Christiani, David C.

    2011-01-01

    Inorganic arsenic is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Limited evidence suggests that the ability to fully metabolize arsenic into DMA influences susceptibility to disease. To determine whether percentage of MMA was predictive of disease, the authors used data from a case-control study conducted in Bangladesh (2001–2003). Persons who were diagnosed with keratosis, melanosis, Bowen's disease, or squamous cell carcinoma were matched on age, sex, and village to persons without these conditions. This analysis was restricted to persons who had no missing data on covariates (859 cases, 868 controls). A path analysis was used to evaluate simultaneously the association between the percentage of all urinary arsenic metabolites and the odds of skin lesions using PROC CALIS in SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina) and Mplus, version 6.1 (Muthén & Muthén, Los Angeles, California). The odds of skin lesions were significantly associated with log10 percentage of MMA (adjusted odds ratio (ORadj) = 1.56, 95% confidence interval (CI): 1.15, 2.12) but not log10 percentage of inorganic arsenic (ORadj = 1.06, 95% CI: 0.75, 1.50) or log10 percentage of DMA (ORadj = 1.07, 95% CI: 0.33, 3.46). This novel analysis confirmed that persons who excrete a higher proportion of MMA have a greater risk of skin lesions after data are adequately controlled for urinary arsenic metabolites, current arsenic exposure, and other risk factors. PMID:21378128

  7. Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes: Assessment by Real-Time PCR Arrays

    PubMed Central

    Mo, Jinyao; Xia, Yajuan; Wade, Timothy J.; DeMarini, David M.; Davidson, Mercy; Mumford, Judy

    2011-01-01

    Chronic arsenic exposure results in higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array (TLDA). We found that expression of tumor necrosis factor-α (TNF-α), which activates both inflammation and NF-κB-dependent survival pathways, was strongly associated with water and urinary arsenic levels. Expression of KCNA5, which encodes a potassium ion channel protein, was positively associated with water and toe nail arsenic levels. Expression of 2 and 11 genes were positively associated with nail and urinary arsenic, respectively. Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans, we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro. Expression of the ion-channel genes CACNA1, KCNH2, KCNQ1 and KCNE1 were down-regulated by 1-μM arsenic. Alteration of some common pathways, including those involved in oxidative stress, inflammatory signaling, and ion-channel function, may underlay the seemingly disparate array of arsenic-associated diseases, such as cancer, cardiovascular disease, and diabetes. PMID:21776218

  8. Tissue distribution and urinary excretion of dimethylated arsenic and its metabolites in dimethylarsinic acid- or arsenate-treated rats

    SciTech Connect

    Adair, Blakely M.; Moore, Tanya; Conklin, Sean D.; Creed, John T.; Wolf, Douglas C.; Thomas, David J. . E-mail: thomas.david@epa.gov

    2007-07-15

    Adult female Fisher 344 rats received drinking water containing 0, 4, 40, 100, or 200 parts per million of dimethylarsinic acid or 100 parts per million of arsenate for 14 days. Urine was collected during the last 24 h of exposure. Tissues were then taken for analysis of dimethylated and trimethylated arsenicals; urines were analyzed for these arsenicals and their thiolated derivatives. In dimethylarsinic acid-treated rats, highest concentrations of dimethylated arsenic were found in blood. In lung, liver, and kidney, concentrations of dimethylated arsenic exceeded those of trimethylated species; in urinary bladder and urine, trimethylated arsenic predominated. Dimethylthioarsinic acid and trimethylarsine sulfide were present in urine of dimethylarsinic acid-treated rats. Concentrations of dimethylated arsenicals were similar in most tissues of dimethylarsinic acid- and arsenate-treated rats, including urinary bladder which is the target for dimethylarsinic acid-induced carcinogenesis in the rat. Mean concentration of dimethylated arsenic was significantly higher (P < 0.05) in urine of dimethylarsinic acid-treated rats than in arsenate-treated rats, suggesting a difference between treatment groups in the flux of dimethylated arsenic through urinary bladder. Concentrations of trimethylated arsenic concentrations were consistently higher in dimethylarsinic acid-treated rats than in arsenate-treated rats; these differences were significant (P < 0.05) in liver, urinary bladder, and urine. Concentrations of dimethylthioarsinic acid and trimethylarsine sulfide were higher in urine from dimethylarsinic acid-treated rats than from arsenate-treated rats. Dimethylarsinic acid is extensively metabolized in the rat, yielding significant concentrations of trimethylated species and of thiolated derivatives. One or more of these metabolites could be the species causing alterations of cellular function that lead to tumors in the urinary bladder.

  9. Iron and Zinc Supplementation Does Not Impact Urinary Arsenic Excretion in Mexican School Children.

    PubMed

    Kordas, Katarzyna; Roy, Aditi; López, Patricia; García-Vargas, Gonzalo; Cebrián, Mariano E; Vera-Aguilar, Eunice; Rosado, Jorge L

    2017-06-01

    To examine the role of iron and zinc in arsenic excretion and metabolism in children. An analysis of urinary arsenic (UAs) concentrations from a double-blind randomized trial originally testing the efficacy of iron and zinc for lowering blood lead levels in children. A 2 × 2 factorial design was used, with children randomized individually, stratified by sex and classroom, to receive 30?mg ferrous fumarate (n?=?148), 30?mg zinc oxide (n?=?144), iron and zinc together (n?=?148), or placebo (n?=?151). Of the 602 children enrolled, 527 completed the 6-month treatment, and 485 had both baseline and final UAs values. The baseline total UAs concentration ranged from 3.2 to 215.9?µg/L. At baseline, children in the highest tertile of serum ferritin concentration had higher excretion of dimethylarsinic acid (DMA; 1.93?±?0.86%; P?arsenic methylation or UAs excretion, but children receiving zinc had lower %DMA in urine (-1.7?±?0.8; P?arsenic metabolism in children, and supplementation with these minerals has limited application in lowering arsenic concentrations. ClinicalTrials.gov: NCT02346188. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh.

    PubMed

    Argos, Maria; Chen, Lin; Jasmine, Farzana; Tong, Lin; Pierce, Brandon L; Roy, Shantanu; Paul-Brutus, Rachelle; Gamble, Mary V; Harper, Kristin N; Parvez, Faruque; Rahman, Mahfuzar; Rakibuz-Zaman, Muhammad; Slavkovich, Vesna; Baron, John A; Graziano, Joseph H; Kibriya, Muhammad G; Ahsan, Habibul

    2015-01-01

    Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity. Among a sample of 400 adult participants, we evaluated the association between arsenic exposure, as measured by blood and urinary total arsenic concentrations, and epigenome-wide white blood cell DNA methylation. We used linear regression models to examine the associations between arsenic exposure and methylation at each CpG site, adjusted for sex, age, and batch. Differentially methylated loci were subsequently examined in relation to corresponding gene expression for functional evidence of gene regulation. In adjusted analyses, we observed four differentially methylated CpG sites with urinary total arsenic concentration and three differentially methylated CpG sites with blood arsenic concentration, based on the Bonferroni-corrected significance threshold of p < 1 × 10(-7). Methylation of PLA2G2C (probe cg04605617) was the most significantly associated locus in relation to both urinary (p = 3.40 × 10(-11)) and blood arsenic concentrations (p = 1.48 × 10(-11)). Three additional novel methylation loci-SQSTM1 (cg01225779), SLC4A4 (cg06121226), and IGH (cg13651690)--were also significantly associated with arsenic exposure. Further, there was evidence of methylation-related gene regulation based on gene expression for a subset of differentially methylated loci. We observed significant associations between arsenic exposure and gene-specific differential white blood cell DNA methylation, suggesting that epigenetic modifications may be an important pathway underlying arsenic toxicity. The specific differentially methylated loci identified may inform potential pathways for future interventions.

  11. Association between maternal urinary arsenic species and infant cord blood leptin levels in a New Hampshire Pregnancy Cohort.

    PubMed

    Gossai, Anala; Lesseur, Corina; Farzan, Shohreh; Marsit, Carmen; Karagas, Margaret R; Gilbert-Diamond, Diane

    2015-01-01

    Leptin is an important pleiotropic hormone involved in the regulation of nutrient intake and energy expenditure, and is known to influence body weight in infants and adults. High maternal levels of arsenic have been associated with reduced infant birth weight, but the mechanism of action is not yet understood. This study aimed to investigate the association between in utero arsenic exposure and infant cord blood leptin concentrations within 156 mother-infant pairs from the New Hampshire Birth Cohort Study (NHBCS) who were exposed to low to moderate levels of arsenic through well water and diet. In utero arsenic exposure was obtained from maternal second trimester urinary arsenic concentration, and plasma leptin levels were assessed through immunoassay. Results indicate that urinary arsenic species concentrations were predictive of infant cord blood leptin levels following adjustment for creatinine, infant birth weight for gestational age percentile, infant sex, maternal pregnancy-related weight gain, and maternal education level amongst 149 white mother-infant pairs in multivariate linear regression models. A doubling or 100% increase in total urinary arsenic concentration (iAs+MMA+DMA) was associated with a 10.3% (95% CI: 0.8-20.7%) increase in cord blood leptin levels. A 100% increase in either monomethylarsonic acid (MMA) or dimethylarsinic acid (DMA) was also associated with an 8.3% (95% CI: -1.0-18.6%) and 10.3% (95% CI: 1.2-20.2%) increase in cord blood leptin levels, respectively. The association between inorganic arsenic (iAs) and cord blood leptin was of similar magnitude and direction as other arsenic species (a 100% increase in iAs was associated with a 6.5% (95% CI: -3.4-17.5%) increase in cord blood leptin levels), albeit not significant. These results suggest in utero exposure to low levels of arsenic influences cord blood leptin concentration and presents a potential mechanism by which arsenic may impact early childhood growth.

  12. Oxidative DNA damage estimated by urinary 8-hydroxy-2'-deoxyguanosine and arsenic in glass production workers.

    PubMed

    Lin, Tser-Sheng; Wu, Chin-Ching; Wu, Jyun-De; Wei, Chun-Han

    2012-07-01

    A total of 130 male glass workers, including 33 administrative workers, 18 batch house workers, 42 craftsmen, and 37 melting process workers, were recruited to investigate the potential DNA damage resulting from toxic element exposure. The occupational exposure to trace elements, including arsenic (As), cadmium (Cd), manganese (Mn), nickel (Ni), lead (Pb), and selenium (Se), was estimated by their urinary levels as internal doses. In addition, all participants filled a self-filled questionnaire indicating their individual information. The average levels of urinary As, Cd, Mn, Ni, Pb, Se, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were 282.3 ± 464.6, 3.07 ± 5.39, 3.81 ± 11.43, 81.48 ± 138.9, 18.23 ± 49.61, 165.2 ± 224.9, and 17.21 ± 26.34 μg/g creatinine, respectively. The urinary levels of 8-OHdG and toxic elements were strongly associated with the work nature of the worker, with an exception of Mn and Pb. In contrast, the levels of toxic element were not influenced by age, smoking behavior, and alcohol consumption. The urinary 8-OHdG was found significantly higher in higher internal exposure groups of As, Cd, Ni, and Se. However, the stepwise multiple regression models showed that urinary 8-OHdG was only associated with urinary As and heat stress but inversely with age.

  13. Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes

    SciTech Connect

    Hsieh, Yi-Chen; Lien, Li-Ming; Chung, Wen-Ting; Hsieh, Fang-I; Hsieh, Pei-Fan; Wu, Meei-Maan; Tseng, Hung-Pin; Chiou, Hung-Yi; Chen, Chien-Jen

    2011-08-15

    Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose-response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50 {mu}g/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50 {mu}g/l in drinking water and those who carried the PNP A-T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79-23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50 {mu}g/l). - Highlights: {yields}Arsenic metabolic genes might be associated with carotid atherosclerosis. {yields

  14. Urinary arsenic metabolism in a Western Chinese population exposed to high-dose inorganic arsenic in drinking water: influence of ethnicity and genetic polymorphisms.

    PubMed

    Fu, Songbo; Wu, Jie; Li, Yuanyuan; Liu, Yan; Gao, Yanhui; Yao, Feifei; Qiu, Chuanying; Song, Li; Wu, Yu; Liao, Yongjian; Sun, Dianjun

    2014-01-01

    To investigate the differences in urinary arsenic metabolism patterns of individuals exposed to a high concentration of inorganic arsenic (iAs) in drinking water, an epidemiological investigation was conducted with 155 individuals living in a village where the arsenic concentration in the drinking water was 969μg/L. Blood and urine samples were collected from 66 individuals including 51 cases with skin lesions and 15 controls without skin lesions. The results showed that monomethylated arsenic (MMA), the percentage of MMA (%MMA) and the ratio of MMA to iAs (MMA/iAs) were significantly increased in patients with skin lesions as compared to controls, while dimethylated arsenic (DMA), the percentage of DMA (%DMA) and the ratio of DMA to MMA (DMA/MMA) were significantly reduced. The percent DMA of individuals with the Ala/Asp genotype of glutathione S-transferase omega 1 (GSTO1) was significantly lower than those with Ala/Ala. The percent MMA of individuals with the A2B/A2B genotype of arsenic (+3 oxidation state) methyltransferase (AS3MT) was significantly lower than those with AB/A2B. The iAs and total arsenic (tAs) content in the urine of a Tibetan population were significantly higher than that of Han and Hui ethnicities, whereas MMA/iAs was significantly lower than that of Han and Hui ethnicities. Our results showed that when exposed to the same arsenic environment, different individuals exhibited different urinary arsenic metabolism patterns. Gender and ethnicity affect these differences and above polymorphisms may be effectors too.

  15. Urinary Arsenic Metabolites in Children and Adults Exposed to Arsenic in Drinking Water in Inner Mongolia, China

    PubMed Central

    Sun, Guifan; Xu, Yuanyuan; Li, Xin; Jin, Yaping; Li, Bing; Sun, Xiance

    2007-01-01

    Background We report the concentrations and distributions of urinary arsenic (As) metabolites in 233 residents exposed to 20, 90, or 160 μg/L inorganic arsenic (iAs) in drinking water from three villages in Hohhot, Inner Mongolia, China, that formed one control and two exposed groups. Methods We used hydride generation-atomic absorption spectrometry (HGAAS) to determine iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA). Results The concentrations of each urinary As species in the two exposed groups were significantly higher than in the control group for both children and adults. Both children and adults in exposed groups had higher percent iAs and MMA and lower percent DMA, and low primary and secondary methylation indices (PMI and SMI, respectively) than those in the control group. However, children showed significant increases in percent DMA and the SMI as well as decreases in the percent MMA when the iAs exposure level increased from 90 to 160 μg/L. In addition, children in the two exposed groups showed lower percent MMA but higher percent DMA and higher SMI than adults in the same exposed group. No significant differences in As metabolite concentrations and distributions were found between males and females in each group. A significant correlation was also found in the SMI between 11 pairs of children and their mothers from the 160-μg/L–exposed group. Conclusions Children had higher a capacity for secondary methylation of As than adults when exposed to the same concentrations of iAs in drinking water. Exposure to As may increase the capacity for methylation in children to some extent. PMID:17450238

  16. Arsenic Relative Bioavailability in Rice Using a Mouse Arsenic Urinary Excretion Bioassay and Its Application to Assess Human Health Risk.

    PubMed

    Li, Hong-Bo; Li, Jie; Zhao, Di; Li, Chao; Wang, Xue-Jiao; Sun, Hong-Jie; Juhasz, Albert L; Ma, Lena Q

    2017-04-18

    A steady-state mouse model was developed to determine arsenic (As) relative bioavailability (RBA) in rice to refine As exposure in humans. Fifty-five rice samples from 15 provinces of China were analyzed for total As, with 11 cooked for As speciation and bioavailability assessment. Arsenic concentrations were 38-335 μg kg(-1), averaging 133 μg kg(-1), with As(III) being dominant (36-79%), followed by DMA(V) (18-58%) and As(V) (0.5-16%). Following oral doses of individual As species to mice at low As exposure (2.5-15 μg As per mouse) over a 7-d period, strong linear correlations (R(2) = 0.99) were observed between As urinary excretion and cumulative As intake, suggesting the suitability and sensitivity of the mouse bioassay to measure As-RBA in rice. Urinary excretion factor for DMA(V) (0.46) was less than inorganic As (0.63-0.69). As-RBA in cooked rice ranged from 13.2 ± 2.2% to 53.6 ± 11.1% (averaging 27.0 ± 12.2%) for DMA(V) and 26.2 ± 7.0% to 49.5 ± 4.7% (averaging 39.9 ± 8.3%) for inorganic As. Calculation of inorganic As intake based on total inorganic As in rice overestimated As exposure by 2.0-3.7 fold compared to that based on bioavailable inorganic As. For accurate assessment of the health risk associated with rice consumption, it is important to consider As bioavailability especially inorganic As in rice.

  17. Urinary arsenic levels in the French adult population: the French National Nutrition and Health Study, 2006-2007.

    PubMed

    Saoudi, Abdessattar; Zeghnoun, Abdelkrim; Bidondo, Marie-Laure; Garnier, Robert; Cirimele, Vincent; Persoons, Renaud; Fréry, Nadine

    2012-09-01

    The French Nutrition and Health Survey (ENNS) was conducted to describe dietary intakes, nutritional status, physical activity, and levels of various biomarkers for environmental chemicals (heavy metals and pesticides) in the French population (adults aged 18-74 years and children aged 3-17 years living in continental France in 2006-2007). The aim of this paper was to describe the distributions of total arsenic and the sum of iAs+MMA+DMA in the general adult population, and to present their main risk factors. In the arsenic study, 1500 and 1515 adults (requested to avoid seafood intake in the previous 3 days preceding urine collection) were included respectively for the analysis of the sum of inorganic arsenic (iAs) and its two metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), and for the total arsenic. Results were presented as geometric means and selected percentiles of urinary arsenic concentrations (μg/L) and creatinine-adjusted urinary arsenic (μg/g of creatinine) for total arsenic, and the sum of inorganic arsenic and metabolites (iAs+MMA+DMA). The geometric mean concentration of the sum of iAs+MMA+DMA in the adult population living in France was 3.34 μg/g of creatinine [3.23-3.45] (3.75 μg/L [3.61-3.90]) with a 95th percentile of 8.9 μg/g of creatinine (10.68 μg/L). The geometric mean concentration of total arsenic was 11.96 μg/g of creatinine [11.41-12.53] (13.42 μg/L [12.77-14.09]) with a 95th percentile of 61.29 μg/g of creatinine (72.75 μg/L). Urinary concentrations of total arsenic and iAS+MMA+DMA were influenced by sociodemographic and economic factors, and by risk factors such as consumption of seafood products and of wine. In our study, covariate-adjusted geometric means demonstrated several slight differences, due to consumption of fish, shellfish/crustaceans or wine. This study provides the first reference value for arsenic in a representative sample of the French population not particularly exposed to high levels

  18. A Cross-sectional Study of the Impact of Blood Selenium on Blood and Urinary Arsenic Concentrations in Bangladesh

    PubMed Central

    2013-01-01

    Background Arsenic can naturally occur in the groundwater without an anthropogenic source of contamination. In Bangladesh over 50 million people are exposed to naturally occurring arsenic concentrations exceeding the World Health Organization’s guideline of 10 μg/L. Selenium and arsenic have been shown to facilitate the excretion of each other in bile. Recent evidence suggests that selenium may play a role in arsenic elimination by forming a selenium-arsenic conjugate in the liver before excretion into the bile. Methods A cross-sectional study of 1601 adults and 287 children was conducted to assess the relationship between blood selenium and urinary and blood arsenic in a study population residing in a moderately arsenic-contaminated rural area in Bangladesh. Results The results of this study indicate a statistically significant inverse relationship between blood selenium and urinary arsenic concentrations in both adult and pediatric populations in rural Bangladesh after adjustment for age, sex, Body Mass Index, plasma folate and B12 (in children), and ever smoking and current betel nut use (in adults). In addition, there appears to be a statistically significant inverse relationship between blood selenium and blood arsenic in children. Conclusions Our results suggest that selenium is inversely associated with biomarkers of arsenic burden in both adults and children. These findings support the hypothesis that Se facilitates the biliary elimination of As, possibly via the putative formation of a Se-As conjugate using a glutathione complex. However, laboratory based studies are needed to provide further evidence to elucidate the presence of Se-As conjugate and its role in arsenic elimination in humans. PMID:23816141

  19. IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC INDUCED BLADDER CANCER BY GENE EXPRESSION.

    EPA Science Inventory

    Arsenic is a human carcinogen that induces urinary bladder cancer. Several mechanisms have been proposed for arsenic-induced cancer. Although inorganic arsenic (iAs) does not induce tumors in adult rodents, dimethylarsinic acid (DMA), a major metabolite of iAs, is a rat bladder c...

  20. MEETING AT SAN DIEGO, CA: GENE EXPRESSION IN NORMAL HUMAN KERATINOCYTES MODULATED BY TRIVALENT ARSENICALS

    EPA Science Inventory

    Arsenic exposure has been correlated with the development of several human cancers including those found in the skin, lung, liver, kidney and urinary bladder. Humans are generally exposed to inorganic forms of arsenic, which may be inhaled or ingested. Arsenic forms mono- and di-...

  1. MEETING AT CAMBRIDGE, MA: GENE EXPRESSION IN NORMAL HUMAN KERATINOCYTES MODULATED BY TRIVALENT ARSENICALS

    EPA Science Inventory

    Arsenic exposure has been correlated with the development of several human cancers including those found in the skin, lung, liver, kidney and urinary bladder. Humans are generally exposed to inorganic forms of arsenic, which may be inhaled or ingested. Arsenic forms mono- and d...

  2. MEETING AT SAN DIEGO, CA: GENE EXPRESSION IN NORMAL HUMAN KERATINOCYTES MODULATED BY TRIVALENT ARSENICALS

    EPA Science Inventory

    Arsenic exposure has been correlated with the development of several human cancers including those found in the skin, lung, liver, kidney and urinary bladder. Humans are generally exposed to inorganic forms of arsenic, which may be inhaled or ingested. Arsenic forms mono- and di-...

  3. MEETING AT CAMBRIDGE, MA: GENE EXPRESSION IN NORMAL HUMAN KERATINOCYTES MODULATED BY TRIVALENT ARSENICALS

    EPA Science Inventory

    Arsenic exposure has been correlated with the development of several human cancers including those found in the skin, lung, liver, kidney and urinary bladder. Humans are generally exposed to inorganic forms of arsenic, which may be inhaled or ingested. Arsenic forms mono- and d...

  4. IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC INDUCED BLADDER CANCER BY GENE EXPRESSION.

    EPA Science Inventory

    Arsenic is a human carcinogen that induces urinary bladder cancer. Several mechanisms have been proposed for arsenic-induced cancer. Although inorganic arsenic (iAs) does not induce tumors in adult rodents, dimethylarsinic acid (DMA), a major metabolite of iAs, is a rat bladder c...

  5. Arsenic in drinking water and risk of urinary tract cancer: a follow-up study from northeastern Taiwan.

    PubMed

    Chen, Chi-Ling; Chiou, Hung-Yi; Hsu, Ling-I; Hsueh, Yu-Mei; Wu, Meei-Maan; Wang, Yuan-Hung; Chen, Chien-Jen

    2010-01-01

    The evidence linking arsenic in drinking water with increased urinary cancer risk comes from populations in relatively high exposure areas (>100 microg/L), whereas studies from lower exposure areas (<100 microg/L) reported inconsistent results. A previous study conducted in northeastern Taiwan, where residents were exposed to relatively lower concentrations, reported increased risk of urinary cancer in a dose-response way. Using the same cohort with longer follow-up, we conducted analysis to elucidate the relationship between ingested arsenic and urinary cancer in lower exposure groups and assessed the influence of duration, recency, and latency of drinking arsenic-containing well water. A total of 8,086 residents from northeastern Taiwan were followed for 12 years. Incident urinary cancer was ascertained through linkage with the national cancer registry. All analysis was done by Cox proportional hazards regression models. There were 45 incidences of urinary cancer and a monotonic increased risk of urinary cancer was found with increasing arsenic concentration (P < 0.001). For the highly exposed (>100 microg/L), the relative risks (RR) were >5-fold, whereas the risk was elevated but not significant for low exposure (<100 microg/L). Relative to the arsenic concentration <10 microg/L, those who drank well water with higher concentration from birth [RR, 3.69; 95% confidence interval (95% CI), 1.31-10.4], still drank at enrollment (RR, 3.50; 95% CI, 1.33-9.22), and drank for >50 years (RR, 4.12; 95% CI, 1.48-11.5) had a significantly increased risk of urinary cancer. When restricted to urothelial carcinoma, all risk estimates including concentration and characteristics of well water consumption were higher.

  6. DIMETHYLARSINIC ACID ALTERS EXPRESSION OF OXIDATIVE STRESS AND DNA REPAIR GENES IN A DOSE DEPENDENT MANNER IN THE TRANSITIONAL EPITHELIUM OF THE URINARY BLADDER FROM FEMALE F344 RATS.

    EPA Science Inventory

    Dose-dependent alteration of oxidative stress and DNA repair gene expression by Dimethylarsinic acid [DMA(V)] in transitional epithelium of urinary bladder from female F344 rats.
    Arsenic (As) is a major concern as millions of people are at risk from drinking arsenic contaminat...

  7. DIMETHYLARSINIC ACID ALTERS EXPRESSION OF OXIDATIVE STRESS AND DNA REPAIR GENES IN A DOSE DEPENDENT MANNER IN THE TRANSITIONAL EPITHELIUM OF THE URINARY BLADDER FROM FEMALE F344 RATS.

    EPA Science Inventory

    Dose-dependent alteration of oxidative stress and DNA repair gene expression by Dimethylarsinic acid [DMA(V)] in transitional epithelium of urinary bladder from female F344 rats.
    Arsenic (As) is a major concern as millions of people are at risk from drinking arsenic contaminat...

  8. COMPARISON OF IN VITRO AND IN VIVO RESPONSES TO ARSENIC: GENE EXPRESSION PROFILING IN NORMAL HUMAN EPIDERMAL KERATINOCYTES AND HYPERKERATOSES FROM ARSENIC-EXPOSED HUMANS

    EPA Science Inventory

    Chronic exposure to arsenic is positively associated with skin, urinary bladder, lung, liver and kidney cancer development in humans. Elucidating the mode of action of arsenic carcinogenesis is a complicated issue as target cells are exposed to different toxic species of arsenic....

  9. COMPARISON OF IN VITRO AND IN VIVO RESPONSES TO ARSENIC: GENE EXPRESSION PROFILING IN NORMAL HUMAN EPIDERMAL KERATINOCYTES AND HYPERKERATOSES FROM ARSENIC-EXPOSED HUMANS

    EPA Science Inventory

    Chronic exposure to arsenic is positively associated with skin, urinary bladder, lung, liver and kidney cancer development in humans. Elucidating the mode of action of arsenic carcinogenesis is a complicated issue as target cells are exposed to different toxic species of arsenic....

  10. DIFFERENTIAL MODULATION OF CANCER-RELATED MOLECULAR NETWORKS IN HUMAN AND RAT URINARY BLADDER CELLS EXPOSED TO TRIVALENT ARSENICALS

    EPA Science Inventory

    Arsenic (As) is classified as a known human carcinogen with primary targets of urinary bladder (UB), skin and lung. The most prevalent source of As exposure in humans is drinking water contaminated with inorganic As (iAs), and millions of people worldwide are exposed to drinking ...

  11. DIFFERENTIAL MODULATION OF CANCER-RELATED MOLECULAR NETWORKS IN HUMAN AND RAT URINARY BLADDER CELLS EXPOSED TO TRIVALENT ARSENICALS

    EPA Science Inventory

    Arsenic (As) is classified as a known human carcinogen with primary targets of urinary bladder (UB), skin and lung. The most prevalent source of As exposure in humans is drinking water contaminated with inorganic As (iAs), and millions of people worldwide are exposed to drinking ...

  12. A Population-based Case–Control Study of Urinary Arsenic Species and Squamous Cell Carcinoma in New Hampshire, USA

    PubMed Central

    Li, Zhigang; Perry, Ann E.; Spencer, Steven K.; Gandolfi, A. Jay; Karagas, Margaret R.

    2013-01-01

    Background: Chronic high arsenic exposure is associated with squamous cell carcinoma (SCC) of the skin, and inorganic arsenic (iAs) metabolites may play an important role in this association. However, little is known about the carcinogenicity of arsenic at levels commonly observed in the United States. Objective: We estimated associations between total urinary arsenic and arsenic species and SCC in a U.S. population. Methods: We conducted a population-based case–control SCC study (470 cases, 447 controls) in a U.S. region with moderate arsenic exposure through private well water and diet. We measured urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), and summed these arsenic species (ΣAs). Because seafood contains arsenolipids and arsenosugars that metabolize into DMA through alternate pathways, participants who reported seafood consumption within 2 days before urine collection were excluded from the analyses. Results: In adjusted logistic regression analyses (323 cases, 319 controls), the SCC odds ratio (OR) was 1.37 for each ln-transformed microgram per liter increase in ln-transformed ΣAs concentration [ln(ΣAs)] (95% CI: 1.04, 1.80). Urinary ln(MMA) and ln(DMA) also were positively associated with SCC (OR = 1.34; 95% CI: 1.04, 1.71 and OR = 1.34; 95% CI: 1.03, 1.74, respectively). A similar trend was observed for ln(iAs) (OR = 1.20; 95% CI: 0.97, 1.49). Percent iAs, MMA, and DMA were not associated with SCC. Conclusions: These results suggest that arsenic exposure at levels common in the United States relates to SCC and that arsenic metabolism ability does not modify the association. Citation: Gilbert-Diamond D, Li Z, Perry AE, Spencer SK, Gandolfi AJ, Karagas MR. 2013. A population-based case–control study of urinary arsenic species and squamous cell carcinoma in New Hampshire, USA. Environ Health Perspect 121:1154–1160; http://dx.doi.org/10.1289/ehp.1206178 PMID:23872349

  13. The factors influencing urinary arsenic excretion and metabolism of workers in steel and iron smelting foundry.

    PubMed

    Shuhua, Xi; Qingshan, Sun; Fei, Wang; Shengnan, Liu; Ling, Yan; Lin, Zhang; Yingli, Song; Nan, Yan; Guifan, Sun

    2014-01-01

    In order to evaluate the degree of arsenic (As) exposure and the factors influencing urinary As excretion and metabolism, 192 workers from a steel and iron smelting plant, with different type of work in production such as roller, steel smelting, iron smelting and metallic charge preparation, were recruited. Information about characteristics of each subject was obtained by questionnaire and inorganic As (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) in urine were determined. The results showed that steel smelters had significantly higher concentrations of DMA and total As (TAs) than rollers and metallic charge preparation workers, and iron and steel smelters had a higher value of primary methylation index and lower proportion of the iAs (iAs%) than rollers and metallic charge preparation workers. In steel smelters, urinary As level exceeded the biological exposure index (BEI) limit for urinary As of 35 μg/l by 65.52%, and higher than metallic charge preparation workers (35.14%). The individuals consumed seafood in recent 3 days had a higher TAs than the individuals without seafood consumption. Multivariate logistic regression analysis showed that different jobs, taken Chinese medicine of bezoar and seafood consumption in recent 3 days were significantly associated with urinary TAs exceeded BEI limit value 35 μg/l. Our results suggest that workers in steel and iron smelting plant had a lower level of As exposure, and seafood consumption and taking Chinese medicine of bezoar also could increase the risk of urinary TAs exceeded BEI limit value.

  14. Arsenic exposure alters hepatic arsenic species composition and stress-mediated gene expression in the common killifish (Fundulus heteroclitus).

    PubMed

    Bears, Heather; Richards, Jeff G; Schulte, Patricia M

    2006-05-10

    In the present paper, we examine how arsenic species accumulate in fish liver and explore the hypothesis that sublethal arsenic concentrations in fish hepatic tissue interfere with stress-mediated gene expression. We exposed killifish (Fundulus heteroclitus) to 787 or 0 microg/L arsenic in tank water for 2 weeks. Arsenic exposure elevated total liver arsenic from 3.4 microg/g wet weight (control fish) to 9.6 microg/g wet weight, and resulted in a higher relative proportion of toxic (e.g. monomethylarsenous acid, dimethylarsenous acid, arsenic V) versus benign (arsenobetaine) arsenic species in this tissue. Following the exposure period, arsenic-treated and control fish were then subjected to a stress protocol: confinement and mechanical chasing for 15 min every 3 h. Liver tissue and blood were sampled from fish not exposed to the stressor at time 0, and at 8, 12, 24 and 40 h following the first stressor. Concentrations of the stress hormone cortisol increased significantly, and glucocorticoid receptor mRNA levels increased and then decreased in both groups, but patterns were nearly identical between arsenic pre-treated and arsenic untreated fish. Prior arsenic exposure prevented the stress-induced increases in stress-responsive LDH-B mRNA levels and enzyme activity observed in fish that had not been exposed to arsenic. However, in another stress-responsive gene, PEPCK, arsenic did not interfere with the stress-induced increase in gene expression, suggesting that the effects of arsenic on stress-mediated gene expression are complex and may involve regulatory pathways that differ between these two genes.

  15. Arsenic

    MedlinePlus

    ... and minerals. Arsenic compounds are used to preserve wood, as pesticides, and in some industries. Arsenic can ... Breathing sawdust or burning smoke from arsenic-treated wood Living in an area with high levels of ...

  16. Arsenic

    MedlinePlus

    ... lesions and skin cancer are the most characteristic effects. Drinking-water and food The greatest threat to public health from arsenic originates from contaminated groundwater. Inorganic arsenic ...

  17. Distribution of blood lead, blood cadmium, urinary cadmium, and urinary arsenic levels in employees of a copper smelter

    SciTech Connect

    Lilis, R.; Valciukas, J.A.; Weber, J.P.; Fischbein, A.; Nicholson, W.J.; Campbell, C.; Malkin, J.; Selikoff, I.J.

    1984-02-01

    A cross-sectional medical examination of a copper smelter work force included determination of blood lead (Pb-B), zinc protoporphyrin (ZPP), blood cadmium (Cd-B), urinary cadmium (Cd-U), and urinary arsenic (As-U), since it was known that such metal impurities were present in the copper concentrate. A total of 776 copper smelter employees (680 active and 96 retirees and ex-employees) were examined. Another 144 men, never employed in the smelter, but who had worked in copper mines (and sometimes in gold mines) were also examined. Mean Pb-B, ZPP, Cd-B, and As-U were significantly higher in active copper smelter employees than in retirees or miners, indicating exposure and absorption in the copper smelter. Significant correlations between Pb-B and Cd-B, and Cd-U and As-U were present, confirming the common source of absorption. Although there was evidence for an increased lead absorption, this was very moderate, with practically no Pb-B levels in excess of 60 ..mu..g/dl. A marked effect of smoking on blood cadmium levels was present; nevertheless, for all smoking categories Cd-B levels were significantly higher in active employees, indicating the independent contribution of exposure to cadmium in the smelter. Cd-U did not exceed 10 ..mu..g/g creatinine, the generally accepted critical level for the kidney, but was higher than 2 ..mu..g/g cretinine, a level very rarely exceeded in the general population, in a sizable proportion of those examined. The highest Cd-U levels were found in retired copper smelter employees; age might have been a contributing factor, besides a longer duration of exposure in the smelter.

  18. Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen

    SciTech Connect

    Waalkes, Michael P. . E-mail: waalkes@niehs.nih.gov; Liu Jie; Ward, Jerrold M.; Diwan, Bhalchandra A.

    2006-09-15

    Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 {mu}g/pup/day) or tamoxifen (TAM; 10 {mu}g/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-{alpha}, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.

  19. Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

    PubMed Central

    Argos, Maria; Chen, Lin; Jasmine, Farzana; Tong, Lin; Pierce, Brandon L.; Roy, Shantanu; Paul-Brutus, Rachelle; Gamble, Mary V.; Harper, Kristin N.; Parvez, Faruque; Rahman, Mahfuzar; Rakibuz-Zaman, Muhammad; Slavkovich, Vesna; Baron, John A.; Graziano, Joseph H.; Kibriya, Muhammad G.

    2014-01-01

    Background: Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity. Objective: Among a sample of 400 adult participants, we evaluated the association between arsenic exposure, as measured by blood and urinary total arsenic concentrations, and epigenome-wide white blood cell DNA methylation. Methods: We used linear regression models to examine the associations between arsenic exposure and methylation at each CpG site, adjusted for sex, age, and batch. Differentially methylated loci were subsequently examined in relation to corresponding gene expression for functional evidence of gene regulation. Results: In adjusted analyses, we observed four differentially methylated CpG sites with urinary total arsenic concentration and three differentially methylated CpG sites with blood arsenic concentration, based on the Bonferroni-corrected significance threshold of p < 1 × 10–7. Methylation of PLA2G2C (probe cg04605617) was the most significantly associated locus in relation to both urinary (p = 3.40 × 10–11) and blood arsenic concentrations (p = 1.48 × 10–11). Three additional novel methylation loci—SQSTM1 (cg01225779), SLC4A4 (cg06121226), and IGH (cg13651690)—were also significantly associated with arsenic exposure. Further, there was evidence of methylation-related gene regulation based on gene expression for a subset of differentially methylated loci. Conclusions: We observed significant associations between arsenic exposure and gene-specific differential white blood cell DNA methylation, suggesting that epigenetic modifications may be an important pathway underlying arsenic toxicity. The specific differentially methylated loci identified may inform potential pathways for future interventions. Citation: Argos M, Chen L, Jasmine F, Tong L, Pierce BL, Roy S, Paul-Brutus R, Gamble MV

  20. Evaluation of gene expression changes in human primary lung epithelial cells following 24-hr exposures to inorganic arsenic and its methylated metabolites and to arsenic trioxide.

    PubMed

    Efremenko, Alina Y; Seagrave, JeanClare; Clewell, Harvey J; Van Landingham, Cynthia; Gentry, P Robinan; Yager, Janice W

    2015-06-01

    The concentration response for altered gene expression in primary lung epithelial cells was determined following two treatments with arsenicals: (1) a mixture of trivalent arsenic compounds representative of urinary arsenic concentrations in exposed human populations, and (2) arsenite (As2 O3 ) a common form of inhaled arsenic dust that is frequently used in both in vivo and in vitro experimental exposures. Biochemical assays did not detect any evidence of cytotoxicity at the concentrations used, apart from a concentration-related increase in cellular heme oxygenase that was also indicated by the genomic analysis. Cell signal pathway enrichment analysis indicated similar responses to both treatments, with concentration-related responses in pathways related to cell adhesion, cytoskeleton remodeling, development (morphogenesis), cell cycle control, and to a lesser extent inflammatory responses. These cellular responses to arsenic were consistent with those observed in a previous study with primary uroepithelial cells. Benchmark dose analysis also demonstrated similar potency of the two treatments as well as comparable sensitivity of the two cell types. A number of genes showing similar concentration-dependent expression across individuals in both bladder and lung cells were identified, including heme oxygenase 1, thioredoxin reductase, DNA damage binding protein 2, and thrombomodulin. The data on human primary lung cells from this study, together with the data from human primary uroepithelial cells, support a conclusion that biological responses to arsenic by human cells under study conditions are unlikely to occur at concentrations below 0.1 µM. Environ. Mol. Mutagen. 56:477-490, 2015. © 2015 Wiley Periodicals, Inc.

  1. Arsenic metabolism efficiency has a causal role in arsenic toxicity: Mendelian randomization and gene-environment interaction

    PubMed Central

    Pierce, Brandon L; Tong, Lin; Argos, Maria; Gao, Jianjun; Jasmine, Farzana; Roy, Shantanu; Paul-Brutus, Rachelle; Rahaman, Ronald; Rakibuz-Zaman, Muhammad; Parvez, Faruque; Ahmed, Alauddin; Quasem, Iftekhar; Hore, Samar K; Alam, Shafiul; Islam, Tariqul; Harjes, Judith; Sarwar, Golam; Slavkovich, Vesna; Gamble, Mary V; Chen, Yu; Yunus, Mohammad; Rahman, Mahfuzar; Baron, John A; Graziano, Joseph H; Ahsan, Habibul

    2013-01-01

    Background Arsenic exposure through drinking water is a serious global health issue. Observational studies suggest that individuals who metabolize arsenic efficiently are at lower risk for toxicities such as arsenical skin lesions. Using two single nucleotide polymorphisms (SNPs) in the 10q24.32 region (near AS3MT) that show independent associations with metabolism efficiency, Mendelian randomization can be used to assess whether the association between metabolism efficiency and skin lesions is likely to be causal. Methods Using data on 2060 arsenic-exposed Bangladeshi individuals, we estimated associations for two 10q24.32 SNPs with relative concentrations of three urinary arsenic species (representing metabolism efficiency): inorganic arsenic (iAs), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). SNP-based predictions of iAs%, MMA% and DMA% were tested for association with skin lesion status among 2483 cases and 2857 controls. Results Causal odds ratios for skin lesions were 0.90 (95% confidence interval [CI]: 0.87, 0.95), 1.19 (CI: 1.10, 1.28) and 1.23 (CI: 1.12, 1.36) for a one standard deviation increase in DMA%, MMA% and iAs%, respectively. We demonstrated genotype-arsenic interaction, with metabolism-related variants showing stronger associations with skin lesion risk among individuals with high arsenic exposure (synergy index: 1.37; CI: 1.11, 1.62). Conclusions We provide strong evidence for a causal relationship between arsenic metabolism efficiency and skin lesion risk. Mendelian randomization can be used to assess the causal role of arsenic exposure and metabolism in a wide array of health conditions. Developing interventions that increase arsenic metabolism efficiency are likely to reduce the impact of arsenic exposure on health. PMID:24536095

  2. Arsenic metabolism efficiency has a causal role in arsenic toxicity: Mendelian randomization and gene-environment interaction.

    PubMed

    Pierce, Brandon L; Tong, Lin; Argos, Maria; Gao, Jianjun; Farzana, Jasmine; Roy, Shantanu; Paul-Brutus, Rachelle; Rahaman, Ronald; Rakibuz-Zaman, Muhammad; Parvez, Faruque; Ahmed, Alauddin; Quasem, Iftekhar; Hore, Samar K; Alam, Shafiul; Islam, Tariqul; Harjes, Judith; Sarwar, Golam; Slavkovich, Vesna; Gamble, Mary V; Chen, Yu; Yunus, Mohammad; Rahman, Mahfuzar; Baron, John A; Graziano, Joseph H; Ahsan, Habibul

    2013-12-01

    Arsenic exposure through drinking water is a serious global health issue. Observational studies suggest that individuals who metabolize arsenic efficiently are at lower risk for toxicities such as arsenical skin lesions. Using two single nucleotide polymorphisms(SNPs) in the 10q24.32 region (near AS3MT) that show independent associations with metabolism efficiency, Mendelian randomization can be used to assess whether the association between metabolism efficiency and skin lesions is likely to be causal. Using data on 2060 arsenic-exposed Bangladeshi individuals, we estimated associations for two 10q24.32 SNPs with relative concentrations of three urinary arsenic species (representing metabolism efficiency): inorganic arsenic (iAs), monomethylarsonic acid(MMA) and dimethylarsinic acid (DMA). SNP-based predictions of iAs%, MMA% and DMA% were tested for association with skin lesion status among 2483 cases and 2857 controls. Causal odds ratios for skin lesions were 0.90 (95% confidence interval[CI]: 0.87, 0.95), 1.19 (CI: 1.10, 1.28) and 1.23 (CI: 1.12, 1.36)for a one standard deviation increase in DMA%, MMA% and iAs%,respectively. We demonstrated genotype-arsenic interaction, with metabolism-related variants showing stronger associations with skin lesion risk among individuals with high arsenic exposure (synergy index: 1.37; CI: 1.11, 1.62). We provide strong evidence for a causal relationship between arsenic metabolism efficiency and skin lesion risk. Mendelian randomization can be used to assess the causal role of arsenic exposure and metabolism in a wide array of health conditions.exposure and metabolism in a wide array of health conditions.Developing interventions that increase arsenic metabolism efficiency are likely to reduce the impact of arsenic exposure on health.

  3. A novel arsenic methyltransferase gene of Westerdykella aurantiaca isolated from arsenic contaminated soil: phylogenetic, physiological, and biochemical studies and its role in arsenic bioremediation.

    PubMed

    Verma, Shikha; Verma, Pankaj Kumar; Meher, Alok Kumar; Dwivedi, Sanjay; Bansiwal, Amit Kumar; Pande, Veena; Srivastava, Pankaj Kumar; Verma, Praveen Chandra; Tripathi, Rudra Deo; Chakrabarty, Debasis

    2016-03-01

    Elevated arsenic concentration in the environment and agricultural soil is a serious concern to crop production and human health. Among different detoxification mechanisms, the methylation of arsenic is a widespread phenomenon in nature. A number of microorganisms are able to methylate arsenic, but less is known about the arsenic metabolism in fungi. We identified a novel arsenic methyltransferase (WaarsM) gene from a soil fungus, Westerdykella aurantiaca. WaarsM showed sequence homology with all known arsenic methyltransferases having three conserved SAM binding motifs. The expression of WaarsM enhanced arsenic resistance in E. coli (Δars) and S. cerevisiae (Δacr2) strains by biomethylation and required endogenous reductants, preferably GSH, for methyltransferase activity. The purified WaarsM catalyzes the production of methylated arsenicals from both AsIII and AsV, and also displays AsV reductase activity. It displayed higher methyltransferase activity and lower KM 0.1945 ± 0.021 mM and KM 0.4034 ± 0.078 mM for AsIII and AsV, respectively. S. cerevisiae (Δacr2) cells expressing WaarsM produced 2.2 ppm volatile arsenic and 0.64 ppm DMA(v) with 0.58 ppm volatile arsenicals when exposed to 20 ppm AsV and 2 ppm AsIII, respectively. Arsenic tolerance in rice after co-culture with genetically engineered yeast suggested its potential role in arsenic bioremediation. Thus, characterization of WaarsM provides a potential strategy to reduce arsenic concentration in soil with reduced arsenic accumulation in crops grown in arsenic contaminated areas, and thereby alleviating human health risks.

  4. Effect of plasma homocysteine level and urinary monomethylarsonic acid on the risk of arsenic-associated carotid atherosclerosis

    SciTech Connect

    Wu, M.-M.; Chiou, H.-Y. . E-mail: hychiou@tmu.edu.tw; Hsueh, Y.-M.; Hong, C.-T.; Su, C.-L.; Chang, S.-F.; Huang, W.-L.; Wang, H.-T.; Wang, Y.-H.; Hsieh, Y.-C.; Chen, C.-J.

    2006-10-01

    Arsenic-contaminated well water has been shown to increase the risk of atherosclerosis. Because of involving S-adenosylmethionine, homocysteine may modify the risk by interfering with the biomethylation of ingested arsenic. In this study, we assessed the effect of plasma homocysteine level and urinary monomethylarsonic acid (MMA{sup V}) on the risk of atherosclerosis associated with arsenic. In total, 163 patients with carotid atherosclerosis and 163 controls were studied. Lifetime cumulative arsenic exposure from well water for study subjects was measured as index of arsenic exposure. Homocysteine level was determined by high-performance liquid chromatography (HPLC). Proportion of MMA{sup V} (MMA%) was calculated by dividing with total arsenic species in urine, including arsenite, arsenate, MMA{sup V}, and dimethylarsinic acid (DMA{sup V}). Results of multiple linear regression analysis show a positive correlation of plasma homocysteine levels to the cumulative arsenic exposure after controlling for atherosclerosis status and nutritional factors (P < 0.05). This correlation, however, did not change substantially the effect of arsenic exposure on the risk of atherosclerosis as analyzed in a subsequent logistic regression model. Logistic regression analyses also show that elevated plasma homocysteine levels did not confer an independent risk for developing atherosclerosis in the study population. However, the risk of having atherosclerosis was increased to 5.4-fold (95% CI, 2.0-15.0) for the study subjects with high MMA% ({>=}16.5%) and high homocysteine levels ({>=}12.7 {mu}mol/l) as compared to those with low MMA% (<9.9%) and low homocysteine levels (<12.7 {mu}mol/l). Elevated homocysteinemia may exacerbate the formation of atherosclerosis related to arsenic exposure in individuals with high levels of MMA% in urine.

  5. Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report

    EPA Science Inventory

    Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions which convert inorganic arsenic to methylated metabolites. This study determined whether the As3mt null genotype in the mouse modifies cytotoxic and proliferative effects seen in urinary bladders of wild t...

  6. Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report

    EPA Science Inventory

    Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions which convert inorganic arsenic to methylated metabolites. This study determined whether the As3mt null genotype in the mouse modifies cytotoxic and proliferative effects seen in urinary bladders of wild t...

  7. Environmental factors affecting the urinary excretion of inorganic arsenic in the general population.

    PubMed

    Lovreglio, P; D'Errico, Maria Nicola; De Pasquale, P; Gilberti, Maria Enrica; Drago, I; Panuzzo, Laura; Lepera, Antonella; Serra, Rosaria; Ferrara, F; Basso, Antonella; Apostoli, P; Soleo, L

    2012-01-01

    To assess the critical issues concerning the use of urinary inorganic arsenic (iAs), including As3, As5, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as biomarker of internal dose in order to monitor environmental and occupational exposure to inorganic As, considering the influence of diet and drinking water on excretion of iAs. The design protocol stipulated collection of weekly urine samples from 6 male subjects for 5 consecutive months. In all the urine samples, iAs was determined by Hydride Generation-Atomic Absorption Spectrophotometry (HG-AAS). In the subjects with iAs higher than 35 microg/L, Biological Exposure Index (BEI) proposed by the American Conference of Governmental Industrial Hygienists (ACGIH), urinary arsenic speciation was performed by HPLC-ICP-MS. Exposure to airborne As was evaluated monthly using personal environmental samplers worn for 8 hours. Throughout the study, the participants filled out a daily food diary, also detailing types of water drunk. Exposure to airborne As was invariably below the limit of detection, equal to 1 ng/m3. A total of 77 urine samples were collected. iAs was always detectable and was higher in 7 urine samples, obtained from 5 of the 6 subjects examined, than the BEI. Among foods with a high As content, the intake of seafood and fish within 72 hours before providing the sample seems to be the principal source of the iAs concentrations, while the intake of rice or drinking water showed no influence on this biological marker. Instead, drinking wine within 24 hours before urine sample collection can cause a significant increase in the excretion of iAs. In populations that eat large amounts of fish and seafood, the use of iAs to monitor occupational and environmental exposure to inorganic As seems to present some problems, and urinary As speciation may be essential at least in cases with As measurements above the biological limit values. In any case, a diet sheet reporting all foods eaten within 3 days

  8. GENE EXPRESSION CHANGES IN MOUSE BLADDER TISSUE IN RESPONSE TO INORGANIC ARSENIC

    EPA Science Inventory

    Chronic human exposures to high arsenic concentrations are associated with lung, skin, and bladder cancer. Considerable controversy exists concerning arsenic mode of action and low dose extrapolation. This investigation was designed to identify dose-response changes in gene expre...

  9. GENE EXPRESSION CHANGES IN MOUSE BLADDER TISSUE IN RESPONSE TO INORGANIC ARSENIC

    EPA Science Inventory

    Chronic human exposures to high arsenic concentrations are associated with lung, skin, and bladder cancer. Considerable controversy exists concerning arsenic mode of action and low dose extrapolation. This investigation was designed to identify dose-response changes in gene expre...

  10. Bacterial community and arsenic functional genes diversity in arsenic contaminated soils from different geographic locations.

    PubMed

    Gu, Yunfu; D Van Nostrand, Joy; Wu, Liyou; He, Zhili; Qin, Yujia; Zhao, Fang-Jie; Zhou, Jizhong

    2017-01-01

    To understand how soil microbial communities and arsenic (As) functional genes respond to soil arsenic (As) contamination, five soils contaminated with As at different levels were collected from diverse geographic locations, incubated for 54 days under flooded conditions, and examined by both MiSeq sequencing of 16S rRNA gene amplicons and functional gene microarray (GeoChip 4.0). The results showed that both bacterial community structure and As functional gene structure differed among geographical locations. The diversity of As functional genes correlated positively with the diversity of 16S rRNA genes (P< 0.05). Higher diversities of As functional genes and 16S rRNA genes were observed in the soils with higher available As. Soil pH, phosphate-extractable As, and amorphous Fe content were the most important factors in shaping the bacterial community structure and As transformation functional genes. Geographic location was also important in controlling both the bacterial community and As transformation functional potential. These findings provide insights into the variation of As transformation functional genes in soils contaminated with different levels of As at different geographic locations, and the impact of environmental As contamination on the soil bacterial community.

  11. Bacterial community and arsenic functional genes diversity in arsenic contaminated soils from different geographic locations

    PubMed Central

    Gu, Yunfu; D. Van Nostrand, Joy; Wu, Liyou; He, Zhili; Qin, Yujia; Zhao, Fang-Jie; Zhou, Jizhong

    2017-01-01

    To understand how soil microbial communities and arsenic (As) functional genes respond to soil arsenic (As) contamination, five soils contaminated with As at different levels were collected from diverse geographic locations, incubated for 54 days under flooded conditions, and examined by both MiSeq sequencing of 16S rRNA gene amplicons and functional gene microarray (GeoChip 4.0). The results showed that both bacterial community structure and As functional gene structure differed among geographical locations. The diversity of As functional genes correlated positively with the diversity of 16S rRNA genes (P< 0.05). Higher diversities of As functional genes and 16S rRNA genes were observed in the soils with higher available As. Soil pH, phosphate-extractable As, and amorphous Fe content were the most important factors in shaping the bacterial community structure and As transformation functional genes. Geographic location was also important in controlling both the bacterial community and As transformation functional potential. These findings provide insights into the variation of As transformation functional genes in soils contaminated with different levels of As at different geographic locations, and the impact of environmental As contamination on the soil bacterial community. PMID:28475654

  12. Urinary Metabolomics Revealed Arsenic Internal Dose-Related Metabolic Alterations: A Proof-of-Concept Study in a Chinese Male Cohort

    PubMed Central

    2015-01-01

    Urinary biomonitoring provides the most accurate arsenic exposure assessment; however, to improve the risk assessment, arsenic-related metabolic biomarkers are required to understand the internal processes that may be perturbed, which may, in turn, link the exposure to a specific health outcome. This study aimed to investigate arsenic-related urinary metabolome changes and identify dose-dependent metabolic biomarkers as a proof-of-concept of the information that could be obtained by combining metabolomics and targeted analyses. Urinary arsenic species such as inorganic arsenic, methylarsonic acid, dimethylarsinic acid and arsenobetaine were quantified using high performance liquid chromatography (HPLC)-inductively coupled plasma-mass spectrometry in a Chinese adult male cohort. Urinary metabolomics was conducted using HPLC-quadrupole time-of-flight mass spectrometry. Arsenic-related metabolic biomarkers were investigated by comparing the samples of the first and fifth quintiles of arsenic exposure classifications using a partial least-squares discriminant model. After the adjustments for age, body mass index, smoking, and alcohol consumption, five potential biomarkers related to arsenic exposure (i.e., testosterone, guanine, hippurate, acetyl-N-formyl-5-methoxykynurenamine, and serine) were identified from 61 candidate metabolites; these biomarkers suggested that endocrine disruption and oxidative stress were associated with urinary arsenic levels. Testosterone, guanine, and hippurate showed a high or moderate ability to discriminate the first and fifth quintiles of arsenic exposure with area-under-curve (AUC) values of 0.89, 0.87, and 0.83, respectively; their combination pattern showed an AUC value of 0.91 with a sensitivity of 88% and a specificity of 80%. Arsenic dose-dependent AUC value changes were also observed. This study demonstrated that metabolomics can be used to investigate arsenic-related biomarkers of metabolic changes; the dose-dependent trends of

  13. Levels of infants' urinary arsenic metabolites related to formula feeding and weaning with rice products exceeding the EU inorganic arsenic standard.

    PubMed

    Signes-Pastor, Antonio J; Woodside, Jayne V; McMullan, Paul; Mullan, Karen; Carey, Manus; Karagas, Margaret R; Meharg, Andrew A

    2017-01-01

    Early childhood inorganic arsenic (i-As) exposure is of particular concern since it may adversely impact on lifetime health outcomes. Infants' urinary arsenic (As) metabolites were analysed in 79 infants by inductively coupled plasma-mass spectrometric detection (IC-ICP-MS) to evaluate i-As exposure pre- and post-weaning. Levels of i-As in rice-based weaning and infants' foods were also determined to relate to urinary As levels. Higher As levels, especially of monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were found in urine from formula fed infants compared to those breastfed. Urine from infants post-weaning consuming rice-products resulted in higher urinary MMA and DMA compared to the paired pre-weaning urine samples. The European Union (EU) has regulated i-As in rice since 1st January 2016. Comparing infants' rice-based foods before and after this date, little change was found. Nearly ¾ of the rice-based products specifically marketed for infants and young children contained i-As over the 0.1 mg/kg EU limit. Efforts should be made to provide low i-As rice and rice-based products consumed by infants and young children that do not exceed the maximum i-As level to protect this vulnerable subpopulation.

  14. COMPARISON OF GENE EXPRESSION IN KIDNEY AND URINARY BLADDER FROM RATS TREATED WITH DIMETHYLARSINIC ACID

    EPA Science Inventory

    Arsenic is widespread in the environment and a human carcinogen. A major metabolite of inorganic arsenic (iAs) in most species, including humans, is dimethylarsinic acid (DMA), which is also used as a pesticide. Unlike iAs, DMA induces urinary bladder tumors in rats. DMA is belie...

  15. COMPARISON OF GENE EXPRESSION IN KIDNEY AND URINARY BLADDER FROM RATS TREATED WITH DIMETHYLARSINIC ACID

    EPA Science Inventory

    Arsenic is widespread in the environment and a human carcinogen. A major metabolite of inorganic arsenic (iAs) in most species, including humans, is dimethylarsinic acid (DMA), which is also used as a pesticide. Unlike iAs, DMA induces urinary bladder tumors in rats. DMA is belie...

  16. The effect of cigarette smoke and arsenic exposure on urothelial carcinoma risk is modified by glutathione S-transferase M1 gene null genotype

    SciTech Connect

    Chung, Chi-Jung; Huang, Chao-Yuan; Pu, Yeong-Shiau; Shiue, Horng-Sheng; Su, Chien-Tien; Hsueh, Yu-Mei

    2013-01-15

    Inter-individual variation in the metabolism of xenobiotics, caused by factors such as cigarette smoking or inorganic arsenic exposure, is hypothesized to be a susceptibility factor for urothelial carcinoma (UC). Therefore, our study aimed to evaluate the role of gene–environment interaction in the carcinogenesis of UC. A hospital-based case–control study was conducted. Urinary arsenic profiles were measured using high-performance liquid chromatography–hydride generator-atomic absorption spectrometry. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism technique. Information about cigarette smoking exposure was acquired from a lifestyle questionnaire. Multivariate logistic regression was applied to estimate the UC risk associated with certain risk factors. We found that UC patients had higher urinary levels of total arsenic, higher percentages of inorganic arsenic (InAs%) and monomethylarsonic acid (MMA%) and lower percentages of dimethylarsinic acid (DMA%) compared to controls. Subjects carrying the GSTM1 null genotype had significantly increased UC risk. However, no association was observed between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and GSTT1 and UC risk after adjustment for age and sex. Significant gene–environment interactions among urinary arsenic profile, cigarette smoking, and GSTM1 wild/null polymorphism and UC risk were observed after adjustment for potential risk factors. Overall, gene–environment interactions simultaneously played an important role in UC carcinogenesis. In the future, large-scale studies should be conducted using tag-SNPs of xenobiotic-metabolism-related enzymes for gene determination. -- Highlights: ► Subjects with GSTM1 null genotype had significantly increased UC risk. ► UC patients had poor arsenic metabolic ability compared to controls. ► GSTM1 null genotype may modify arsenic related UC risk.

  17. EFFECTS OF DIETARY FOLATE ON ARSENIC-INDUCED GENE EXPRESSION IN MICE

    EPA Science Inventory

    Effects of Dietary Folate on Arsenic-induced Gene Expression in Mice

    Arsenic, a drinking water contaminant, is a known carcinogen. Human exposure to inorganic arsenic has been linked to tumors of skin, bladder, lung, and to a lesser extent, kidney and liver. Dietary fola...

  18. EFFECTS OF DIETARY FOLATE ON ARSENIC-INDUCED GENE EXPRESSION IN MICE

    EPA Science Inventory

    Effects of Dietary Folate on Arsenic-induced Gene Expression in Mice

    Arsenic, a drinking water contaminant, is a known carcinogen. Human exposure to inorganic arsenic has been linked to tumors of skin, bladder, lung, and to a lesser extent, kidney and liver. Dietary fola...

  19. Urinary arsenic profiles and the risks of cancer mortality: A population-based 20-year follow-up study in arseniasis-endemic areas in Taiwan

    SciTech Connect

    Chung, Chi-Jung; Huang, Ya-Li; Huang, Yung-Kai; Wu, Meei-Maan; Chen, Shu-Yuan; Hsueh, Yu-Mei; Chen, Chien-Jen

    2013-04-15

    Few studies investigated the association between chronic arsenic exposure and the mortality of cancers by estimating individual urinary arsenic methylation profiles. Therefore, we compared with the general population in Taiwan to calculate the standardized mortality ratio (SMR) in arseniasis-endemic area of Taiwan from 1996 to 2010 and evaluated the dose-response relationships between environmental arsenic exposure indices or urinary arsenic profiles and the mortality of cause-specific cancer. A cohort of 1563 residents was conducted and collected their urine sample and information regarding arsenic exposure from a questionnaire. All-cause death was identified using the National Death Registry of Taiwan. Urinary arsenic profiles were measured using high performance liquid chromatography–hydride generator–atomic absorption spectrometry. We used Cox proportional hazard models to evaluate the mortality risks. In results, 193 all-site cancer deaths, and 29, 71, 43 deaths respectively for liver, lung and bladder cancers were ascertained. The SMRs were significantly high in arseniasis-endemic areas for liver, lung, and bladder cancers. People with high urinary InAs% or low DMA% or low secondary methylation index (SMI) were the most likely to suffer bladder cancer after adjusting other risk factors. Even stopping exposure to arsenic from the artesian well water, the mortality rates of the residents were higher than general population. Finally, urinary InAs%, DMA% and SMI could be the potential biomarkers to predict the mortality risk of bladder cancer. -- Highlights: ► The SMRs were significantly high in arseniasis-endemic areas for liver, lung, and bladder cancers. ► People with high urinary InAs% were the most likely to suffer bladder cancer. ► People with low DMA% or low SMI were the most likely to suffer bladder cancer.

  20. Distribution of Microbial Arsenic Reduction, Oxidation and Extrusion Genes along a Wide Range of Environmental Arsenic Concentrations

    PubMed Central

    Escudero, Lorena V.; Casamayor, Emilio O.; Chong, Guillermo; Pedrós-Alió, Carles; Demergasso, Cecilia

    2013-01-01

    The presence of the arsenic oxidation, reduction, and extrusion genes arsC, arrA, aioA, and acr3 was explored in a range of natural environments in northern Chile, with arsenic concentrations spanning six orders of magnitude. A combination of primers from the literature and newly designed primers were used to explore the presence of the arsC gene, coding for the reduction of As (V) to As (III) in one of the most common detoxification mechanisms. Enterobacterial related arsC genes appeared only in the environments with the lowest As concentration, while Firmicutes-like genes were present throughout the range of As concentrations. The arrA gene, involved in anaerobic respiration using As (V) as electron acceptor, was found in all the systems studied. The As (III) oxidation gene aioA and the As (III) transport gene acr3 were tracked with two primer sets each and they were also found to be spread through the As concentration gradient. Sediment samples had a higher number of arsenic related genes than water samples. Considering the results of the bacterial community composition available for these samples, the higher microbial phylogenetic diversity of microbes inhabiting the sediments may explain the increased number of genetic resources found to cope with arsenic. Overall, the environmental distribution of arsenic related genes suggests that the occurrence of different ArsC families provides different degrees of protection against arsenic as previously described in laboratory strains, and that the glutaredoxin (Grx)-linked arsenate reductases related to Enterobacteria do not confer enough arsenic resistance to live above certain levels of As concentrations. PMID:24205341

  1. Distribution of microbial arsenic reduction, oxidation and extrusion genes along a wide range of environmental arsenic concentrations.

    PubMed

    Escudero, Lorena V; Casamayor, Emilio O; Chong, Guillermo; Pedrós-Alió, Carles; Demergasso, Cecilia

    2013-01-01

    The presence of the arsenic oxidation, reduction, and extrusion genes arsC, arrA, aioA, and acr3 was explored in a range of natural environments in northern Chile, with arsenic concentrations spanning six orders of magnitude. A combination of primers from the literature and newly designed primers were used to explore the presence of the arsC gene, coding for the reduction of As (V) to As (III) in one of the most common detoxification mechanisms. Enterobacterial related arsC genes appeared only in the environments with the lowest As concentration, while Firmicutes-like genes were present throughout the range of As concentrations. The arrA gene, involved in anaerobic respiration using As (V) as electron acceptor, was found in all the systems studied. The As (III) oxidation gene aioA and the As (III) transport gene acr3 were tracked with two primer sets each and they were also found to be spread through the As concentration gradient. Sediment samples had a higher number of arsenic related genes than water samples. Considering the results of the bacterial community composition available for these samples, the higher microbial phylogenetic diversity of microbes inhabiting the sediments may explain the increased number of genetic resources found to cope with arsenic. Overall, the environmental distribution of arsenic related genes suggests that the occurrence of different ArsC families provides different degrees of protection against arsenic as previously described in laboratory strains, and that the glutaredoxin (Grx)-linked arsenate reductases related to Enterobacteria do not confer enough arsenic resistance to live above certain levels of As concentrations.

  2. Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in C57BL6 mice following subchronic exposure to arsenate in drinking water

    SciTech Connect

    Kenyon, E.M. Hughes, M.F.; Adair, B.M.; Highfill, J.H.; Crecelius, E.A.; Clewell, H.J.; Yager, J.W.

    2008-11-01

    The relationship of exposure and tissue concentration of parent chemical and metabolites over prolonged exposure is a critical issue for chronic toxicities mediated by metabolite(s) rather than parent chemical alone. This is an issue for As{sup V} because its trivalent metabolites have unique toxicities and relatively greater potency compared to their pentavalent counterparts for many endpoints. In this study, dose-dependency in tissue distribution and urinary excretion for inorganic arsenic and its methylated metabolites was assessed in female C57Bl/6 mice exposed to 0, 0.5, 2, 10 or 50 ppm arsenic (as arsenate, As{sup V}) in their drinking water for 12 weeks. No adverse effects were observed and body weight gain did not differ significantly among groups. Urinary excretion of arsenite monomethylarsonous acid (MMA{sup III}), dimethylarsinous acid (DMA{sup III}), dimethylarsinic acid (DMA{sup V}), and trimethylarsine oxide (TMAO) increased linearly with dose, whereas As{sup V} and monomethylarsonic acid (MMA{sup V}) excretion was non-linear with respect to dose. Total tissue arsenic accumulation was greatest in kidney > lung > urinary bladder >>> skin > blood > liver. Monomethyl arsenic (MMA, i.e. MMA{sup III} + MMA{sup V}) was the predominant metabolite in kidney, whereas dimethylarsenic (DMA, i.e., DMA{sup III} + DMA{sup V}) was the predominant metabolite in lung. Urinary bladder tissue had roughly equivalent levels of inorganic arsenic and dimethylarsenic, as did skin. These data indicate that pharmacokinetic models for arsenic metabolism and disposition need to include mechanisms for organ-specific accumulation of some arsenicals and that urinary metabolite profiles are not necessarily reflective of target tissue dosimetry.

  3. Oxidative DNA damage and repair in children exposed to low levels of arsenic in utero and during early childhood: Application of salivary and urinary biomarkers

    SciTech Connect

    Hinhumpatch, Pantip; Navasumrit, Panida; Chaisatra, Krittinee; Promvijit, Jeerawan; Mahidol, Chulabhorn; Ruchirawat, Mathuros

    2013-12-15

    The present study aimed to assess arsenic exposure and its effect on oxidative DNA damage and repair in young children exposed in utero and continued to live in arsenic-contaminated areas. To address the need for biological specimens that can be acquired with minimal discomfort to children, we used non-invasive urinary and salivary-based assays for assessing arsenic exposure and early biological effects that have potentially serious health implications. Levels of arsenic in nails showed the greatest magnitude of difference between exposed and control groups, followed by arsenic concentrations in saliva and urine. Arsenic levels in saliva showed significant positive correlations with other biomarkers of arsenic exposure, including arsenic accumulation in nails (r = 0.56, P < 0.001) and arsenic concentration in urine (r = 0.50, P < 0.05). Exposed children had a significant reduction in arsenic methylation capacity indicated by decreased primary methylation index and secondary methylation index in both urine and saliva samples. Levels of salivary 8-OHdG in exposed children were significantly higher (∼ 4-fold, P < 0.01), whereas levels of urinary 8-OHdG excretion and salivary hOGG1 expression were significantly lower in exposed children (∼ 3-fold, P < 0.05), suggesting a defect in hOGG1 that resulted in ineffective cleavage of 8-OHdG. Multiple regression analysis results showed that levels of inorganic arsenic (iAs) in saliva and urine had a significant positive association with salivary 8-OHdG and a significant negative association with salivary hOGG1 expression. - Highlights: • The effects of arsenic exposure in utero and through early childhood were studied. • Arsenic-exposed children had a reduction in arsenic methylation capacity. • Exposed children had more DNA damage, observed as elevated salivary 8-OHdG. • Lower salivary hOGG1 in exposed children indicated impairment of 8-OHdG repair. • Salivary and urinary 8-OHdG levels were discordant.

  4. Arsenic

    MedlinePlus

    ... As a preservative in pressure-treated lumber In pesticides As a preservative in animal hides As an ... dust. Arsenic was a common ingredient in many pesticides and herbicides in the past. People who made, ...

  5. Arsenic exposure is associated with DNA hypermethylation of the tumor suppressor gene p16.

    PubMed

    Lu, Guangming; Xu, Huiwen; Chang, De; Wu, Zhenglai; Yao, Xiaoyuan; Zhang, Shiying; Li, Zhenlong; Bai, Jieben; Cai, Qing; Zhang, Wen

    2014-01-01

    Occupational and environmental exposure to inorganic arsenic leads to development of cancer and represents a significant health hazard in more than 70 countries. The underlying mechanism for arsenic-induced carcinogenesis remains unclear. Laboratory studies suggest that arsenic is a poor mutagen but may cause epigenetic silencing of key tumor suppressor genes such as p16 through DNA hypermethylation. However, the evidence for an association between human arsenic exposure and abnormal DNA methylation of tumor suppressor genes is lacking. Paired case-control studies were conducted involving 40 individuals with high arsenic exposure and arsenicosis, 40 individuals with similarly high exposure to arsenic but without arsenicosis, and 40 individuals with normal exposure to arsenic. DNA methylation status of p16 was determined using methylation-specific PCR. Conditional logistic regression analysis showed that DNA hypermethylation of p16 gene was significantly associated with high arsenic exposure (Odds Ratio = 10.0, P = 0.0019) independently of the development of arsenicosis (Odds Ratio = 2.0, P = 0.1343). High exposure of arsenic in human is positively linked to DNA hypermethylation of p16 gene, suggesting that epigenetic silencing of key tumor suppressor may be an important mechanism by which arsenic promotes cancer initiation.

  6. Differential Methylation of the Arsenic (III) Methyltransferase Promoter According to Arsenic Exposure

    PubMed Central

    Gribble, Matthew O.; Tang, Wan-yee; Shang, Yan; Pollak, Jonathan; Umans, Jason G.; Francesconi, Kevin A.; Goessler, Walter; Silbergeld, Ellen K.; Guallar, Eliseo; Cole, Shelley A.; Fallin, M. Daniele; Navas-Acien, Ana

    2013-01-01

    Inorganic arsenic is methylated in the body by arsenic (III) methyltransferase. Arsenic methylation is thought to play a role in arsenic-related epigenetic phenomena including aberrant DNA and histone methylation. However, it is unclear whether the promoter of the AS3MT gene, which codes for arsenic (III) methyltransferase, is differentially methylated as a function of arsenic exposure. In this study we evaluated AS3MT promoter methylation according to exposure, assessed by urinary arsenic excretion in a stratified random sample of 48 participants from the Strong Heart Study who had urine arsenic measured at baseline and DNA available from 1989–1991 and 1998–1999. For this study, all data are from the 1989–1991 visit. We measured AS3MT promoter methylation at its 48 CpG loci by bisulphite sequencing. We compared mean % methylation at each CpG locus by arsenic exposure group using linear regression adjusted for study centre, age and sex. A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure. In vitro, arsenic induced AS3MT promoter hypomethylation and it increased AS3MT expression in human peripheral blood mononuclear cells. These findings may suggest that arsenic exposure influences the epigenetic regulation of a major arsenic metabolism gene. PMID:24154821

  7. Novel arsenic-transforming bacteria and the diversity of their arsenic-related genes and enzymes arising from arsenic-polluted freshwater sediment.

    PubMed

    Suhadolnik, Maria L S; Salgado, Ana P C; Scholte, Larissa L S; Bleicher, Lucas; Costa, Patrícia S; Reis, Mariana P; Dias, Marcela F; Ávila, Marcelo P; Barbosa, Francisco A R; Chartone-Souza, Edmar; Nascimento, Andréa M A

    2017-09-11

    Bacteria are essential in arsenic cycling. However, few studies have addressed 16S rRNA and arsenic-related functional gene diversity in long-term arsenic-contaminated tropical sediment. Here, using culture-based, metagenomic and computational approaches, we describe the diversity of bacteria, genes and enzymes involved in AsIII and AsV transformation in freshwater sediment and in anaerobic AsIII- and AsV-enrichment cultures (ECs). The taxonomic profile reveals significant differences among the communities. Arcobacter, Dechloromonas, Sedimentibacter and Clostridium thermopalmarium were exclusively found in ECs, whereas Anaerobacillus was restricted to AsV-EC. Novel taxa that are both AsV-reducers and AsIII-oxidizers were identified: Dechloromonas, Acidovorax facilis, A. delafieldii, Aquabacterium, Shewanella, C. thermopalmarium and Macellibacteroides fermentans. Phylogenic discrepancies were revealed among the aioA, arsC and arrA genes and those of other species, indicating horizontal gene transfer. ArsC and AioA have sets of amino acids that can be used to assess their functional and structural integrity and familial subgroups. The positions required for AsV reduction are conserved, suggesting strong selective pressure for maintaining the functionality of ArsC. Altogether, these findings highlight the role of freshwater sediment bacteria in arsenic mobility, and the untapped diversity of dissimilatory arsenate-reducing and arsenate-resistant bacteria, which might contribute to arsenic toxicity in aquatic environments.

  8. Males in rural Bangladeshi communities are more susceptible to chronic arsenic poisoning than females: analyses based on urinary arsenic.

    PubMed Central

    Watanabe, C; Inaoka, T; Kadono, T; Nagano, M; Nakamura, S; Ushijima, K; Murayama, N; Miyazaki, K; Ohtsuka, R

    2001-01-01

    Spot urine samples were collected from the inhabitants of two rural communities in northwestern Bangladesh. We compared arsenic levels in the urine samples ([As](u); n = 346) with those in water from tube wells ([As](tw); range < 1-535 microg/L; n = 86) on an individual basis. The small variation of [As](u) within subjects and highly positive correlation with [As](tw) indicate that [As](u) is a useful indicator of exposure. Analyses of [As](u) showed that creatinine correction was necessary, that [As](u) only reflected recent exposure, and that there were substantial interindividual differences for a given [As](tw) level. To evaluate the toxic effects of arsenic exposure, we constructed a system for rating skin manifestations, which revealed distinct sex-related differences. Comparison of males and females in the same households confirmed that skin manifestations were more severe in the males, and in the males of one community a dose-response relationship between [As](u) and the degree of skin manifestation was evident. The results of this study indicate that [As](u) in spot urine samples can be used as an exposure indicator for As. They suggest that there might be sex-related, and perhaps community-related, differences in the relationship between [As](u) and skin manifestations, although several confounding factors, including sunlight exposure and smoking habits, might contribute to the observed sex difference. The existence of such differences should be further confirmed and examined in other populations to identify the subpopulations sensitive to chronic arsenic toxicity. PMID:11748034

  9. Polymorphisms in Endothelin System Genes, Arsenic Levels and Obesity Risk

    PubMed Central

    Martínez-Barquero, Vanesa; de Marco, Griselda; Martínez-Hervas, Sergio; Rentero, Pilar; Galan-Chilet, Inmaculada; Blesa, Sebastian; Morchon, David; Morcillo, Sonsoles; Rojo, Gemma; Ascaso, Juan Francisco; Real, José Tomás; Martín-Escudero, Juan Carlos; Chaves, Felipe Javier

    2015-01-01

    Background/Objectives Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity. Subjects/Methods We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex. Results We found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53) Conclusions Our results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to

  10. Polymorphisms in endothelin system genes, arsenic levels and obesity risk.

    PubMed

    Martínez-Barquero, Vanesa; de Marco, Griselda; Martínez-Hervas, Sergio; Rentero, Pilar; Galan-Chilet, Inmaculada; Blesa, Sebastian; Morchon, David; Morcillo, Sonsoles; Rojo, Gemma; Ascaso, Juan Francisco; Real, José Tomás; Martín-Escudero, Juan Carlos; Chaves, Felipe Javier

    2015-01-01

    Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity. We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex. We found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53). Our results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to obesity and can interact with plasma arsenic levels.

  11. Polymorphism of inflammatory genes and arsenic methylation capacity are associated with urothelial carcinoma

    SciTech Connect

    Wu, Chia-Chang; Huang, Yung-Kai; Chung, Chi-Jung; Huang, Chao-Yuan; Pu, Yeong-Shiau; Shiue, Horng-Sheng; Lai, Li-An; Lin, Ying-Chin; Su, Chien-Tien; Hsueh, Yu-Mei

    2013-10-01

    Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). TNF-α, IL-6 and IL-8 have been shown to be involved in the development and progression of various cancers, including bladder cancer. This study aimed to investigate the joint effect of the polymorphism of TNF-α − 308 G/A, IL-6 − 174 G/C, IL-8 − 251 T/A and urinary arsenic profiles on urothelial carcinoma (UC) risk. This study evaluated 300 pathologically-confirmed cases of UC and 594 cancer-free controls. Urinary arsenic species were detected using high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphism of TNF-α − 308 G/A, IL-6 − 174 G/C and IL-8 − 251 T/A was determined using polymerase chain reaction-restriction fragment length polymorphism. The joint effects on UC risk were estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. We found that the TNF-α − 308 A/A and IL-8 − 251 T/T polymorphisms were significantly associated with UC. Moreover, significant dose–response joint effect of TNF-α − 308 A/A or IL-8 − 251 T/T genotypes and arsenic methylation indices were seen to affect UC risk. The present results also showed a significant increase in UC risk in subjects with the IL-8 − 251 T/T genotype for each SD increase in urinary total arsenic and MMA%. In contrast, a significant decrease in UC risk was found in subjects who carried the IL-8 − 251 T/T genotype for each SD increase in DMA%. - Highlights: • Joint effect of the TNF-α -308 A/A genotype and urinary total arsenic affected UC. • Joint effect of the IL-8 -251 T/T genotype and urinary total arsenic affected UC. • Urinary total arsenic level, TNF-α -308 A/A and IL-8 -251 T/T genotype affected UC.

  12. Joint effects of urinary arsenic methylation capacity with potential modifiers on arsenicosis: a cross-sectional study from an endemic arsenism area in Huhhot Basin, northern China.

    PubMed

    Zhang, Qiang; Wang, Da; Zheng, Quanmei; Zheng, Yi; Wang, Huihui; Xu, Yuanyuan; Li, Xin; Sun, Guifan

    2014-07-01

    A lower arsenic methylation capacity is believed to be associated with various arsenic-related diseases. However, the synergistic effect of the arsenic methylation capacity and potential modifiers on arsenicosis risk is unclear. The current study evaluated the joint effect of the arsenic methylation capacity with several risk factors on the risk of arsenicosis characterized by skin lesions. In total, 302 adults (79 arsenicosis and 223 non-arsenicosis) residing in an endemic arsenism area in Huhhot Basin were included. Urinary levels of inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were determined, and the percentages of arsenic species (iAs%, MMA%, and DMA%), as well as two methylation indices (primary methylation index, PMI, and secondary methylation index, SMI), were calculated to assess the arsenic methylation capacity of individuals. The results showed that a lower methylation capacity, which is indicated by higher MMA% values and lower DMA% and SMI values, was significantly associated with arsenicosis after the adjustment for multiple confounders. The relative excess risk for interactions between higher MMA% values and older age was 2.35 (95% CI: -0.56, 5.27), and the relative excess risk for interactions between higher MMA% values and lower BMI was 1.08 (95% CI: -1.20, 3.36). The data also indicated a suggestive synergistic effect of a lower arsenic methylation capacity (lower DMA% and SMI) with older age, lower BMI, and male gender. The findings of the present study suggest that a lower arsenic methylation capacity was associated with arsenicosis and that certain risk factors may enhance the risk of arsenic-induced skin lesions. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Effects of arsenic exposure on DNA methylation and epigenetic gene regulation.

    PubMed

    Reichard, John F; Puga, Alvaro

    2010-02-01

    Arsenic is a nonmutagenic human carcinogen that induces tumors through unknown mechanisms. A growing body of evidence suggests that its carcinogenicity results from epigenetic changes, particularly in DNA methylation. Changes in gene methylation status, mediated by arsenic, have been proposed to activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in the activity of genes controlling cell transformation. Mostly descriptive, and often contradictory, studies have demonstrated that arsenic exposure is associated with both hypo- and hyper-methylation at various genetic loci in vivo or in vitro. This ambiguity has made it difficult to assess whether the changes induced by arsenic are causally involved in the transformation process or are simply a reflection of the altered physiology of rapidly dividing cancer cells. Here, we discuss the evidence supporting changes in DNA methylation as a cause of arsenic carcinogenesis and highlight the strengths and limitations of these studies, as well as areas where consistencies and inconsistencies exist.

  14. Effects of arsenic exposure on DNA methylation and epigenetic gene regulation

    PubMed Central

    Reichard, John F; Puga, Alvaro

    2010-01-01

    Arsenic is a nonmutagenic human carcinogen that induces tumors through unknown mechanisms. A growing body of evidence suggests that its carcinogenicity results from epigenetic changes, particularly in DNA methylation. Changes in gene methylation status, mediated by arsenic, have been proposed activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in activity of genes controlling cell transformation. Mostly descriptive, and often contradictory, studies have demonstrated that arsenic exposure is associated with both hypo- and hyper-methylation at various genetic loci in vivo or in vitro. This ambiguity has made it difficult to assess whether the changes induced by arsenic are causally involved in the transformation process or are simply a reflection of the altered physiology of rapidly dividing cancer cells. Here, we discuss the evidence supporting changes in DNA methylation as a cause of arsenic carcinogenesis and highlight the strengths and limitations of these studies, as well areas where consistencies and inconsistencies exist. PMID:20514360

  15. Patterns of gene expressions induced by arsenic trioxide in cultured human fibroblasts.

    PubMed

    Burnichon, Vanina; Jean, Séverine; Bellon, Laurence; Maraninchi, Marie; Bideau, Chantal; Orsière, Thierry; Margotat, Alain; Gérolami, Victoria; Botta, Alain; Bergé-Lefranc, Jean Louis

    2003-07-20

    Arsenic exposure is associated with several human diseases and particularly, with neoplasia. Although the mechanism of arsenic toxicity is not fully understood, several recent works pointed out the involvement of oxidative stress in arsenic-induced DNA damage that, in living cells, correlates with changes in gene expressions. In cultured human fibroblasts exposed for 24 h to micromolar arsenic concentrations, we studied, using real-time RT-PCR, the expression profile of a limited number of genes: genes coding for a stress protein (HSP70), transcription factors (cJUN, cFOS, ETR103, ETR101 and TTP) and cell cycle or DNA repair proteins (P21, GADD153). We observed that the expression profile of genes followed individual different patterns that can be summed up in early-transient gene expression by contrast to delayed gene expression.

  16. Arsenic resistance and prevalence of arsenic resistance genes in Campylobacter jejuni and Campylobacter coli isolated from retail meats.

    PubMed

    Noormohamed, Aneesa; Fakhr, Mohamed K

    2013-08-07

    Studies that investigate arsenic resistance in the foodborne bacterium Campylobacter are limited. A total of 552 Campylobacter isolates (281 Campylobacter jejuni and 271 Campylobacter coli) isolated from retail meat samples were subjected to arsenic resistance profiling using the following arsenic compounds: arsanilic acid (4-2,048 μg/mL), roxarsone (4-2048 μg/mL), arsenate (16-8,192 μg/mL) and arsenite (4-2,048 μg/mL). A total of 223 of these isolates (114 Campylobacter jejuni and 109 Campylobacter coli) were further analyzed for the presence of five arsenic resistance genes (arsP, arsR, arsC, acr3, and arsB) by PCR. Most of the 552 Campylobacter isolates were able to survive at higher concentrations of arsanilic acid (512-2,048 μg/mL), roxarsone (512-2,048 μg/mL), and arsenate (128-1,024 μg/mL), but at lower concentrations for arsenite (4-16 μg/mL). Ninety seven percent of the isolates tested by PCR showed the presence of arsP and arsR genes. While 95% of the Campylobacter coli isolates contained a larger arsenic resistance operon that has all of the four genes (arsP, arsR, arsC and acr3), 85% of the Campylobacter jejuni isolates carried the short operon (arsP, and arsR). The presence of arsC and acr3 did not significantly increase arsenic resistance with the exception of conferring resistance to higher concentrations of arsenate to some Campylobacter isolates. arsB was prevalent in 98% of the tested Campylobacter jejuni isolates, regardless of the presence or absence of arsC and acr3, but was completely absent in Campylobacter coli. To our knowledge, this is the first study to determine arsenic resistance and the prevalence of arsenic resistance genes in such a large number of Campylobacter isolates.

  17. Sex differences in the reduction of arsenic methylation capacity as a function of urinary total and inorganic arsenic in Mexican children.

    PubMed

    Torres-Sánchez, Luisa; López-Carrillo, Lizbeth; Rosado, Jorge L; Rodriguez, Valentina M; Vera-Aguilar, Eunice; Kordas, Katarzyna; García-Vargas, Gonzalo G; Cebrian, Mariano E

    2016-11-01

    Chronic arsenic (As) exposure decreases adult and children's ability to methylate inorganic As (iAs); however, few studies have examined children's sex differences. We measured urinary concentrations of iAs, monomethylarsonic (MMA), and dimethylarsinic (DMA) acids, and calculated the primary (PMI: MMA/iAs) and secondary (SMI: DMA/MMA) methylation capacity indexes in 591 children 6-8 years in Torreón, Mexico. We determined iAs, MMA, and DMA by hydride generation cryotrapping AAS. Lineal regression models estimated associations between methylation capacity and total As (TAs) or iAs. Interactions with sex were tested at p<0.10. Boys had significantly higher TAs levels, (58.4µg/L) than girls (46.2µg/L). We observed negative associations between TAs and PMI (β=-0.039; p<0.18) and SMI (β=-0.08; p=0.002) with significant sex differences; PMI reduction was significant in boys (β=-0.09; p=0.02) but not in girls (β=0.021; p=0.63), p for interaction=0.06. In contrast, SMI reduction was significantly more pronounced in girls. Furthermore, negative associations PMI (β=-0.19; p<0.001) and SMI (β=-0.35; p<0.001) were a function of urinary iAs levels, independently of TAs; however, the reduction in PMI was more pronounced in boys (β=-0.24; p<0.001; girls β=-0.15; p<0.001), p for interaction=0.04. A significant negative association was observed between SMI and iAs levels without significant sex differences. TAs and iAs associations with metabolite percentages were in good agreement with those observed with methylation indexes. Our results suggest that iAs plays an important role in reducing As methylation ability and that significant sex differences are present in As metabolism. These differences merit further investigation to confirm our findings and their potential implications for arsenic toxicity in children.

  18. Microbial communities and functional genes associated with soil arsenic contamination and the rhizosphere of the arsenic-hyperaccumulating plant Pteris vittata L.

    PubMed

    Xiong, Jinbo; Wu, Liyou; Tu, Shuxin; Van Nostrand, Joy D; He, Zhili; Zhou, Jizhong; Wang, Gejiao

    2010-11-01

    To understand how microbial communities and functional genes respond to arsenic contamination in the rhizosphere of Pteris vittata, five soil samples with different arsenic contamination levels were collected from the rhizosphere of P. vittata and nonrhizosphere areas and investigated by Biolog, geochemical, and functional gene microarray (GeoChip 3.0) analyses. Biolog analysis revealed that the uncontaminated soil harbored the greatest diversity of sole-carbon utilization abilities and that arsenic contamination decreased the metabolic diversity, while rhizosphere soils had higher metabolic diversities than did the nonrhizosphere soils. GeoChip 3.0 analysis showed low proportions of overlapping genes across the five soil samples (16.52% to 45.75%). The uncontaminated soil had a higher heterogeneity and more unique genes (48.09%) than did the arsenic-contaminated soils. Arsenic resistance, sulfur reduction, phosphorus utilization, and denitrification genes were remarkably distinct between P. vittata rhizosphere and nonrhizosphere soils, which provides evidence for a strong linkage among the level of arsenic contamination, the rhizosphere, and the functional gene distribution. Canonical correspondence analysis (CCA) revealed that arsenic is the main driver in reducing the soil functional gene diversity; however, organic matter and phosphorus also have significant effects on the soil microbial community structure. The results implied that rhizobacteria play an important role during soil arsenic uptake and hyperaccumulation processes of P. vittata.

  19. Urinary arsenic and porphyrin profile in C57BL/6J mice chronically exposed to monomethylarsonous acid (MMA{sup III}) for two years

    SciTech Connect

    Krishnamohan, Manonmanii; Qi, Lixia; Lam, Paul K.S.; Moore, Michael R.; Ng, Jack C.

    2007-10-01

    Arsenicals are proven carcinogens in humans and it imposes significant health impacts on both humans and animals. Recently monomethylarsonous acid (MMA{sup III}), the toxic metabolite of arsenic has been identified in human urine and believed to be more acutely toxic than arsenite and arsenate. Arsenic also affects the activity of a number of haem biosynthesis enzymes. As a part of 2-year arsenic carcinogenicity study, young female C57BL/6J mice were given drinking water containing 0, 100, 250 and 500 {mu}g/L arsenic as MMA{sup III}ad libitum. 24 h urine samples were collected at 0, 1, 2, 4, 8 weeks and every 8 weeks for up to 104 weeks. Urinary arsenic speciation and porphyrins were measured using HPLC-ICP-MS and HPLC with fluorescence detection respectively. DMA{sup V} was a major urinary metabolite detected. Significant dose-response relationship was observed between control and treatment groups after 1, 4, 24, 32, 48, 56, 88, 96 and 104 weeks. The level of uroporphyrin in 250 and 500 {mu}g As/L group is significantly different from the control group after 4, 8, 16, 32, 56, 72, 80, 96 and 104 weeks. Coproporphyrin I level in 500 {mu}As/L group is significantly different from control group after 8, 24, 32, 40, 56, 72, 80, 88 and 104 weeks. After 4 weeks the level of coproporphyrin III concentration significantly increased in all the treatment groups compared to the control except week 16 and 48. Our results show urinary DMA{sup V} and porphyrin profile can be used as an early warning biomarker for chronic MMA{sup III} exposure before the onset of cancer.

  20. Arsenic-induced alteration in the expression of genes related to type 2 diabetes mellitus.

    PubMed

    Díaz-Villaseñor, Andrea; Burns, Anna L; Hiriart, Marcia; Cebrián, Mariano E; Ostrosky-Wegman, Patricia

    2007-12-01

    Chronic exposure to high concentrations of arsenic in drinking water is associated with an increased risk for developing type 2 diabetes. The present revision focuses on the effect of arsenic on tissues that participate directly in glucose homeostasis, integrating the most important published information about the impairment of the expression of genes related to type 2 diabetes by arsenic as one of the possible mechanisms by which it leads to the disease. Many factors are involved in the manner in which arsenic contributes to the occurrence of diabetes. The reviewed studies suggest that arsenic might increase the risk for type 2 diabetes via multiple mechanisms, affecting a cluster of regulated events, which in conjunction trigger the disease. Arsenic affects insulin sensitivity in peripheral tissue by modifying the expression of genes involved in insulin resistance and shifting away cells from differentiation to the proliferation pathway. In the liver arsenic disturbs glucose production, whereas in pancreatic beta-cells arsenic decreases insulin synthesis and secretion and reduces the expression of antioxidant enzymes. The consequences of these changes in gene expression include the reduction of insulin secretion, induction of oxidative stress in the pancreas, alteration of gluconeogenesis, abnormal proliferation and differentiation pattern of muscle and adipocytes as well as peripheral insulin resistance.

  1. Arsenic-induced alteration in the expression of genes related to type 2 diabetes mellitus

    SciTech Connect

    Diaz-Villasenor, Andrea Burns, Anna L.; Hiriart, Marcia; Cebrian, Mariano E.; Ostrosky-Wegman, Patricia

    2007-12-01

    Chronic exposure to high concentrations of arsenic in drinking water is associated with an increased risk for developing type 2 diabetes. The present revision focuses on the effect of arsenic on tissues that participate directly in glucose homeostasis, integrating the most important published information about the impairment of the expression of genes related to type 2 diabetes by arsenic as one of the possible mechanisms by which it leads to the disease. Many factors are involved in the manner in which arsenic contributes to the occurrence of diabetes. The reviewed studies suggest that arsenic might increase the risk for type 2 diabetes via multiple mechanisms, affecting a cluster of regulated events, which in conjunction trigger the disease. Arsenic affects insulin sensitivity in peripheral tissue by modifying the expression of genes involved in insulin resistance and shifting away cells from differentiation to the proliferation pathway. In the liver arsenic disturbs glucose production, whereas in pancreatic beta-cells arsenic decreases insulin synthesis and secretion and reduces the expression of antioxidant enzymes. The consequences of these changes in gene expression include the reduction of insulin secretion, induction of oxidative stress in the pancreas, alteration of gluconeogenesis, abnormal proliferation and differentiation pattern of muscle and adipocytes as well as peripheral insulin resistance.

  2. Arsenic Methylation in Arabidopsis thaliana Expressing an Algal Arsenite Methyltransferase Gene Increases Arsenic Phytotoxicity

    PubMed Central

    Tang, Zhong; Lv, Yanling; Chen, Fei; Zhang, Wenwen; Rosen, Barry P.; Zhao, Fang-Jie

    2016-01-01

    Arsenic (As) contamination in soil can lead to elevated transfer of As to the food chain. One potential mitigation strategy is to genetically engineer plants to enable them to transform inorganic As to methylated and volatile As species. In this study, we genetically engineered two ecotypes of Arabidopsis thaliana with the arsenite (As(III)) S-adenosylmethyltransferase (arsM) gene from the eukaryotic alga Chlamydomonas reinhardtii. The transgenic A. thaliana plants gained a strong ability to methylate As, converting most of the inorganic As into dimethylarsenate [DMA(V)] in the shoots. Small amounts of volatile As were detected from the transgenic plants. However, the transgenic plants became more sensitive to As(III) in the medium, suggesting that DMA(V) is more phytotoxic than inorganic As. The study demonstrates a negative consequence of engineered As methylation in plants and points to a need for arsM genes with a strong ability to methylate As to volatile species. PMID:26998776

  3. Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+ 3 oxidation state) methyltransferase knockout mice. A preliminary report

    SciTech Connect

    Yokohira, Masanao; Arnold, Lora L.; Pennington, Karen L.; Suzuki, Shugo; Kakiuchi-Kiyota, Satoko; Herbin-Davis, Karen; Thomas, David J.; Cohen, Samuel M.

    2010-07-15

    Arsenic (+ 3 oxidation state) methyltransferase (As3mt) catalyzes reactions which convert inorganic arsenic to methylated metabolites. This study determined whether the As3mt null genotype in the mouse modifies cytotoxic and proliferative effects seen in urinary bladders of wild type mice after exposure to inorganic arsenic. Female wild type C57BL/6 mice and As3mt KO mice were divided into 3 groups each (n = 8) with free access to a diet containing 0, 100 or 150 ppm of arsenic as arsenite (As{sup III}). During the first week of As{sup III} exposure, As3mt KO mice exhibited severe and lethal systemic toxicity. At termination, urinary bladders of both As3mt KO and wild type mice showed hyperplasia by light microscopy. As expected, arsenic-containing granules were found in the superficial urothelial layer of wild type mice. In As3mt KO mice these granules were present in all layers of the bladder epithelium and were more abundant and larger than in wild type mice. Scanning electron microscopy of the bladder urothelium of As3mt KO mice treated with 100 ppm As{sup III} showed extensive superficial necrosis and hyperplastic changes. In As3mt KO mice, livers showed severe acute inflammatory changes and spleen size and lymphoid areas were decreased compared with wild type mice. Thus, diminished arsenic methylation in As3mt KO mice exacerbates systemic toxicity and the effects of As{sup III} on the bladder epithelium, showing that altered kinetic and dynamic behavior of arsenic can affect its toxicity.

  4. Influence of GSTT1 Genetic Polymorphisms on Arsenic Metabolism

    PubMed Central

    Kile, Molly L.; Houseman, E. Andres; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Mostofa, Golam; Hsueh, Yu-Mei; Christiani, David C.

    2014-01-01

    SUMMARY A repeated measures study was conducted in Pabna, Bangladesh to investigate factors that influence biomarkers of arsenic exposure. Drinking water arsenic concentrations were measured by inductively-coupled plasma mass spectrometry (ICP-MS) and urinary arsenic species [arsenite (As3), arsenate (As5), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] were detected using High Performance Liquid Chromatography (HPLC) and Hydride Generated Atomic Absorption Spectrometry (HGAAS). Linear mixed effects models with random intercepts were used to evaluate the effects of arsenic contaminated drinking water, genetic polymorphisms in glutathione-S-transferase (GSTT1 and GSTM1) on total urinary arsenic, primary methylation index [MMA/(As3+As5)], secondary methylation index (DMA/MMA), and total methylation index [(MMA+DMA)/(As3+As5)]. Drinking water arsenic concentrations were positively associated with total urinary arsenic concentrations and total methylation index. A significant gene-environment interaction was observed between urinary arsenic exposure in drinking water GSTT1 but not GSTM1 where GSTT1 null individuals had a slightly higher excretion rate of arsenic compared to GSTT1 wildtypes after adjusting for other factors. Additionally, individuals with GSTT1 null genotypes had a higher primary methylation index and lower secondary methylation index compared to GSTT1 wildtype after adjusting for other factors. This data suggests that GSTT1 contributes to the observed variability in arsenic metabolism. Since individuals with a higher primary methylation index and lower secondary methylation index are more susceptible to arsenic related disease, these results suggest that GSTT1 null individuals may be more susceptible to arsenic-related toxicity. No significant associations were observed between GSTM1 and any of the arsenic methylation indices. PMID:24511153

  5. Influence of GSTT1 Genetic Polymorphisms on Arsenic Metabolism.

    PubMed

    Kile, Molly L; Houseman, E Andres; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Mostofa, Golam; Hsueh, Yu-Mei; Christiani, David C

    2013-08-01

    A repeated measures study was conducted in Pabna, Bangladesh to investigate factors that influence biomarkers of arsenic exposure. Drinking water arsenic concentrations were measured by inductively-coupled plasma mass spectrometry (ICP-MS) and urinary arsenic species [arsenite (As3), arsenate (As5), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] were detected using High Performance Liquid Chromatography (HPLC) and Hydride Generated Atomic Absorption Spectrometry (HGAAS). Linear mixed effects models with random intercepts were used to evaluate the effects of arsenic contaminated drinking water, genetic polymorphisms in glutathione-S-transferase (GSTT1 and GSTM1) on total urinary arsenic, primary methylation index [MMA/(As3+As5)], secondary methylation index (DMA/MMA), and total methylation index [(MMA+DMA)/(As3+As5)]. Drinking water arsenic concentrations were positively associated with total urinary arsenic concentrations and total methylation index. A significant gene-environment interaction was observed between urinary arsenic exposure in drinking water GSTT1 but not GSTM1 where GSTT1 null individuals had a slightly higher excretion rate of arsenic compared to GSTT1 wildtypes after adjusting for other factors. Additionally, individuals with GSTT1 null genotypes had a higher primary methylation index and lower secondary methylation index compared to GSTT1 wildtype after adjusting for other factors. This data suggests that GSTT1 contributes to the observed variability in arsenic metabolism. Since individuals with a higher primary methylation index and lower secondary methylation index are more susceptible to arsenic related disease, these results suggest that GSTT1 null individuals may be more susceptible to arsenic-related toxicity. No significant associations were observed between GSTM1 and any of the arsenic methylation indices.

  6. Urinary arsenic species in Devon and Cornwall residents, UK. A pilot study.

    PubMed

    Kavanagh, P; Farago, M E; Thornton, I; Goessler, W; Kuehnelt, D; Schlagenhaufen, C; Irgolic, K J

    1998-01-01

    First void urine samples were collected from 24 residents in an area of past intense mining and smelting activity of arsenical ores. Seven samples were also taken from a control village. The arsenic species in the urine were separated and quantified with an HPLC-ICP-MS system equipped with a hydraulic high-pressure nebulizer. The detection limit for arsenic in urine using this system is 0.05 microgram dm-3. Creatinine was also determined for all samples to remove the influence of urine density and all results were expressed in microgram As g-1 creatinine. The results showed elevated levels of both organic and inorganic arsenic compounds in the 'exposed' population's urine when compared with those of the control group. The total As concentrations (less arsenobetaine) in the 'exposed' population were in the range 2.7-58.9 micrograms g-1 creatinine (mean 13.4, median 9.2 micrograms g-1) compared with the control group data range 2.5-5.3 micrograms g-1 (mean 4.2, median 4.7 micrograms g-1).

  7. Dimethylarsinic acid in drinking water changed the morphology of urinary bladder but not the expression of DNA repair genes of bladder transitional epithelium in F344 rats.

    PubMed

    Wang, Amy; Wolf, Douglas C; Sen, Banalata; Knapp, Geremy W; Holladay, Steven D; Huckle, William R; Caceci, Thomas; Robertson, John L

    2009-06-01

    Inorganic arsenic increases urinary bladder transitional cell carcinoma in humans. In F344 rats, dimethylarsinic acid (DMA[V]) increases transitional cell carcinoma. Arsenic-induced inhibition of DNA repair has been reported in cultured cell lines and in lymphocytes of arsenic-exposed humans, but it has not been studied in urinary bladder. Should inhibition of DNA damage repair in transitional epithelium occur, it may contribute to carcinogenesis or cocarcinogenesis. We investigated morphology and expression of DNA repair genes in F344 rat transitional cells following up to 100 ppm DMA(V) in drinking water for four weeks. Mitochondria were very sensitive to DMA(V), and swollen mitochondria appeared to be the main source of vacuoles in the transitional epithelium. Real-time reverse transcriptase polymerase chain reaction (Real-Time RT PCR) showed the mRNA levels of tested DNA repair genes, ataxia telangectasia mutant (ATM), X-ray repair cross-complementing group 1 (XRCC1), excision repair cross-complementing group 3/xeroderma pigmentosum B (ERCC3/XPB), and DNA polymerase beta (Polbeta), were not altered by DMA(V). These data suggested that either DMA(V) does not affect DNA repair in the bladder or DMA(V) affects DNA repair without affecting baseline mRNA levels of repair genes. The possibility remains that DMA(V) may lower damage-induced increases in repair gene expression or cause post-translational modification of repair enzymes.

  8. Immunomodulatory effect of arsenic on cytokine and HSP gene expression in Labeo rohita fingerlings.

    PubMed

    Banerjee, Sudeshna; Mitra, Tandrima; Purohit, Gopal Krishna; Mohanty, Sasmita; Mohanty, Bimal Prasanna

    2015-05-01

    Immune system is fundamental for survival of an organism against invading pathogens and other harmful agents. Cytokines, the signaling proteins that are produced transiently after cell activation and exert pleiotropic effects on cells of the immune system, are important mediators of cell mediated immune response. When expressed in a dysregulated fashion cytokines can underlie either immunodeficient or immunopathologic states. Heat shock proteins (stress proteins, HSPs) are also key proteins, which play important role in immunomodulation, apoptosis and influence the immune responses. Arsenic is a major toxic environmental contaminant and a human carcinogen. Prolonged drinking of arsenic-contaminated water leads to chronic arsenic toxicity (arsenicosis). Arsenic is also immunotoxic and renders the host immunocompromised. Arsenic exposure has been reported to result in growth retardation, gross pathology including skin and eye lesions, ulcerations, cataract development etc. in different fish species. The present study was undertaken to investigate the effect of arsenic exposure on the expression of immune genes IFN-γ, IL-4, IL-10, IL-12, complement C3a and HSP genes HSP47, HSP60, HSP70, HSC71, HSP78, and HSP90 in Labeo rohita, an important aquacultured species, as such information is not available on this major carp. Cytokine and HSP gene expression analyses were carried out in kidney and liver tissues, respectively, in arsenic-exposed fishes by RT-PCR and HSPs were analyzed by immunoblotting. It was observed that arsenic has a generalized immune-suppressive effect leading to down regulation of both Th1 and Th2 cytokines; besides, it led to up regulation of the HSP genes indicating arsenic-induced cellular stress. Thus arsenic exposure makes L. rohita immunocompromised and could increase its susceptibility to pathogen attacks. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Effect of Dietary Treatment with Dimethylarsinous Acid (DMAIII) on the Urinary Bladder Epithelium of Arsenic (+3 Oxidation State) Methyltransferase (As3mt) Knockout and C57BL/6 Wild Type Female Mice

    EPA Science Inventory

    Abstract Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMAv, a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the...

  10. Effect of Dietary Treatment with Dimethylarsinous Acid (DMAIII) on the Urinary Bladder Epithelium of Arsenic (+3 Oxidation State) Methyltransferase (As3mt) Knockout and C57BL/6 Wild Type Female Mice

    EPA Science Inventory

    Abstract Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMAv, a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the...

  11. Co-expression of Cyanobacterial Genes for Arsenic Methylation and Demethylation in Escherichia coli Offers Insights into Arsenic Resistance

    PubMed Central

    Yan, Yu; Xue, Xi-Mei; Guo, Yu-Qing; Zhu, Yong-Guan; Ye, Jun

    2017-01-01

    Arsenite [As(III)] and methylarsenite [MAs(III)] are the most toxic inorganic and methylated arsenicals, respectively. As(III) and MAs(III) can be interconverted in the unicellular cyanobacterium Nostoc sp. PCC 7120 (Nostoc), which has both the arsM gene (NsarsM), which is responsible for arsenic methylation, and the arsI gene (NsarsI), which is responsible for MAs(III) demethylation. It is not clear how the cells prevent a futile cycle of methylation and demethylation. To investigate the relationship between arsenic methylation and demethylation, we constructed strains of Escherichia coli AW3110 (ΔarsRBC) expressing NsarsM or/and NsarsI. Expression of NsarsI conferred MAs(III) resistance through MAs(III) demethylation. Compared to NsArsI, NsArsM conferred higher resistance to As(III) and lower resistance to MAs(III) by methylating both As(III) and MAs(III). The major species found in solution was dimethylarsenate [DMAs(V)]. Co-expression of NsarsM and NsarsI conferred As(III) resistance at levels similar to that with NsarsM alone, although the main species found in solution after As(III) biotransformation was methylarsenate [MAs(V)] rather than DMAs(V). Co-expression of NsarsM and NsarsI conferred a higher level of resistance to MAs(III) than found with expression of NsarsM alone but lower than expression of only NsarsI. Cells co-expressing both genes converted MAs(III) to a mixture of As(III) and DMAs(V). In Nostoc NsarsM is constitutively expressed, while NsarsI is inducible by either As(III) or MAs(III). Thus, our results suggest that at low concentrations of arsenic, NsArsM activity predominates, while NsArsI activity predominates at high concentrations. We propose that coexistence of arsM and arsI genes in Nostoc could be advantageous for several reasons. First, it confers a broader spectrum of resistance to both As(III) and MAs(III). Second, at low concentrations of arsenic, the MAs(III) produced by NsArsM will possibly have antibiotic-like properties and

  12. Magnesium, zinc, arsenic, selenium and platinum urinary excretion from cancer patients of Antofagasta region, Chile: multi-metal approach

    PubMed Central

    Pizarro, I; Rivera, L; Ávila, J; Cortés, P

    2016-01-01

    Objectives To evaluate the short-term 24 h urinary excretion of platinum, arsenic, selenium, magnesium and zinc in patients with lung cancer and with cancer other than lungs treated with cisplatin or/and carboplatin from Antofagasta, Chile. Design Urine measurements of Pt and Se were made by inductively coupled plasma optical emission spectrometry, As by hydride-generation atomic absorption spectrometry and Mg and Zn by means of flame furnace atomic absorption spectrometry. Setting All samples were provided by the Oncological Centre of Antofagasta Regional Hospital (Region of Antofagasta, Chile). Participants Ninety 24-h urine samples from cancer patients after the infusion of Pt-base drugs and 10 24-h urine samples from cancer patients not treated with metal-base drugs. Main outcome measures Concentrations of Pt, Se, As, Zn and Mg coming from 24-h urine samples. Results Pt excreted was not significantly different between patients with lung and other cancers treated with cisplatin. The excretion of Mg, Zn and Se was greater than As. Then, Pt favours the excretion of essential elements. For lung and other types of cancers treated with drugs without Pt, excretion of Mg, Zn and Se was also greater than that of As, suggesting antagonism Mg-Zn-Se–anti-cancer drug relationship. Conclusions The amounts of Mg, Zn and Se excreted were greater than for As either with or without Pt-containing drugs, suggesting antagonist Mg-Zn-Se–anti-cancer drug relationships. The excretion of As, Mg, Zn and Se is induced by Pt. Knowledge obtained can contribute to understanding the arsenic cancer mechanism and the As-Mg-Zn-Se-Pt inter-element association for lung cancer and other types of cancer. PMID:27757244

  13. Metagenomic analysis revealed highly diverse microbial arsenic metabolism genes in paddy soils with low-arsenic contents.

    PubMed

    Xiao, Ke-Qing; Li, Li-Guan; Ma, Li-Ping; Zhang, Si-Yu; Bao, Peng; Zhang, Tong; Zhu, Yong-Guan

    2016-04-01

    Microbe-mediated arsenic (As) metabolism plays a critical role in global As cycle, and As metabolism involves different types of genes encoding proteins facilitating its biotransformation and transportation processes. Here, we used metagenomic analysis based on high-throughput sequencing and constructed As metabolism protein databases to analyze As metabolism genes in five paddy soils with low-As contents. The results showed that highly diverse As metabolism genes were present in these paddy soils, with varied abundances and distribution for different types and subtypes of these genes. Arsenate reduction genes (ars) dominated in all soil samples, and significant correlation existed between the abundance of arr (arsenate respiration), aio (arsenite oxidation), and arsM (arsenite methylation) genes, indicating the co-existence and close-relation of different As resistance systems of microbes in wetland environments similar to these paddy soils after long-term evolution. Among all soil parameters, pH was an important factor controlling the distribution of As metabolism gene in five paddy soils (p = 0.018). To the best of our knowledge, this is the first study using high-throughput sequencing and metagenomics approach in characterizing As metabolism genes in the five paddy soil, showing their great potential in As biotransformation, and therefore in mitigating arsenic risk to humans.

  14. Measuring Escherichia coli Gene Expression during Human Urinary Tract Infections

    PubMed Central

    Mobley, Harry L. T.

    2016-01-01

    Extraintestinal Escherichia coli (E. coli) evolved by acquisition of pathogenicity islands, phage, plasmids, and DNA segments by horizontal gene transfer. Strains are heterogeneous but virulent uropathogenic isolates more often have specific fimbriae, toxins, and iron receptors than commensal strains. One may ask whether it is the virulence factors alone that are required to establish infection. While these virulence factors clearly contribute strongly to pathogenesis, bacteria must survive by metabolizing nutrients available to them. By constructing mutants in all major metabolic pathways and co-challenging mice transurethrally with each mutant and the wild type strain, we identified which major metabolic pathways are required to infect the urinary tract. We must also ask what else is E. coli doing in vivo? To answer this question, we examined the transcriptome of E. coli CFT073 in the murine model of urinary tract infection (UTI) as well as for E. coli strains collected and analyzed directly from the urine of patients attending either a urology clinic or a university health clinic for symptoms of UTI. Using microarrays and RNA-seq, we measured in vivo gene expression for these uropathogenic E. coli strains, identifying genes upregulated during murine and human UTI. Our findings allow us to propose a new definition of bacterial virulence. PMID:26784237

  15. Volatilization of Arsenic from Polluted Soil by Pseudomonas putida Engineered for Expression of the arsM Arsenic(III) S-Adenosine Methyltransferase Gene

    PubMed Central

    2015-01-01

    Even though arsenic is one of the most widespread environmental carcinogens, methods of remediation are still limited. In this report we demonstrate that a strain of Pseudomonas putida KT2440 endowed with chromosomal expression of the arsM gene encoding the As(III) S-adenosylmethionine (SAM) methyltransfase from Rhodopseudomonas palustris to remove arsenic from contaminated soil. We genetically engineered the P. putida KT2440 with stable expression of an arsM-gfp fusion gene (GE P. putida), which was inserted into the bacterial chromosome. GE P. putida showed high arsenic methylation and volatilization activity. When exposed to 25 μM arsenite or arsenate overnight, most inorganic arsenic was methylated to the less toxic methylated arsenicals methylarsenate (MAs(V)), dimethylarsenate (DMAs(V)) and trimethylarsine oxide (TMAs(V)O). Of total added arsenic, the species were about 62 ± 2.2% DMAs(V), 25 ± 1.4% MAs(V) and 10 ± 1.2% TMAs(V)O. Volatilized arsenicals were trapped, and the predominant species were dimethylarsine (Me2AsH) (21 ± 1.0%) and trimethylarsine (TMAs(III)) (10 ± 1.2%). At later times, more DMAs(V) and volatile species were produced. Volatilization of Me2AsH and TMAs(III) from contaminated soil is thus possible with this genetically engineered bacterium and could be instrumental as an agent for reducing the inorganic arsenic content of soil and agricultural products. PMID:25122054

  16. Volatilization of arsenic from polluted soil by Pseudomonas putida engineered for expression of the arsM Arsenic(III) S-adenosine methyltransferase gene.

    PubMed

    Chen, Jian; Sun, Guo-Xin; Wang, Xiao-Xue; Lorenzo, Víctor de; Rosen, Barry P; Zhu, Yong-Guan

    2014-09-02

    Even though arsenic is one of the most widespread environmental carcinogens, methods of remediation are still limited. In this report we demonstrate that a strain of Pseudomonas putida KT2440 endowed with chromosomal expression of the arsM gene encoding the As(III) S-adenosylmethionine (SAM) methyltransfase from Rhodopseudomonas palustris to remove arsenic from contaminated soil. We genetically engineered the P. putida KT2440 with stable expression of an arsM-gfp fusion gene (GE P. putida), which was inserted into the bacterial chromosome. GE P. putida showed high arsenic methylation and volatilization activity. When exposed to 25 μM arsenite or arsenate overnight, most inorganic arsenic was methylated to the less toxic methylated arsenicals methylarsenate (MAs(V)), dimethylarsenate (DMAs(V)) and trimethylarsine oxide (TMAs(V)O). Of total added arsenic, the species were about 62 ± 2.2% DMAs(V), 25 ± 1.4% MAs(V) and 10 ± 1.2% TMAs(V)O. Volatilized arsenicals were trapped, and the predominant species were dimethylarsine (Me2AsH) (21 ± 1.0%) and trimethylarsine (TMAs(III)) (10 ± 1.2%). At later times, more DMAs(V) and volatile species were produced. Volatilization of Me2AsH and TMAs(III) from contaminated soil is thus possible with this genetically engineered bacterium and could be instrumental as an agent for reducing the inorganic arsenic content of soil and agricultural products.

  17. T-Box Genes in the Kidney and Urinary Tract.

    PubMed

    Kispert, A

    2017-01-01

    T-box (Tbx) genes encode an ancient group of transcription factors that play important roles in patterning, specification, proliferation, and differentiation programs in vertebrate organogenesis. This is testified by severe organ malformation syndromes in mice homozygous for engineered null alleles of specific T-box genes and by the large number of human inherited organ-specific diseases that have been linked to mutations in these genes. One of the organ systems that has not been associated with loss of specific T-box gene function in human disease for long is the excretory system. However, this has changed with the finding that mutations in TBX18, a member of a vertebrate-specific subgroup within the Tbx1-subfamily of T-box transcription factor genes, cause congenital anomalies of the kidney and urinary tract, predominantly hydroureter and ureteropelvic junction obstruction. Gene expression analyses, loss-of-function studies, and lineage tracing in the mouse suggest a primary role for this transcription factor in specifying the ureteric mesenchyme in the common anlage of the kidney, the ureter, and the bladder. We review the function of Tbx18 in ureterogenesis and discuss the body of evidence that Tbx18 and other members of the T-box gene family, namely, Tbx1, Tbx2, Tbx3, and Tbx20, play additional roles in development and homeostasis of other components of the excretory system in vertebrates.

  18. Urinary arsenic, cadmium, manganese, nickel, and vanadium levels of schoolchildren in the vicinity of the industrialised area of Asaluyeh, Iran.

    PubMed

    Kafaei, Raheleh; Tahmasbi, Rahim; Ravanipour, Masomeh; Vakilabadi, Dariush Ranjbar; Ahmadi, Mehdi; Omrani, Abdolmajid; Ramavandi, Bahman

    2017-08-28

    Asaluyeh is one of the most heavily industrialised areas in the world where gas, petrochemical, and many downstream industries are located. This study aims to survey the biomonitoring of four metals and one metalloid in children living in the vicinity of Asaluyeh area. To do this, we analysed the creatinine-adjusted urinary levels of arsenic (As), cadmium (Cd), vanadium (V), manganese (Mn), and nickel (Ni) in 184 elementary schoolchildren (99 boys and 85 girls) living in Asaluyeh and compared them with a reference population. The comparisons were done for two seasons (spring and fall). The results showed that in the case area (Asaluyeh), the levels of As, V, Mn, and Ni were significantly higher and that of Cd was not significantly higher than the reference city for both seasons. The mean concentration of metal(loid)s in Asaluyeh (case) and Sadabad (reference) area as μg g(-1) creatinine was As 2.90 and 2.24, V 0.06 and 0.03, Mn 0.28 and 0.25, Ni 0.54 and 0.29, and Cd 0.31 and 0.28 in spring and As 3.08 and 2.28, V 0.07 and 0.03, Mn 0.30 and 0.26, Ni 0.91 and 0.30, and Cd 0.36 and 0.31 in the fall. Seasonal variations played a key role in determining urinary metal(loid) concentration, as we saw the significant level of As, Cd, V, and Ni in fall than in spring. With regard to the impact of gender on the absorption and accumulation of urinary metal(loid)s, boys showed higher levels of the studied elements, especially for As, than girls as outdoor activities are more popular among boys. Due to the values being lower than those reported in literature, more research is needed on various population groups and other exposure sources in order to judge whether living in the vicinity of the gas and petrochemical industries in Asaluyeh is a threat to nearby residents.

  19. Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population.

    PubMed

    Argos, Maria; Kibriya, Muhammad G; Parvez, Faruque; Jasmine, Farzana; Rakibuz-Zaman, Muhammad; Ahsan, Habibul

    2006-07-01

    Millions of individuals worldwide are chronically exposed to arsenic through their drinking water. In this study, the effect of arsenic exposure and arsenical skin lesion status on genome-wide gene expression patterns was evaluated using RNA from peripheral blood lymphocytes of individuals selected from the Health Effects of Arsenic Longitudinal Study. Affymetrix HG-U133A GeneChip (Affymetrix, Santa Clara, CA) arrays were used to measure the expression of approximately 22,000 transcripts. Our primary statistical analysis involved identifying differentially expressed genes between participants with and without arsenical skin lesions based on the significance analysis of microarrays statistic with an a priori defined 1% false discovery rate to minimize false positives. To better characterize differential expression, we also conducted Gene Ontology and pathway comparisons in addition to the gene-specific analyses. Four-hundred sixty-eight genes were differentially expressed between these two groups, from which 312 differentially expressed genes were identified by restricting the analysis to female never-smokers. We also explored possible differential gene expression by arsenic exposure levels among individuals without manifest arsenical skin lesions; however, no differentially expressed genes could be identified from this comparison. Our findings show that microarray-based gene expression analysis is a powerful method to characterize the molecular profile of arsenic exposure and arsenic-induced diseases. Genes identified from this analysis may provide insights into the underlying processes of arsenic-induced disease and represent potential targets for chemoprevention studies to reduce arsenic-induced skin cancer in this population.

  20. Exploring the diversity of arsenic resistance genes from acid mine drainage microorganisms.

    PubMed

    Morgante, Verónica; Mirete, Salvador; de Figueras, Carolina G; Postigo Cacho, Marina; González-Pastor, José E

    2015-06-01

    The microbial communities from the Tinto River, a natural acid mine drainage environment, were explored to search for novel genes involved in arsenic resistance using a functional metagenomic approach. Seven pentavalent arsenate resistance clones were selected and analysed to find the genes responsible for this phenotype. Insights about their possible mechanisms of resistance were obtained from sequence similarities and cellular arsenic concentration. A total of 19 individual open reading frames were analysed, and each one was individually cloned and assayed for its ability to confer arsenic resistance in Escherichia coli cells. A total of 13 functionally active genes involved in arsenic resistance were identified, and they could be classified into different global processes: transport, stress response, DNA damage repair, phospholipids biosynthesis, amino acid biosynthesis and RNA-modifying enzymes. Most genes (11) encode proteins not previously related to heavy metal resistance or hypothetical or unknown proteins. On the other hand, two genes were previously related to heavy metal resistance in microorganisms. In addition, the ClpB chaperone and the RNA-modifying enzymes retrieved in this work were shown to increase the cell survival under different stress conditions (heat shock, acid pH and UV radiation). Thus, these results reveal novel insights about unidentified mechanisms of arsenic resistance.

  1. Synergistic effect of polymorphisms of paraoxonase gene cluster and arsenic exposure on electrocardiogram abnormality

    SciTech Connect

    Liao, Y.-T.; Li, W.-F.; Chen, C.-J.; Prineas, Ronald J.; Chen, Wei J.; Zhang Zhuming; Sun, C.-W.; Wang, S.-L.

    2009-09-01

    Arsenic has been linked to increased prevalence of cancer and cardiovascular disease (CVD), but the long-term impact of arsenic exposure remains unclear. Human paraoxonase (PON1) is a high-density lipoprotein-associated antioxidant enzyme which hydrolyzes oxidized lipids and is thought to be protective against atherosclerosis, but evidence remains limited to case-control studies. Only recently have genes encoding enzymes responsible for arsenic metabolism, such as AS3MT and GSTO, been cloned and characterized. This study was designed to evaluate the synergistic interaction of genetic factors and arsenic exposure on electrocardiogram abnormality. A total of 216 residents from three tap water implemented villages of previous arseniasis-hyperendemic regions in Taiwan were prospectively followed for an average of 8 years. For each resident, a 12-lead conventional electrocardiogram (ECG) was recorded and coded by Minnesota Code standard criteria. Eight functional polymorphisms of PON1, PON2, AS3MT, GSTO1, and GSTO2 were examined for genetic susceptibility to ECG abnormality. Among 42 incident cases with ECG deterioration identified among 121 baseline-normal subjects, arsenic exposure was significantly correlated with incidence of ECG abnormality. In addition, polymorphisms in two paraoxonase genes were also found associated with the incidence of ECG abnormality. A haplotype R-C-S constituted by polymorphisms of PON1 Q192R, -108C/T and PON2 C311S was linked to the increased risk. Subjects exposed to high levels of As (cumulative As exposure > 14.7 ppm-year or drinking artesian well water > 21 years) and carrying the R-C-S haplotype had significantly increased risks for ECG abnormality over those with only one risk factor. Results of this study showed a long-term arsenic effect on ECG abnormality and significant gene-gene and gene-environment interactions linked to the incidence of CVD. This finding might have important implications for a novel and potentially useful

  2. Arsenic Exposure Perturbs Epithelial-Mesenchymal Cell Transition and Gene Expression In a Collagen Gel Assay

    PubMed Central

    Lencinas, Alejandro; Broka, Derrick M.; Konieczka, Jay H.; Klewer, Scott E.; Antin, Parker B.; Camenisch, Todd D.; Runyan, Raymond B.

    2010-01-01

    Arsenic is a naturally occurring metalloid and environmental contaminant. Arsenic exposure in drinking water is reported to cause cancer of the liver, kidneys, lung, bladder, and skin as well as birth defects, including neural tube, facial, and vasculogenic defects. The early embryonic period most sensitive to arsenic includes a variety of cellular processes. One key cellular process is epithelial-mesenchymal transition (EMT) where epithelial sheets develop into three-dimensional structures. An embryonic prototype of EMT is found in the atrioventricular (AV) canal of the developing heart, where endothelia differentiate to form heart valves. Effects of arsenic on this cellular process were examined by collagen gel invasion assay (EMT assay) using explanted AV canals from chicken embryo hearts. AV canals treated with 12.5–500 ppb arsenic showed a loss of mesenchyme at 12.5 ppb, and mesenchyme formation was completely inhibited at 500 ppb. Altered gene expression in arsenic-treated explants was investigated by microarray analysis. Genes whose expression was altered consistently at exposure levels of 10, 25, and 100 ppb were identified, and results showed that 25 ppb in vitro was particularly effective. Three hundred and eighty two genes were significantly altered at this exposure level. Cytoscape analysis of the microarray data using the chicken interactome identified four clusters of altered genes based on published relationships and pathways. This analysis identified cytoskeleton and cell adhesion–related genes whose disruption is consistent with an altered ability to undergo EMT. These studies show that EMT is sensitive to arsenic and that an interactome-based approach can be useful in identifying targets. PMID:20308225

  3. Chronic Exposure to Low-Dose Arsenic Modulates Lipogenic Gene Expression in Mice

    PubMed Central

    Adebayo, Adeola O.; Zandbergen, Fokko; Kozul-Horvath, Courtney D.; Gruppuso, Philip A.; Hamilton, Joshua W.

    2016-01-01

    Arsenic, a ubiquitous environmental toxicant, can affect lipid metabolism through mechanisms that are not well understood. We studied the effect of arsenic on serum lipids, lipid-regulating genes, and transcriptional regulator sterol regulatory element binding protein 1c (SREBP-1c). C57BL/6 mice were administered 0 or 100 ppb sodium arsenite in drinking water for 5 weeks. Arsenic exposure was associated with decreased liver weight but no change in body weight. Serum triglycerides level fell in arsenic-exposed animals, but not in fed animals, after short-term fasting. Hepatic expression of SREBP-1c was reduced in arsenic-exposed fed animals, with a 16-fold change in reduction. Similar effects were seen for SREBP-1c in white adipose tissue. However, fasting resulted in dissociation of the expression of SREBP-1c and its targets, and SREBP-1c protein content could not be shown to correlate with its mRNA expression. We conclude that arsenic modulates hepatic expression of genes involved in lipid regulation through mechanisms that are independent of SREBP-1c expression. PMID:25155036

  4. Arsenic Requires Sphingosine-1-Phosphate Type 1 Receptors to Induce Angiogenic Genes and Endothelial Cell Remodeling

    PubMed Central

    Straub, Adam C.; Klei, Linda R.; Stolz, Donna B.; Barchowsky, Aaron

    2009-01-01

    Arsenic in drinking water is a major public health concern as it increases risk and incidence of cardiovascular disease and cancer. Arsenic exposure affects multiple vascular beds, promoting liver sinusoidal capillarization and portal hypertension, ischemic heart disease, peripheral vascular disease, and tumor angiogenesis. While Rac1-GTPase and NADPH oxidase activities are essential for arsenic-stimulated endothelial cell signaling for angiogenesis or liver sinusoid capillarization, the mechanism for initiating these effects is unknown. We found that arsenic-stimulated cell signaling and angiogenic gene expression in human microvascular endothelial cells were Pertussis toxin sensitive, indicating a G-protein coupled signaling pathway. Incubating human microvascular endothelial cells with the sphingosine-1-phosphate type 1 receptor (S1P1) inhibitor VPC23019 or performing small interfering RNA knockdown of S1P1 blocked arsenic-stimulated HMVEC angiogenic gene expression and tube formation, but did not affect induction of either HMOX1 or IL8. Liver sinusoidal endothelial cells (LSECs) defenestrate and capillarize in response to aging and environmental oxidant stresses. We found that S1P1 was enriched on LSECs in vivo and in primary cell culture and that VPC23019 inhibited both sphingosine-1-phosphate-stimulated and arsenic-stimulated LSEC oxidant generation and defenestration. These studies identified novel roles for S1P1 in mediating arsenic stimulation of both angiogenesis and pathogenic LSEC capillarization, as well as demonstrating a role for S1P1 in mediating environmental responses in the liver vasculature, providing possible mechanistic insight into arsenic-induced vascular pathogenesis and disease. PMID:19349368

  5. Effect of the ARG1 gene on arsenic resistance of 293T cells.

    PubMed

    Mu, X L; Li, L; Li, H

    2013-12-19

    To study the relationship between arsenic resistance of 293T cells and overexpression of ARG1, the ARG1 gene in a recombinant plasmid was transfected into 293T cells via liposomes, and then ARG1 overexpression was examined by real-time PCR and immunocytochemistry. The survival rate, arsenic accumulation and arsenic efflux, GSH level, and GST activity of 293T cells overexpressing ARG1 were assayed by MTT, atomic absorption spectrophotometry, and DTNB, and expression of MRP-2 was detected by Western blot analysis. Compared to that in the control cells, the survival rate of ARG1 gene-overexpressing cells was much higher following exposure to lower sodium arsenite (≤ 8 µM). When cells were exposed to lower sodium arsenite for 24 h, the arsenite content of ARG1 gene-overexpressing cells decreased and arsenic efflux increased. After 48 h, the GSH level, GST activity, and expression of MRP2 increased in a concentration-dependent manner. We conclude that the ARG1 gene increases arsenic resistance of 293T cells.

  6. The Comparative Toxicogenomics Database facilitates identification and understanding of chemical-gene-disease associations: arsenic as a case study

    PubMed Central

    Davis, Allan P; Murphy, Cynthia G; Rosenstein, Michael C; Wiegers, Thomas C; Mattingly, Carolyn J

    2008-01-01

    Background The etiology of many chronic diseases involves interactions between environmental factors and genes that modulate physiological processes. Understanding interactions between environmental chemicals and genes/proteins may provide insights into the mechanisms of chemical actions, disease susceptibility, toxicity, and therapeutic drug interactions. The Comparative Toxicogenomics Database (CTD; ) provides these insights by curating and integrating data describing relationships between chemicals, genes/proteins, and human diseases. To illustrate the scope and application of CTD, we present an analysis of curated data for the chemical arsenic. Arsenic represents a major global environmental health threat and is associated with many diseases. The mechanisms by which arsenic modulates these diseases are not well understood. Methods Curated interactions between arsenic compounds and genes were downloaded using export and batch query tools at CTD. The list of genes was analyzed for molecular interactions, Gene Ontology (GO) terms, KEGG pathway annotations, and inferred disease relationships. Results CTD contains curated data from the published literature describing 2,738 molecular interactions between 21 different arsenic compounds and 1,456 genes and proteins. Analysis of these genes and proteins provide insight into the biological functions and molecular networks that are affected by exposure to arsenic, including stress response, apoptosis, cell cycle, and specific protein signaling pathways. Integrating arsenic-gene data with gene-disease data yields a list of diseases that may be associated with arsenic exposure and genes that may explain this association. Conclusion CTD data integration and curation strategies yield insight into the actions of environmental chemicals and provide a basis for developing hypotheses about the molecular mechanisms underlying the etiology of environmental diseases. While many reports describe the molecular response to arsenic, CTD

  7. Genomic evidence reveals the extreme diversity and wide distribution of the arsenic-related genes in Burkholderiales.

    PubMed

    Li, Xiangyang; Zhang, Linshuang; Wang, Gejiao

    2014-01-01

    So far, numerous genes have been found to associate with various strategies to resist and transform the toxic metalloid arsenic (here, we denote these genes as "arsenic-related genes"). However, our knowledge of the distribution, redundancies and organization of these genes in bacteria is still limited. In this study, we analyzed the 188 Burkholderiales genomes and found that 95% genomes harbored arsenic-related genes, with an average of 6.6 genes per genome. The results indicated: a) compared to a low frequency of distribution for aio (arsenite oxidase) (12 strains), arr (arsenate respiratory reductase) (1 strain) and arsM (arsenite methytransferase)-like genes (4 strains), the ars (arsenic resistance system)-like genes were identified in 174 strains including 1,051 genes; b) 2/3 ars-like genes were clustered as ars operon and displayed a high diversity of gene organizations (68 forms) which may suggest the rapid movement and evolution for ars-like genes in bacterial genomes; c) the arsenite efflux system was dominant with ACR3 form rather than ArsB in Burkholderiales; d) only a few numbers of arsM and arrAB are found indicating neither As III biomethylation nor AsV respiration is the primary mechanism in Burkholderiales members; (e) the aio-like gene is mostly flanked with ars-like genes and phosphate transport system, implying the close functional relatedness between arsenic and phosphorus metabolisms. On average, the number of arsenic-related genes per genome of strains isolated from arsenic-rich environments is more than four times higher than the strains from other environments. Compared with human, plant and animal pathogens, the environmental strains possess a larger average number of arsenic-related genes, which indicates that habitat is likely a key driver for bacterial arsenic resistance.

  8. Genomic Evidence Reveals the Extreme Diversity and Wide Distribution of the Arsenic-Related Genes in Burkholderiales

    PubMed Central

    Li, Xiangyang; Zhang, Linshuang; Wang, Gejiao

    2014-01-01

    So far, numerous genes have been found to associate with various strategies to resist and transform the toxic metalloid arsenic (here, we denote these genes as “arsenic-related genes”). However, our knowledge of the distribution, redundancies and organization of these genes in bacteria is still limited. In this study, we analyzed the 188 Burkholderiales genomes and found that 95% genomes harbored arsenic-related genes, with an average of 6.6 genes per genome. The results indicated: a) compared to a low frequency of distribution for aio (arsenite oxidase) (12 strains), arr (arsenate respiratory reductase) (1 strain) and arsM (arsenite methytransferase)-like genes (4 strains), the ars (arsenic resistance system)-like genes were identified in 174 strains including 1,051 genes; b) 2/3 ars-like genes were clustered as ars operon and displayed a high diversity of gene organizations (68 forms) which may suggest the rapid movement and evolution for ars-like genes in bacterial genomes; c) the arsenite efflux system was dominant with ACR3 form rather than ArsB in Burkholderiales; d) only a few numbers of arsM and arrAB are found indicating neither As III biomethylation nor AsV respiration is the primary mechanism in Burkholderiales members; (e) the aio-like gene is mostly flanked with ars-like genes and phosphate transport system, implying the close functional relatedness between arsenic and phosphorus metabolisms. On average, the number of arsenic-related genes per genome of strains isolated from arsenic-rich environments is more than four times higher than the strains from other environments. Compared with human, plant and animal pathogens, the environmental strains possess a larger average number of arsenic-related genes, which indicates that habitat is likely a key driver for bacterial arsenic resistance. PMID:24632831

  9. Genes That Mediate Arsenic and Heavy Metal Detoxification in Plants

    SciTech Connect

    Lee, David A.; Gong, Ji-Ming; Schroeder, Julian I.

    2003-03-26

    To gain insight into the mechanisms of arsenic tolerance in plants, we developed a genetic screen to isolate Arabidopsis thaliana mutants with altered tolerance to arsenic. We report here on the isolation of ars1, a novel mutant with significantly increased tolerance to arsenate. ars1 accumulates similar levels of arsenic as wild type plants, but ars1 tolerance does not appear to be phytochelatin or glutathione dependent. ars1 plants do have a higher rate of phosphate uptake than wild type plants and plants grown with an excess of phosphate show increased tolerance to arsenate. Traditional models of arsenate tolerance in plants are based on the suppression of phosphate uptake pathways and, consequently, the reduced uptake of arsenate. Our data suggest that arsenate tolerance in ars1 is due to a new mechanism mediated by increased phosphate uptake in ars1. Results exploring increased metal tolerance through engineered phytochelatin expression will also be discussed.

  10. Arsenic resistance in Halobacterium sp. strain NRC-1 examined by using an improved gene knockout system.

    PubMed

    Wang, Gejiao; Kennedy, Sean P; Fasiludeen, Sabeena; Rensing, Christopher; DasSarma, Shiladitya

    2004-05-01

    The genome sequence of Halobacterium sp. strain NRC-1 encodes genes homologous to those responsible for conferring resistance to arsenic. These genes occur on both the large extrachromosomal replicon pNRC100 (arsADRC and arsR2M) and on the chromosome (arsB). We studied the role of these ars genes in arsenic resistance genetically by construction of gene knockouts. Deletion of the arsADRC gene cluster in a Halobacterium NRC-1 Deltaura3 strain resulted in increased sensitivity to arsenite and antimonite but not arsenate. In contrast, knockout of the chromosomal arsB gene did not show significantly increased sensitivity to arsenite or arsenate. We also found that knockout of the arsM gene produced sensitivity to arsenite, suggesting a second novel mechanism of arsenic resistance involving a putative arsenite(III)-methyltransferase. These results indicate that Halobacterium sp. strain NRC-1 contains an arsenite and antimonite extrusion system with significant differences from bacterial counterparts. Deletion analysis was facilitated by an improved method for gene knockouts/replacements in Halobacterium that relies on both selection and counterselection of ura3 using a uracil dropout medium and 5-fluoroorotic acid. The arsenite and antimonite resistance elements were shown to be regulated, with resistance to arsenic in the wild type inducible by exposure to a sublethal concentration of the metal. Northern hybridization and reverse transcription-PCR analyses showed that arsA, arsD, arsR, arsM, arsC, and arsB, but not arsR2, are inducible by arsenite and antimonite. We discuss novel aspects of arsenic resistance in this halophilic archaeon and technical improvements in our capability for gene knockouts in the genome.

  11. Arsenic Resistance in Halobacterium sp. Strain NRC-1 Examined by Using an Improved Gene Knockout System

    PubMed Central

    Wang, Gejiao; Kennedy, Sean P.; Fasiludeen, Sabeena; Rensing, Christopher; DasSarma, Shiladitya

    2004-01-01

    The genome sequence of Halobacterium sp. strain NRC-1 encodes genes homologous to those responsible for conferring resistance to arsenic. These genes occur on both the large extrachromosomal replicon pNRC100 (arsADRC and arsR2M) and on the chromosome (arsB). We studied the role of these ars genes in arsenic resistance genetically by construction of gene knockouts. Deletion of the arsADRC gene cluster in a Halobacterium NRC-1 Δura3 strain resulted in increased sensitivity to arsenite and antimonite but not arsenate. In contrast, knockout of the chromosomal arsB gene did not show significantly increased sensitivity to arsenite or arsenate. We also found that knockout of the arsM gene produced sensitivity to arsenite, suggesting a second novel mechanism of arsenic resistance involving a putative arsenite(III)-methyltransferase. These results indicate that Halobacterium sp. strain NRC-1 contains an arsenite and antimonite extrusion system with significant differences from bacterial counterparts. Deletion analysis was facilitated by an improved method for gene knockouts/replacements in Halobacterium that relies on both selection and counterselection of ura3 using a uracil dropout medium and 5-fluoroorotic acid. The arsenite and antimonite resistance elements were shown to be regulated, with resistance to arsenic in the wild type inducible by exposure to a sublethal concentration of the metal. Northern hybridization and reverse transcription-PCR analyses showed that arsA, arsD, arsR, arsM, arsC, and arsB, but not arsR2, are inducible by arsenite and antimonite. We discuss novel aspects of arsenic resistance in this halophilic archaeon and technical improvements in our capability for gene knockouts in the genome. PMID:15126481

  12. A cultural practice of drinking realgar wine leading to elevated urinary arsenic and its potential health risk.

    PubMed

    Zhang, Ying-Nan; Sun, Guo-Xin; Huang, Qing; Williams, Paul N; Zhu, Yong-Guan

    2011-07-01

    Toasting friends and family with realgar wines and painting children's foreheads and limbs with the leftover realgar/alcohol slurries is an important customary ritual during the Dragon Boat Festival (DBF); a Chinese national holiday and ancient feast day celebrated throughout Asia. Realgar is an arsenic sulfide mineral, and source of highly toxic inorganic arsenic. Despite the long history of realgar use during the DBF, associated risk to human health by arsenic ingestion or percutaneous adsorption is unknown. To address this urine samples were collected from a cohort of volunteers who were partaking in the DBF festivities. The total concentration of arsenic in the wine consumed was 70 mg L⁻¹ with all the arsenic found to be inorganic. Total arsenic concentrations in adult urine reached a maximum of ca. 550 μg L⁻¹ (mean 220.2 μg L⁻¹) after 16 h post-ingestion of realgar wine, while face painting caused arsenic levels in children's urine to soar to 100 μg L⁻¹ (mean 85.3 μg L⁻¹) 40 h after the initial paint application. The average concentration of inorganic arsenic in the urine of realgar wine drinkers on average doubled 16 h after drinking, although this was not permanent and levels subsided after 28 h. As would be expected in young children, the proportions of organic arsenic in the urine remained high throughout the 88-h monitoring period. However, even when arsenic concentrations in the urine peaked at 40 h after paint application, concentrations in the urine only declined slightly thereafter, suggesting pronounced longer term dermal accumulation and penetration of arsenic. Drinking wines blended with realgar or using realgar based paints on children does result in the significant absorption of arsenic and therefore presents a potentially serious and currently unquantified health risk. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer

    PubMed Central

    Rager, Julia E.; Miller, Sloane; Tulenko, Samantha E.; Smeester, Lisa; Ray, Paul D.; Yosim, Andrew; Currier, Jenna M.; Ishida, María C.; González-Horta, Maria del Carmen; Sánchez-Ramírez, Blanca; Ballinas-Casarrubias, Lourdes; Gutiérrez-Torres, Daniela S.; Drobná, Zuzana; Del Razo, Luz M.; García-Vargas, Gonzalo G.; Kim, William Y.; Zhou, Yi-Hui; Wright, Fred A.; Stýblo, Miroslav; Fry, Rebecca C.

    2016-01-01

    There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to a myriad of adverse health effects, including cancer of the bladder. The present study set out to identify DNA methylation patterns associated with iAs and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic (As)-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total As (tAs) and As species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 As-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the As- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer. PMID:26039340

  14. Dose-Responsive Gene Expression Changes in Juvenile and Adult Mummichogs (Fundulus heteroclitus) After Arsenic Exposure

    PubMed Central

    Gonzalez, Horacio O.; Hu, Jianjun; Gaworecki, Kristen M.; Roling, Jonathan A.; Baldwin, William S.; Gardea-Torresdey, Jorge L.; Bain, Lisa J.

    2010-01-01

    The present study investigated arsenic's effects on mummichogs (Fundulus heteroclitus), while also examining what role that gender or exposure age might play. Adult male and female mummichogs were exposed to 172ppb, 575ppb, or 1,720ppb arsenic as sodium arsenite for 10 days immediately prior to spawning. No differences were noted in the number or viability of eggs between the groups, but there was a significant increase in deformities in 1,720ppb arsenic exposure group. Total RNA from adult livers or 6-week old juveniles was used to probe custom macroarrays for changes in gene expression. In females, 3% of the genes were commonly differentially expressed in the 172 and 575ppb exposure groups compared to controls. In the males, between 1.1-3% of the differentially expressed genes were in common between the exposure groups. Several genes, including apolipoprotein and serum amyloid precursor were commonly expressed in either a dose-responsive manner or were dose-specific, but consistent across genders. These patterns of regulation were confirmed by QPCR. These findings will provide us with a better understanding of the effects of dose, gender, and exposure age on the response to arsenic. PMID:20451245

  15. Elevated ERCC-1 Gene Expression in blood cells associated with exposure to arsenic from drinking water in Inner Mongolia

    EPA Science Inventory

    Background: Chronic arsenic exposure has been associated with human cancers. The objective of this study was to investigate arsenic effects on a DNA nucleotide excision repair gene, ERCC1, expression in human blood cells. Material and Methods: Water and toe nail samples were coll...

  16. Elevated ERCC-1 Gene Expression in blood cells associated with exposure to arsenic from drinking water in Inner Mongolia

    EPA Science Inventory

    Background: Chronic arsenic exposure has been associated with human cancers. The objective of this study was to investigate arsenic effects on a DNA nucleotide excision repair gene, ERCC1, expression in human blood cells. Material and Methods: Water and toe nail samples were coll...

  17. Association of oxidative stress with arsenic methylation in chronic arsenic-exposed children and adults

    SciTech Connect

    Xu Yuanyuan; Wang Yi; Zheng Quanmei; Li Xin; Li Bing; Jin Yaping; Sun Xiance; Sun Guifan

    2008-10-01

    Though oxidative stress is recognized as an important pathogenic mechanism of arsenic, and arsenic methylation capacity is suggested to be highly involved in arsenic-related diseases, the association of arsenic methylation capacity with arsenic-induced oxidative stress remains unclear. To explore oxidative stress and its association with arsenic methylation, cross-sectional studies were conducted among 208 high and 59 low arsenic-exposed subjects. Levels of urinary arsenic species [inorganic arsenic (iAs), monomethylated arsenic (MMA) and dimethylated arsenic (DMA)] were determined by hydride generation atomic absorption spectrometry. Proportions of urinary arsenic species, the first methylation ratio (FMR) and the secondary methylation ratio (SMR) were used as indicators for arsenic methylation capacity. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations were analyzed by enzyme-linked immunosorbent assay kits. Reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity in whole blood were determined to reflect anti-oxidative status. The high arsenic-exposed children and adults were significantly increased in urinary 8-OHdG concentrations but decreased in blood GSH levels compared with the low exposed children and adults. In multiple linear regression models, blood GSH levels and urinary 8-OHdG concentrations of arsenic-exposed children and adults showed strong associations with the levels of urinary arsenic species. Arsenic-exposed subjects in the lower and the upper quartiles of proportions of urinary arsenic species, FMR or SMR were significantly different in urinary 8-OHdG, blood GSH and SOD. The associations of arsenic methylation capacity with 8-OHdG, GSH and SOD were also observed in multivariate regression analyses. These results may provide linkage between arsenic methylation capacity and oxidative stress in humans and suggest that adverse health effects induced by arsenic are related to arsenic methylation through oxidative stress.

  18. Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity

    PubMed Central

    Wlodarczyk, Bogdan J.; Zhu, Huiping; Finnell, Richard H.

    2014-01-01

    Background In utero exposure to arsenic is known to adversely affect reproductive outcomes. Evidence of arsenic teratogenicity vary widely and depend on individual genotypic differences in sensitivity to As. In this study, we investigated the potential interaction between 5,10-methylenetetrahydrofolate reductase (Mthfr) genotype and arsenic embryotoxicity using the Mthfr knockout mouse model. Methods Pregnant dams were treated with sodium arsenate, and reproductive outcomes including: implantation, resorption, congenital malformation and fetal birth weight were recorded at E18.5. Results When the dams in Mthfr+/− x Mthfr+/− matings were treated with 7.2mg/kg As, the resorption rate increased to 43.4%, from a background frequency of 7.2%. The As treatment also induced external malformations (40.9%) and significantly lowered the average fetal birth weight among fetuses, without any obvious toxic effect on the dam. When comparing the pregnancy outcomes resulting from different mating scenarios (Mthfr+/+ x Mthfr+/−, Mthfr+/− x Mthfr+/− and Mthfr−/− x Mthfr+/−) and arsenic exposure; the resorption rate showed a linear relationship with the number of null alleles (0, 1 or 2) in the Mthfr dams. Fetuses from nullizygous dams had the highest rate of external malformations (43%) and lowest average birth weight. When comparing the outcomes of reciprocal matings (nullizygote x wild-type versus wild-type x nullizygote) after As treatment, the null dams showed significantly higher rates of resorptions and malformations, along with lower fetal birth weights. Conclusions Maternal genotype contributes to the sensitivity of As embryotoxicity in the Mthfr mouse model. The fetal genotype, however, does not appear to affect the reproductive outcome after in utero As exposure. PMID:24384392

  19. [Modification of GSTM1, GSTT1 and GSTP1 gene polymorphisms on urinary 1-hydroxypyrene excretions].

    PubMed

    Gao, Qiang; Xu, Zhi-yin; Li, Shu-guang; Jin, Tai-guang; Chen, Bo

    2011-01-01

    To investigate the modification of GSTM1, GSTT1 and GSTP1 gene polymorphisms on urinary 1-hydroxypyrene (1-OHP) excretions in workers under different exposure levels. Four hundred and forty-seven occupationally exposed workers from two coking plants and 220 control workers from a wire rod plant were genotyped to analyze the modification of GSTM1, GSTT1 and GSTP1 gene polymorphisms on urinary 1-OHP excretions. The urinary 1-OHP concentration in exposed group was much higher than that in control group (4.61 vs 0.34 µmol/mol Cr, P < 0.05). Occupational exposure levels and cigarette smoking were of the dominating factors affecting 1-OHP excretions in urine. After controlling potential confounders, decreased excretion of urinary 1-OHP was associated with GSTP1 I105V AG + GG genotype in coke oven workers (single-gene model, P = 0.012; multi-gene model, P = 0.011) and with GSTT1 null type in the analysis including all subjects (P = 0.055 in both single-gene and multi-gene models). GSTT1 and GSTP1 were interacted on the urinary concentrations of 1-OHP. Urinary 1-OHP concentrations can be modified by GSTM1, GSTT1 and GSTP1 gene polymorphisms, indicating that these genes are involved in the metabolism of polycyclic aromatic hydrocarbons.

  20. Expression profiling of Crambe abyssinica under arsenate stress identifies genes and gene networks involved in arsenic metabolism and detoxification.

    PubMed

    Paulose, Bibin; Kandasamy, Suganthi; Dhankher, Om Parkash

    2010-06-14

    Arsenic contamination is widespread throughout the world and this toxic metalloid is known to cause cancers of organs such as liver, kidney, skin, and lung in human. In spite of a recent surge in arsenic related studies, we are still far from a comprehensive understanding of arsenic uptake, detoxification, and sequestration in plants. Crambe abyssinica, commonly known as 'abyssinian mustard', is a non-food, high biomass oil seed crop that is naturally tolerant to heavy metals. Moreover, it accumulates significantly higher levels of arsenic as compared to other species of the Brassicaceae family. Thus, C. abyssinica has great potential to be utilized as an ideal inedible crop for phytoremediation of heavy metals and metalloids. However, the mechanism of arsenic metabolism in higher plants, including C. abyssinica, remains elusive. To identify the differentially expressed transcripts and the pathways involved in arsenic metabolism and detoxification, C. abyssinica plants were subjected to arsenate stress and a PCR-Select Suppression Subtraction Hybridization (SSH) approach was employed. A total of 105 differentially expressed subtracted cDNAs were sequenced which were found to represent 38 genes. Those genes encode proteins functioning as antioxidants, metal transporters, reductases, enzymes involved in the protein degradation pathway, and several novel uncharacterized proteins. The transcripts corresponding to the subtracted cDNAs showed strong upregulation by arsenate stress as confirmed by the semi-quantitative RT-PCR. Our study revealed novel insights into the plant defense mechanisms and the regulation of genes and gene networks in response to arsenate toxicity. The differential expression of transcripts encoding glutathione-S-transferases, antioxidants, sulfur metabolism, heat-shock proteins, metal transporters, and enzymes in the ubiquitination pathway of protein degradation as well as several unknown novel proteins serve as molecular evidence for the

  1. Expression profiling of Crambe abyssinica under arsenate stress identifies genes and gene networks involved in arsenic metabolism and detoxification

    PubMed Central

    2010-01-01

    Background Arsenic contamination is widespread throughout the world and this toxic metalloid is known to cause cancers of organs such as liver, kidney, skin, and lung in human. In spite of a recent surge in arsenic related studies, we are still far from a comprehensive understanding of arsenic uptake, detoxification, and sequestration in plants. Crambe abyssinica, commonly known as 'abyssinian mustard', is a non-food, high biomass oil seed crop that is naturally tolerant to heavy metals. Moreover, it accumulates significantly higher levels of arsenic as compared to other species of the Brassicaceae family. Thus, C. abyssinica has great potential to be utilized as an ideal inedible crop for phytoremediation of heavy metals and metalloids. However, the mechanism of arsenic metabolism in higher plants, including C. abyssinica, remains elusive. Results To identify the differentially expressed transcripts and the pathways involved in arsenic metabolism and detoxification, C. abyssinica plants were subjected to arsenate stress and a PCR-Select Suppression Subtraction Hybridization (SSH) approach was employed. A total of 105 differentially expressed subtracted cDNAs were sequenced which were found to represent 38 genes. Those genes encode proteins functioning as antioxidants, metal transporters, reductases, enzymes involved in the protein degradation pathway, and several novel uncharacterized proteins. The transcripts corresponding to the subtracted cDNAs showed strong upregulation by arsenate stress as confirmed by the semi-quantitative RT-PCR. Conclusions Our study revealed novel insights into the plant defense mechanisms and the regulation of genes and gene networks in response to arsenate toxicity. The differential expression of transcripts encoding glutathione-S-transferases, antioxidants, sulfur metabolism, heat-shock proteins, metal transporters, and enzymes in the ubiquitination pathway of protein degradation as well as several unknown novel proteins serve as

  2. Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity

    SciTech Connect

    Wlodarczyk, Bogdan J. Zhu, Huiping; Finnell, Richard H.

    2014-02-15

    Background: In utero exposure to arsenic is known to adversely affect reproductive outcomes. Evidence of arsenic teratogenicity varies widely and depends on individual genotypic differences in sensitivity to As. In this study, we investigated the potential interaction between 5,10-methylenetetrahydrofolate reductase (Mthfr) genotype and arsenic embryotoxicity using the Mthfr knockout mouse model. Methods: Pregnant dams were treated with sodium arsenate, and reproductive outcomes including: implantation, resorption, congenital malformation and fetal birth weight were recorded at E18.5. Results: When the dams in Mthfr{sup +/−} × Mthfr{sup +/−} matings were treated with 7.2 mg/kg As, the resorption rate increased to 43.4%, from a background frequency of 7.2%. The As treatment also induced external malformations (40.9%) and significantly lowered the average fetal birth weight among fetuses, without any obvious toxic effect on the dam. When comparing the pregnancy outcomes resulting from different mating scenarios (Mthfr{sup +/+} × Mthfr{sup +/−}, Mthfr{sup +/−} × Mthfr{sup +/−} and Mthfr{sup −/−} × {sup Mthfr+/−}) and arsenic exposure; the resorption rate showed a linear relationship with the number of null alleles (0, 1 or 2) in the Mthfr dams. Fetuses from nullizygous dams had the highest rate of external malformations (43%) and lowest average birth weight. When comparing the outcomes of reciprocal matings (nullizygote × wild-type versus wild-type × nullizygote) after As treatment, the null dams showed significantly higher rates of resorptions and malformations, along with lower fetal birth weights. Conclusions: Maternal genotype contributes to the sensitivity of As embryotoxicity in the Mthfr mouse model. The fetal genotype, however, does not appear to affect the reproductive outcome after in utero As exposure. - Highlights: • An interaction between Mthfr genotype and arsenic embryotoxicity is presented. • Maternal Mthfr genotype

  3. Expression of arsenic resistance genes in the obligate anaerobe Bacteroides vulgatus ATCC 8482, a gut microbiome bacterium.

    PubMed

    Li, Jiaojiao; Mandal, Goutam; Rosen, Barry P

    2016-06-01

    The response of the obligate anaerobe Bacteroides vulgatus ATCC 8482, a common human gut microbiota, to arsenic was determined. B. vulgatus ATCC 8482 is highly resistant to pentavalent As(V) and methylarsenate (MAs(V)). It is somewhat more sensitive to trivalent inorganic As(III) but 100-fold more sensitive to methylarsenite (MAs(III)) than to As(III). B. vulgatus ATCC 8482 has eight continuous genes in its genome that we demonstrate form an arsenical-inducible transcriptional unit. The first gene of this ars operon, arsR, encodes a putative ArsR As(III)-responsive transcriptional repressor. The next three genes encode proteins of unknown function. The remaining genes, arsDABC, have well-characterized roles in detoxification of inorganic arsenic, but there are no known genes for MAs(III) resistance. Expression of each gene after exposure to trivalent and pentavalent inorganic and methylarsenicals was analyzed. MAs(III) was the most effective inducer. The arsD gene was the most highly expressed of the ars operon genes. These results demonstrate that this anaerobic microbiome bacterium has arsenic-responsive genes that confer resistance to inorganic arsenic and may be responsible for the organism's ability to maintain its prevalence in the gut following dietary exposure to inorganic arsenic. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Expression of arsenic resistance genes in the obligate anaerobe Bacteroides vulgatus ATCC 8482, a gut microbiome bacterium

    PubMed Central

    Li, Jiaojiao; Mandal, Goutam; Rosen, Barry P.

    2016-01-01

    The response of the obligate anaerobe Bacteroides vulgatus ATCC 8482, a common human gut microbiota, to arsenic was determined. B. vulgatus ATCC 8482 is highly resistant to pentavalent As(V) and methylarsenate (MAs(V)). It is somewhat more sensitive to trivalent inorganic As(III) but 100-fold more sensitive to methylarsenite (MAs(III)) than to As(III). B. vulgatus ATCC 8482 has eight continuous genes in its genome that we demonstrate form an arsenical-inducible transcriptional unit. The first gene of this ars operon, arsR, encodes a putative ArsR As(III)-responsive transcriptional repressor. The next three genes encode proteins of unknown function. The remaining genes, arsDABC, have well-characterized roles in detoxification of inorganic arsenic, but there are no known genes for MAs(III) resistance. Expression of each gene after exposure to trivalent and pentavalent inorganic and methylarsenicals was analyzed. MAs(III) was the most effective inducer. The arsD gene was the most highly expressed of the ars operon genes. These results demonstrate that this anaerobic microbiome bacterium has arsenic-responsive genes that confer resistance to inorganic arsenic and may be responsible for the organism's ability to maintain its prevalence in the gut following dietary exposure to inorganic arsenic. PMID:27040269

  5. Diversity and Distribution of Arsenic-Related Genes Along a Pollution Gradient in a River Affected by Acid Mine Drainage.

    PubMed

    Desoeuvre, Angélique; Casiot, Corinne; Héry, Marina

    2016-04-01

    Some microorganisms have the capacity to interact with arsenic through resistance or metabolic processes. Their activities contribute to the fate of arsenic in contaminated ecosystems. To investigate the genetic potential involved in these interactions in a zone of confluence between a pristine river and an arsenic-rich acid mine drainage, we explored the diversity of marker genes for arsenic resistance (arsB, acr3.1, acr3.2), methylation (arsM), and respiration (arrA) in waters characterized by contrasted concentrations of metallic elements (including arsenic) and pH. While arsB-carrying bacteria were representative of pristine waters, Acr3 proteins may confer to generalist bacteria the capacity to cope with an increase of contamination. arsM showed an unexpected wide distribution, suggesting biomethylation may impact arsenic fate in contaminated aquatic ecosystems. arrA gene survey suggested that only specialist microorganisms (adapted to moderately or extremely contaminated environments) have the capacity to respire arsenate. Their distribution, modulated by water chemistry, attested the specialist nature of the arsenate respirers. This is the first report of the impact of an acid mine drainage on the diversity and distribution of arsenic (As)-related genes in river waters. The fate of arsenic in this ecosystem is probably under the influence of the abundance and activity of specific microbial populations involved in different As biotransformations.

  6. DIETARY ARSENIC EXPOSURE ASSESSMENT USING ENZYMATIC BASED EXTRACTION CONDITIONS AND DETECTION OF URINARY THIO-ARSENICALS AS METABOLITES OF EXPOSURE - MCEARD2

    EPA Science Inventory

    Inorganic arsenic is classified as a carcinogen and has been linked to lung and bladder cancer as well as other non-cancerous health effects. Because of these health effects the U.S. EPA has set a Maximum Contaminant Level (MCL) at 10ppb based on a linear extrapolation of risk an...

  7. DIETARY ARSENIC EXPOSURE ASSESSMENT USING ENZYMATIC BASED EXTRACTION CONDITIONS AND DETECTION OF URINARY THIO-ARSENICALS AS METABOLITES OF EXPOSURE - MCEARD2

    EPA Science Inventory

    Inorganic arsenic is classified as a carcinogen and has been linked to lung and bladder cancer as well as other non-cancerous health effects. Because of these health effects the U.S. EPA has set a Maximum Contaminant Level (MCL) at 10ppb based on a linear extrapolation of risk an...

  8. Urinary excretion of platinum, arsenic and selenium of cancer patients from the Antofagasta region in Chile treated with platinum-based drugs

    PubMed Central

    2012-01-01

    Background Arsenic exposure increases the risk of non-cancerous and cancerous diseases. In the Antofagasta region in Chile, an established relationship exists between arsenic exposure and the risk of cancer of the bladder, lung and skin. Platinum-based drugs are first-line treatments, and many works recognise selenium as a cancer-fighting nutrient. We characterised the short-term urinary excretion amounts of arsenic, selenium and platinum in 24-h urine samples from patients with lung cancer and those with cancer other than lung treated with cisplatin or/and carboplatin. As - Se - Pt inter-element relationships were also investigated. Results The amounts of platinum excreted in urine were not significantly different between patients with lung cancer and those with other cancers treated with cisplatin, despite the significant variation in platinum amounts supplied from platinum-based drugs. In general, the analytical amounts of excreted selenium were greater than those for arsenic, which could imply that platinum favours the excretion of selenium. For other types of cancers treated with drugs without platinum, excretion of selenium was also greater than that of arsenic, suggesting an antagonist selenium-anti-cancer drug relationship. Conclusions Regards the baseline status of patients, the analytical amounts of excreted Se is greater than those for As, particularly, for cisplatin chemotherapy. This finding could imply that for over the As displacement Pt favours the excretion of Se. The analytical amounts of excreted Se were greater than those for As, either with and without Pt-containing drugs, suggesting an antagonist Se-anti-cancer drug relationship. However, it seemed that differences existed between As - Se - Pt inter-element associations in patients treated for lung cancer in comparison with those treated for cancer other than lung. Therefore, knowledge obtained in this work, can contribute to understanding the arsenic cancer mechanism and the As - Se - Pt

  9. Biological monitoring of arsenic exposure of gallium arsenide- and inorganic arsenic-exposed workers by determination of inorganic arsenic and its metabolites in urine and hair

    SciTech Connect

    Yamauchi, H.; Takahashi, K.; Mashiko, M.; Yamamura, Y. )

    1989-11-01

    In an attempt to establish a method for biological monitoring of inorganic arsenic exposure, the chemical species of arsenic were measured in the urine and hair of gallium arsenide (GaAs) plant and copper smelter workers. Determination of urinary inorganic arsenic concentration proved sensitive enough to monitor the low-level inorganic arsenic exposure of the GaAs plant workers. The urinary inorganic arsenic concentration in the copper smelter workers was far higher than that of a control group and was associated with high urinary concentrations of the inorganic arsenic metabolites, methylarsonic acid (MAA) and dimethylarsinic acid (DMAA). The results established a method for exposure level-dependent biological monitoring of inorganic arsenic exposure. Low-level exposures could be monitored only by determining urinary inorganic arsenic concentration. High-level exposures clearly produced an increased urinary inorganic arsenic concentration, with an increased sum of urinary concentrations of inorganic arsenic and its metabolites (inorganic arsenic + MAA + DMAA). The determination of urinary arsenobetaine proved to determine specifically the seafood-derived arsenic, allowing this arsenic to be distinguished clearly from the arsenic from occupational exposure. Monitoring arsenic exposure by determining the arsenic in the hair appeared to be of value only when used for environmental monitoring of arsenic contamination rather than for biological monitoring.

  10. Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population.

    PubMed

    Andrew, Angeline S; Jewell, David A; Mason, Rebecca A; Whitfield, Michael L; Moore, Jason H; Karagas, Margaret R

    2008-04-01

    Arsenic exposure impairs development and can lead to cancer, cardiovascular disease, and diabetes. The mechanism underlying these effects remains unknown. Primarily because of geologic sources of contamination, drinking-water arsenic levels are above the current recommended maximum contaminant level of 10 microg/L in the northeastern, western, and north central regions of the United States. We investigated the effects of arsenic exposure, defined by internal biomarkers at levels relevant to the United States and similarly exposed populations, on gene expression. We conducted separate Affymetrix microarray-based genomewide analyses of expression patterns. Peripheral blood lymphocyte samples from 21 controls interviewed (1999-2002) as part of a case-control study in New Hampshire were selected based on high- versus low-level arsenic exposure levels. The biologic functions of the transcripts that showed statistically significant abundance differences between high- and low-arsenic exposure groups included an overrepresentation of genes involved in defense response, immune function, cell growth, apoptosis, regulation of cell cycle, T-cell receptor signaling pathway, and diabetes. Notably, the high-arsenic exposure group exhibited higher levels of several killer cell immunoglobulin-like receptors that inhibit natural killer cell activity. These findings define biologic changes that occur with chronic arsenic exposure in humans and provide leads and potential targets for understanding and monitoring the pathogenesis of arsenic-induced diseases.

  11. Drinking-Water Arsenic Exposure Modulates Gene Expression in Human Lymphocytes from a U.S. Population

    PubMed Central

    Andrew, Angeline S.; Jewell, David A.; Mason, Rebecca A.; Whitfield, Michael L.; Moore, Jason H.; Karagas, Margaret R.

    2008-01-01

    Background Arsenic exposure impairs development and can lead to cancer, cardiovascular disease, and diabetes. The mechanism underlying these effects remains unknown. Primarily because of geologic sources of contamination, drinking-water arsenic levels are above the current recommended maximum contaminant level of 10 μg/L in the northeastern, western, and north central regions of the United States. Objectives We investigated the effects of arsenic exposure, defined by internal biomarkers at levels relevant to the United States and similarly exposed populations, on gene expression. Methods We conducted separate Affymetrix microarray-based genomewide analyses of expression patterns. Peripheral blood lymphocyte samples from 21 controls interviewed (1999–2002) as part of a case–control study in New Hampshire were selected based on high- versus low-level arsenic exposure levels. Results The biologic functions of the transcripts that showed statistically significant abundance differences between high- and low-arsenic exposure groups included an overrepresentation of genes involved in defense response, immune function, cell growth, apoptosis, regulation of cell cycle, T-cell receptor signaling pathway, and diabetes. Notably, the high-arsenic exposure group exhibited higher levels of several killer cell immunoglobulin-like receptors that inhibit natural killer cell activity. Conclusions These findings define biologic changes that occur with chronic arsenic exposure in humans and provide leads and potential targets for understanding and monitoring the pathogenesis of arsenic-induced diseases. PMID:18414638

  12. Characterization of the ars gene cluster from extremely arsenic-resistant Microbacterium sp. strain A33.

    PubMed

    Achour-Rokbani, Asma; Cordi, Audrey; Poupin, Pascal; Bauda, Pascale; Billard, Patrick

    2010-02-01

    The arsenic resistance gene cluster of Microbacterium sp. A33 contains a novel pair of genes (arsTX) encoding a thioredoxin system that are cotranscribed with an unusual arsRC2 fusion gene, ACR3, and arsC1 in an operon divergent from arsC3. The whole ars gene cluster is required to complement an Escherichia coli ars mutant. ArsRC2 negatively regulates the expression of the pentacistronic operon. ArsC1 and ArsC3 are related to thioredoxin-dependent arsenate reductases; however, ArsC3 lacks the two distal catalytic cysteine residues of this class of enzymes.

  13. A genomic island harboring arsenic resistance genes varies in gene content and is located in different chromosomal loci among Listeria monocytogenes strains

    USDA-ARS?s Scientific Manuscript database

    In the foodborne pathogen Listeria monocytogenes, arsenic resistance has been often encountered among certain clonal groups of serotype 4b and was earlier found to be strongly associated with an arsenic resistance gene cluster within a 35 kb chromosomal region, designated Listeria genomic island 2 (...

  14. Arsenic in drinking water and urinary tract cancers: a systematic review of 30 years of epidemiological evidence

    PubMed Central

    2014-01-01

    Background Arsenic in drinking water is a public health issue affecting hundreds of millions of people worldwide. This review summarizes 30 years of epidemiological studies on arsenic exposure in drinking water and the risk of bladder or kidney cancer, quantifying these risks using a meta-analytical framework. Methods Forty studies met the selection criteria. Seventeen provided point estimates of arsenic concentrations in drinking water and were used in a meta-analysis of bladder cancer incidence (7 studies) and mortality (10 studies) and kidney cancer mortality (2 studies). Risk estimates for incidence and mortality were analyzed separately using Generalized Linear Models. Predicted risks for bladder cancer incidence were estimated at 10, 50 and 150 μg/L arsenic in drinking water. Bootstrap randomizations were used to assess robustness of effect size. Results Twenty-eight studies observed an association between arsenic in drinking water and bladder cancer. Ten studies showed an association with kidney cancer, although of lower magnitude than that for bladder cancer. The meta-analyses showed the predicted risks for bladder cancer incidence were 2.7 [1.2–4.1]; 4.2 [2.1–6.3] and; 5.8 [2.9–8.7] for drinking water arsenic levels of 10, 50, and 150 μg/L, respectively. Bootstrapped randomizations confirmed this increased risk, but, lowering the effect size to 1.4 [0.35–4.0], 2.3 [0.59–6.4], and 3.1 [0.80–8.9]. The latter suggests that with exposures to 50 μg/L, there was an 83% probability for elevated incidence of bladder cancer; and a 74% probability for elevated mortality. For both bladder and kidney cancers, mortality rates at 150 ug/L were about 30% greater than those at 10 μg/L. Conclusion Arsenic in drinking water is associated with an increased risk of bladder and kidney cancers, although at lower levels (<150 μg/L), there is uncertainty due to the increased likelihood of exposure misclassification at the lower end of the exposure curve. Meta

  15. Toenail arsenic concentrations, GSTT1 gene polymorphisms, and arsenic exposure from drinking water.

    PubMed

    Kile, Molly L; Houseman, E Andres; Rodrigues, Ema; Smith, Thomas J; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Su, Li; Christiani, David C

    2005-10-01

    Toenail arsenic (As) concentrations were evaluated as a biomarker of inorganic As (As(in)) exposure in a population residing in an As-endemic region of Bangladesh. Drinking water and toenail samples were collected from 48 families (n = 223) every 3 months for 2 years and analyzed for As using inductively coupled plasma-mass spectrometry. Drinking water collected 3, 6, and 9 months before each toenail sample collection was combined into a weighted lagged exposure variable. The contribution of each water sample to the measured toenail As concentration was estimated using maximum likelihood that accounted for fluctuations in drinking water exposure and toenail growth. The best model attributed 69%, 14%, and 17% of the toenail As content to drinking water exposures that occurred 3, 6, and 9 months before toenail collection [95% confidence intervals (95% CI), 0.46-0.97, 0.00-0.31, and 0.03-0.35, respectively]. Generalized additive mixed models using penalized regression splines were employed to model the data. Below a drinking water concentration of 2 mug As/L, no relationship between drinking water As and toenail As concentrations was observed. Above this concentration, toenail As content increased in a dose-dependent fashion as drinking water As increased. Age was a significant effect modifier of drinking water As exposure on toenail As (beta = 0.01; 95% CI, 0.002-0.02). Individuals possessing GSTT1-null genotypes had significantly more As in their toenails in contrast to GSTT1 wild-type individuals (beta = 0.11; 95% CI, 0.06-0.2). Therefore, it seems that GSTT1 modifies the relationship between As(in) exposure and toenail As(in) content.

  16. PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC

    EPA Science Inventory

    PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC.

    Arsenic is a human carcinogen in skin, lung, liver, urinary bladder and kidney. In contrast,
    there is no accepted experimental animal model of inorganic arsenic carcinogenesis.
    Proposed mechanisms/modes of action for a...

  17. PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC

    EPA Science Inventory

    PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC.

    Arsenic is a human carcinogen in skin, lung, liver, urinary bladder and kidney. In contrast,
    there is no accepted experimental animal model of inorganic arsenic carcinogenesis.
    Proposed mechanisms/modes of action for a...

  18. Evaluation of a GFP Report Gene Construct for Environmental Arsenic Detection

    SciTech Connect

    Roberto, F.F.; Barnes, J.M.; Bruhn, D.F.

    2002-03-28

    Detection of arsenic and other heavy metal contaminants in the environment is critical to ensuring safe drinking water and effective cleanup of historic activities that have led to widespread contamination of soil and groundwater. Biosensors have the potential to significantly reduce the costs associated with site characterization and long term environmental monitoring. By exploiting the highly selective and sensitive natural mechanisms by which bacteria and other living organisms respond to heavy metals, and fusing transcriptionally active components of these mechanisms to reporter genes, such as B-galactosidase, bacterial luciferase (lux), or green fluorescent protein (GFP) from marine jellyfish, it is possible to produce inexpensive, yet effective biosensors. This article describes the response to submicrogram quantities of arsenite and arsenate of a whole cell arsenic biosensor utilizing a GFP reporter gene.

  19. Changes in rat urinary porphyrin profiles predict the magnitude of the neurotoxic effects induced by a mixture of lead, arsenic and manganese.

    PubMed

    Andrade, Vanda; Mateus, M Luísa; Batoréu, M Camila; Aschner, Michael; Marreilha dos Santos, A P

    2014-12-01

    The neurotoxic metals lead (Pb), arsenic (As) and manganese (Mn) are ubiquitous contaminants occurring as mixtures in environmental settings. The three metals may interfere with enzymes of the heme bioshyntetic pathway, leading to excessive porphyrin accumulation, which per se may trigger neurotoxicity. Given the multi-mechanisms associated with metal toxicity, we posited that a single biomarker is unlikely to predict neurotoxicity that is induced by a mixture of metals. Our objective was to evaluate the ability of a combination of urinary porphyrins to predict the magnitude of motor activity impairment induced by a mixture of Pb/As/Mn. Five groups of Wistar rats were treated for 8 days with Pb (5mg/kg), As (60 mg/L) or Mn (10mg/kg), and the 3-metal mixture (same doses as the single metals) along with a control group. Motor activity was evaluated after the administration of the last dose and 24-hour (h) urine was also collected after the treatments. Porphyrin profiles were determined both in the urine and brain. Rats treated with the metal-mixture showed a significant decrease in motor parameters compared with controls and the single metal-treated groups. Both brain and urinary porphyrin levels, when combined and analyzed by multiple linear regressions, were predictable of motor activity (p<0.05). The magnitude of change in urinary porphyrin profiles was consistent with the greatest impairments in motor activity as determined by receiver operating characteristic (ROC) curves, with a sensitivity of 88% and a specificity of 96%. Our work strongly suggests that the use of a linear combination of urinary prophyrin levels accurately predicts the magnitude of motor impairments in rats that is induced by a mixture of Pb, As and Mn. Copyright © 2014. Published by Elsevier B.V.

  20. METHYLATED TRIVALENT ARSENICALS AS CANDIDATE ULTIMATE GENOTOXIC FORMS OF ARSENIC: INDUCTION OF CHROMOSOMAL MUTATIONS BUT NOT GENE MUTATIONS

    EPA Science Inventory

    ABSTRACT
    Arsenic is a prevalent human carcinogen whose mutagenicity has not been characterized fully. Exposure to either form of inorganic arsenic, AsIII or AsV, can result in the formation of at least four organic metabolites: monomethylarsonic acid, monomethylarsonous aci...

  1. Specific histone modification responds to arsenic-induced oxidative stress.

    PubMed

    Ma, Lu; Li, Jun; Zhan, Zhengbao; Chen, Liping; Li, Daochuan; Bai, Qing; Gao, Chen; Li, Jie; Zeng, Xiaowen; He, Zhini; Wang, Shan; Xiao, Yongmei; Chen, Wen; Zhang, Aihua

    2016-07-01

    To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P<0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: β=0.16; P=0.042, H3K18ac: β=-0.24; P=0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO2 treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans.

    PubMed

    Vivante, Asaf; Kohl, Stefan; Hwang, Daw-Yang; Dworschak, Gabriel C; Hildebrandt, Friedhelm

    2014-04-01

    Congenital anomalies of the kidney and urinary tract (CAKUT) cover a wide range of structural malformations that result from defects in the morphogenesis of the kidney and/or urinary tract. These anomalies account for about 40-50 % of children with chronic kidney disease worldwide. Knowledge from genetically modified mouse models suggests that single gene mutations in renal developmental genes may lead to CAKUT in humans. However, until recently, only a handful of CAKUT-causing genes were reported, most of them in familial syndromic cases. Recent findings suggest that CAKUT may arise from mutations in a multitude of different single gene causes. We focus here on single-gene causes of CAKUT and their developmental origin. Currently, more than 20 monogenic CAKUT-causing genes have been identified. High-throughput sequencing techniques make it likely that additional CAKUT-causing genes will be identified in the near future.

  3. Coregulated genes link sulfide:quinone oxidoreductase and arsenic metabolism in Synechocystis sp. strain PCC6803.

    PubMed

    Nagy, Csaba I; Vass, Imre; Rákhely, Gábor; Vass, István Zoltán; Tóth, András; Duzs, Agnes; Peca, Loredana; Kruk, Jerzy; Kós, Péter B

    2014-10-01

    Although the biogeochemistry of the two environmentally hazardous compounds arsenic and sulfide has been extensively investigated, the biological interference of these two toxic but potentially energy-rich compounds has only been hypothesized and indirectly proven. Here we provide direct evidence for the first time that in the photosynthetic model organism Synechocystis sp. strain PCC6803 the two metabolic pathways are linked by coregulated genes that are involved in arsenic transport, sulfide oxidation, and probably in sulfide-based alternative photosynthesis. Although Synechocystis sp. strain PCC6803 is an obligate photoautotrophic cyanobacterium that grows via oxygenic photosynthesis, we discovered that specific genes are activated in the presence of sulfide or arsenite to exploit the energy potentials of these chemicals. These genes form an operon that we termed suoRSCT, located on a transposable element of type IS4 on the plasmid pSYSM of the cyanobacterium. suoS (sll5036) encodes a light-dependent, type I sulfide:quinone oxidoreductase. The suoR (sll5035) gene downstream of suoS encodes a regulatory protein that belongs to the ArsR-type repressors that are normally involved in arsenic resistance. We found that this repressor has dual specificity, resulting in 200-fold induction of the operon upon either arsenite or sulfide exposure. The suoT gene encodes a transmembrane protein similar to chromate transporters but in fact functioning as an arsenite importer at permissive concentrations. We propose that the proteins encoded by the suoRSCT operon might have played an important role under anaerobic, reducing conditions on primordial Earth and that the operon was acquired by the cyanobacterium via horizontal gene transfer. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  4. Dietary arsenic exposure with low level of arsenic in drinking water and biomarker: a study in West Bengal.

    PubMed

    Mazumder, Debendra Nath Guha; Deb, Debasree; Biswas, Anirban; Saha, Chandan; Nandy, Ashoke; Das, Arabinda; Ghose, Aloke; Bhattacharya, Kallol; Mazumdar, Kunal Kanti

    2014-01-01

    The authors investigated association of arsenic intake through water and diet and arsenic level in urine in people living in arsenic endemic region in West Bengal supplied with arsenic-safe water (<50 μg L(-1)). Out of 94 (Group-1A) study participants using water with arsenic level <50 μg L(-1), 72 participants (Group-1B) were taking water with arsenic level <10 μg L(-1). Multiple regressions analysis conducted on the Group-1A participants showed that daily arsenic dose from water and diet were found to be significantly positively associated with urinary arsenic level. However, daily arsenic dose from diet was found to be significantly positively associated with urinary arsenic level in Group-1B participants only, but no significant association was found with arsenic dose from water in this group. In a separate analysis, out of 68 participants with arsenic exposure through diet only, urinary arsenic concentration was found to correlate positively (r = 0.573) with dietary arsenic in 45 participants with skin lesion while this correlation was insignificant (r = 0.007) in 23 participants without skin lesion. Our study suggested that dietary arsenic intake was a potential pathway of arsenic exposure even where arsenic intake through water was reduced significantly in arsenic endemic region in West Bengal. Observation of variation in urinary arsenic excretion in arsenic-exposed subjects with and without skin lesion needed further study.

  5. Nutrients in one-carbon metabolism and urinary arsenic methylation in the National Health and Nutrition Examination Survey (NHANES) 2003-2004.

    PubMed

    Kurzius-Spencer, Margaret; da Silva, Vanessa; Thomson, Cynthia A; Hartz, Vern; Hsu, Chiu-Hsieh; Burgess, Jefferey L; O'Rourke, Mary Kay; Harris, Robin B

    2017-12-31

    Exposure to inorganic arsenic (inAs), a potent toxicant, occurs primarily through ingestion of food and water. The efficiency with which it is methylated to mono and dimethyl arsenicals (MMA and DMA) affects toxicity. Folate, vitamins B12 and B6 are required for 1C metabolism, and studies have found that higher levels of these nutrients increase methylation capacity and are associated with protection against adverse health effects from inAs, especially in undernourished populations. Our aim was to determine whether 1C-related nutrients are associated with greater inAs methylation capacity in a general population sample with overall adequate nutrition and low levels of As exposure. Univariate and multivariable regression models were used to evaluate the relationship of dietary and blood nutrients to urinary As methylation in the National Health and Nutrition Examination Survey (NHANES) 2003-2004. Outcome variables were the percent of the sum of inAs and methylated As species (inAs+MMA+DMA) excreted as inAs, MMA, and DMA, and the ratio of MMA:DMA. In univariate models, dietary folate, vitamin B6 and protein intake were associated with lower urinary inAs% and greater DMA% in adults (≥18years), with similar trends in children (6-18). In adjusted models, vitamin B6 intake (p=0.011) and RBC folate (p=0.036) were associated with lower inAs%, while dietary vitamin B12 was associated with higher inAs% (p=0.002) and lower DMA% (p=0.030). Total plasma homocysteine was associated with higher MMA% (p=0.004) and lower DMA% (p=0.003), but not with inAs%; other blood nutrients showed no association with urinary As. Although effect size is small, these findings suggest that 1C nutrients can influence inAs methylation and potentially play an indirect role in reducing toxicity in a general population sample. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Arsenic Exposure through Drinking Water Is Associated with Longer Telomeres in Peripheral Blood

    PubMed Central

    2012-01-01

    Inorganic arsenic is a strong carcinogen, possibly by interaction with the telomere length. The aim of the study was to evaluate how chronic arsenic exposure from drinking water as well as the arsenic metabolism efficiency affect the individual telomere length and the expression of telomere-related genes. Two hundred two women with a wide range in exposure to arsenic via drinking water (3.5–200 μg/L) were recruited. Concentrations of arsenic metabolites in urine [inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA)] were measured. The relative telomere length in blood was measured by quantitative real-time polymerase chain reaction. Genotyping (N = 172) for eight SNPs in AS3MT and gene expression of telomere-related genes (in blood; N = 90) were performed. Urinary arsenic (sum of metabolites) was positively associated with telomere length (β = 0.65 × 10–4, 95% CI = 0.031 × 10–4–1.3 × 10–4, adjusted for age and BMI). Individuals with above median fractions of iAs and MMA showed significantly longer telomeres by increasing urinary arsenic (β = 1.0 × 10–4, 95% CI = 0.21 × 10–4–1.8 × 10–4 at high % iAs; β = 0.88 × 10–4 95% CI = 0.12 × 10–4–1.6 × 10–4 at high % MMA) than those below the median (p = 0.80 and 0.44, respectively). Similarly, carriers of the slow and more toxic metabolizing AS3MT haplotype showed stronger positive associations between arsenic exposure and telomere length, as compared to noncarriers (interaction urinary arsenic and haplotype p = 0.025). Urinary arsenic was positively correlated with the expression of telomerase reverse transcriptase (TERT, Spearman r = 0.22, p = 0.037), but no association was found between TERT expression and telomere length. Arsenic in drinking water influences the telomere length, and this may be a mechanism for its carcinogenicity. A faster and less toxic arsenic metabolism diminishes arsenic-related telomere elongation. PMID:22917110

  7. Arsenic exposure through drinking water is associated with longer telomeres in peripheral blood.

    PubMed

    Li, Huiqi; Engström, Karin; Vahter, Marie; Broberg, Karin

    2012-11-19

    Inorganic arsenic is a strong carcinogen, possibly by interaction with the telomere length. The aim of the study was to evaluate how chronic arsenic exposure from drinking water as well as the arsenic metabolism efficiency affect the individual telomere length and the expression of telomere-related genes. Two hundred two women with a wide range in exposure to arsenic via drinking water (3.5-200 μg/L) were recruited. Concentrations of arsenic metabolites in urine [inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA)] were measured. The relative telomere length in blood was measured by quantitative real-time polymerase chain reaction. Genotyping (N = 172) for eight SNPs in AS3MT and gene expression of telomere-related genes (in blood; N = 90) were performed. Urinary arsenic (sum of metabolites) was positively associated with telomere length (β = 0.65 × 10(-4), 95% CI = 0.031 × 10(-4)-1.3 × 10(-4), adjusted for age and BMI). Individuals with above median fractions of iAs and MMA showed significantly longer telomeres by increasing urinary arsenic (β = 1.0 × 10(-4), 95% CI = 0.21 × 10(-4)-1.8 × 10(-4) at high % iAs; β = 0.88 × 10(-4) 95% CI = 0.12 × 10(-4)-1.6 × 10(-4) at high % MMA) than those below the median (p = 0.80 and 0.44, respectively). Similarly, carriers of the slow and more toxic metabolizing AS3MT haplotype showed stronger positive associations between arsenic exposure and telomere length, as compared to noncarriers (interaction urinary arsenic and haplotype p = 0.025). Urinary arsenic was positively correlated with the expression of telomerase reverse transcriptase (TERT, Spearman r = 0.22, p = 0.037), but no association was found between TERT expression and telomere length. Arsenic in drinking water influences the telomere length, and this may be a mechanism for its carcinogenicity. A faster and less toxic arsenic metabolism diminishes arsenic-related telomere elongation.

  8. Chronic arsenic toxicity: studies in West Bengal, India.

    PubMed

    Guha Mazumder, Debendranath; Dasgupta, U B

    2011-09-01

    Chronic arsenic toxicity (arsenicosis) as a result of drinking arsenic-contaminated groundwater is a major environmental health hazard throughout the world, including India. A lot of research on health effects, including genotoxic effect of chronic arsenic toxicity in humans, have been carried out in West Bengal during the last 2 decades. A review of literature including information available from West Bengal has been made to characterize the problem. Scientific journals, monographs, and proceedings of conferences with regard to human health effects, including genotoxicity, of chronic arsenic toxicity have been reviewed. Pigmentation and keratosis are the specific skin diseases characteristic of chronic arsenic toxicity. However, in West Bengal, it was found to produce various systemic manifestations, such as chronic lung disease, characterized by chronic bronchitis, chronic obstructive and/or restrictive pulmonary disease, and bronchiectasis; liver diseases, such as non cirrhotic portal fibrosis; polyneuropathy; peripheral vascular disease; hypertension; nonpitting edema of feet/hands; conjunctival congestion; weakness; and anemia. High concentrations of arsenic, greater than or equal to 200 μg/L, during pregnancy were found to be associated with a sixfold increased risk for stillbirth. Cancers of skin, lung, and urinary bladder are the important cancers associated with this toxicity. Of the various genotoxic effects of arsenic in humans, chromosomal aberration and increased frequency of micronuclei in different cell types have been found to be significant. Various probable mechanisms have been incriminated to cause DNA damage because of chronic arsenic toxicity. The results of the study in West Bengal suggest that deficiency in DNA repair capacity, perturbation of methylation of promoter region of p53 and p16 genes, and genomic methylation alteration may be involved in arsenic-induced disease manifestation in humans. P53 polymorphism has been found to be

  9. Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS)

    PubMed Central

    Balakrishnan, Poojitha; Vaidya, Dhananjay; Franceschini, Nora; Voruganti, V. Saroja; Gribble, Matthew O.; Haack, Karin; Laston, Sandra; Umans, Jason G.; Francesconi, Kevin A.; Goessler, Walter; North, Kari E.; Lee, Elisa; Yracheta, Joseph; Best, Lyle G.; MacCluer, Jean W.; Kent, Jack; Cole, Shelley A.; Navas-Acien, Ana

    2016-01-01

    Background: Metabolism of inorganic arsenic (iAs) is subject to inter-individual variability, which is explained partly by genetic determinants. Objectives: We investigated the association of genetic variants with arsenic species and principal components of arsenic species in the Strong Heart Family Study (SHFS). Methods: We examined variants previously associated with cardiometabolic traits (~ 200,000 from Illumina Cardio MetaboChip) or arsenic metabolism and toxicity (670) among 2,428 American Indian participants in the SHFS. Urine arsenic species were measured by high performance liquid chromatography–inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and percent arsenic species [iAs, monomethylarsonate (MMA), and dimethylarsinate (DMA), divided by their sum × 100] were logit transformed. We created two orthogonal principal components that summarized iAs, MMA, and DMA and were also phenotypes for genetic analyses. Linear regression was performed for each phenotype, dependent on allele dosage of the variant. Models accounted for familial relatedness and were adjusted for age, sex, total arsenic levels, and population stratification. Single nucleotide polymorphism (SNP) associations were stratified by study site and were meta-analyzed. Bonferroni correction was used to account for multiple testing. Results: Variants at 10q24 were statistically significant for all percent arsenic species and principal components of arsenic species. The index SNP for iAs%, MMA%, and DMA% (rs12768205) and for the principal components (rs3740394, rs3740393) were located near AS3MT, whose gene product catalyzes methylation of iAs to MMA and DMA. Among the candidate arsenic variant associations, functional SNPs in AS3MT and 10q24 were most significant (p < 9.33 × 10–5). Conclusions: This hypothesis-driven association study supports the role of common variants in arsenic metabolism, particularly AS3MT and 10q24. Citation: Balakrishnan P, Vaidya D, Franceschini N, Voruganti

  10. Low dose of arsenic trioxide triggers oxidative stress in zebrafish brain: expression of antioxidant genes.

    PubMed

    Sarkar, Shuvasree; Mukherjee, Sandip; Chattopadhyay, Ansuman; Bhattacharya, Shelley

    2014-09-01

    Occurrence of arsenic in the aquatic environment of West Bengal (India), Bangladesh and other countries are of immediate environmental concern. In the present study, zebrafish (Danio rerio) was used as a model to investigate oxidative stress related enzyme activities and expression of antioxidant genes in the brain to 50µg/L arsenic trioxide for 90 days. In treated fish, generation of reactive oxygen species (ROS), malondialdehyde (MDA) and conjugated diene (CD) showed a triphasic response attaining a peak at the end of the exposure. In addition, a gradual increase in GSH level was noted until 60 days and at 90 days, a sudden fall was recorded which heightened arsenic toxicity. However, GSH level does not correlate well with the glutathione reductase (GR) activity. Generation of ROS in zebrafish brain due to As2O3 exposure was further evidenced by significant alteration of glutathione peroxidase (GPx) and catalase (CAT) activity, which converts H2O2 to water and helps in detoxication. Moreover, enhanced mRNA level of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in As2O3 exposed zebrafish indicates a protective role of Nrf2. kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, inversely correlates with the mRNA expression of Nrf2. As2O3 induced toxicity was also validated by the alteration in NRF2 and NRF2 dependent expression of proteins such as heme oxygenase1 (HO1) and NAD(P)H dehydrogenase quinone1 (NQO1). The mRNA expression of glutathione peroxidase (Gpx1), catalase (Cat), manganese superoxide dismutase (Mn-Sod), copper/zinc superoxide dismutase (Cu/Zn Sod) and cytochrome c oxidase1 (Cox1) were also up regulated. The expression of uncoupling protein 2 (Ucp2), an important mitochondrial enzyme was also subdued in arsenic exposed zebrafish. The oxidative stress induced by arsenic also cause reduced mRNA expression of B-cell lymphoma 2 (Bcl2) present in the inner mitochondrial membrane and thereby indicating onset of apoptosis in

  11. The Chromosomal Arsenic Resistance Genes of Thiobacillus ferrooxidans Have an Unusual Arrangement and Confer Increased Arsenic and Antimony Resistance to Escherichia coli

    PubMed Central

    Butcher, Bronwyn G.; Deane, Shelly M.; Rawlings, Douglas E.

    2000-01-01

    The chromosomal arsenic resistance genes of the acidophilic, chemolithoautotrophic, biomining bacterium Thiobacillus ferrooxidans were cloned and sequenced. Homologues of four arsenic resistance genes, arsB, arsC, arsH, and a putative arsR gene, were identified. The T. ferrooxidans arsB (arsenite export) and arsC (arsenate reductase) gene products were functional when they were cloned in an Escherichia coli ars deletion mutant and conferred increased resistance to arsenite, arsenate, and antimony. Therefore, despite the fact that the ars genes originated from an obligately acidophilic bacterium, they were functional in E. coli. Although T. ferrooxidans is gram negative, its ArsC was more closely related to the ArsC molecules of gram-positive bacteria. Furthermore, a functional trxA (thioredoxin) gene was required for ArsC-mediated arsenate resistance in E. coli; this finding confirmed the gram-positive ArsC-like status of this resistance and indicated that the division of ArsC molecules based on Gram staining results is artificial. Although arsH was expressed in an E. coli-derived in vitro transcription-translation system, ArsH was not required for and did not enhance arsenic resistance in E. coli. The T. ferrooxidans ars genes were arranged in an unusual manner, and the putative arsR and arsC genes and the arsBH genes were translated in opposite directions. This divergent orientation was conserved in the four T. ferrooxidans strains investigated. PMID:10788346

  12. Identifying arsenic trioxide (ATO) functions in leukemia cells by using time series gene expression profiles.

    PubMed

    Yang, Hong; Lin, Shan; Cui, Jingru

    2014-02-10

    Arsenic trioxide (ATO) is presently the most active single agent in the treatment of acute promyelocytic leukemia (APL). In order to explore the molecular mechanism of ATO in leukemia cells with time series, we adopted bioinformatics strategy to analyze expression changing patterns and changes in transcription regulation modules of time series genes filtered from Gene Expression Omnibus database (GSE24946). We totally screened out 1847 time series genes for subsequent analysis. The KEGG (Kyoto encyclopedia of genes and genomes) pathways enrichment analysis of these genes showed that oxidative phosphorylation and ribosome were the top 2 significantly enriched pathways. STEM software was employed to compare changing patterns of gene expression with assigned 50 expression patterns. We screened out 7 significantly enriched patterns and 4 tendency charts of time series genes. The result of Gene Ontology showed that functions of times series genes mainly distributed in profiles 41, 40, 39 and 38. Seven genes with positive regulation of cell adhesion function were enriched in profile 40, and presented the same first increased model then decreased model as profile 40. The transcription module analysis showed that they mainly involved in oxidative phosphorylation pathway and ribosome pathway. Overall, our data summarized the gene expression changes in ATO treated K562-r cell lines with time and suggested that time series genes mainly regulated cell adhesive. Furthermore, our result may provide theoretical basis of molecular biology in treating acute promyelocytic leukemia. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Arsenic metabolites affect expression of the neurofilament and tau genes: an in-vitro study into the mechanism of arsenic neurotoxicity.

    PubMed

    Vahidnia, A; van der Straaten, R J H M; Romijn, F; van Pelt, J; van der Voet, G B; de Wolff, F A

    2007-09-01

    Neurological studies indicate that the central (CNS) and peripheral nervous system (PNS) may be affected by arsenic (As). As-exposed patients show significantly lower nerve conduction velocities (NCVs) in their peripheral nerves in comparison to healthy subjects. As may play a role in the disruption of neuroskeletal integrity, but the mechanisms by which it exerts a toxic effect on the peripheral and central nervous system are still unclear. In the present study, we examined the neurotoxic effects of various arsenic metabolites (iAs(III), iAs(V), MMA(V) and DMA(V)) on two different cell lines derived from the peripheral (ST-8814) and central (SK-N-SH) nervous system. The effects of the arsenic metabolites were examined on the relative quantification levels of the cytoskeletal genes, neurofilament-light (NEFL), neurofilament-medium (NEF3), neurofilament-heavy (NEFH) and microtubule-associated protein-tau (MAPT), using real-time PCR. Our results show that iAs(III) and iAs(V) have no significant effects on either cell lines. On the other hand, MMA(V) and DMA(V) cause significant changes in expression levels of NEF3 and NEFL genes, while the expression level of the NEFH gene is significantly increased in both cell lines.

  14. Low-level arsenic exposure, AS3MT gene polymorphism and cardiovascular diseases in rural Texas counties.

    PubMed

    Gong, Gordon; O'Bryant, Sid E

    2012-02-01

    Most Americans living in rural areas use groundwater for drinking. Exposure to low-level (around the current U.S. standard 10 μg/L) arsenic in drinking water is associated with increased mortality of cardiovascular diseases. The current study was to determine if coronary heart disease, hypertension, and hyperlipidemia were associated with low-level arsenic exposure and AS3MT gene single nucleotide polymorphism (SNP) A35991G (rs10748835) in rural Texas. Subjects (156 men, 343 women, 40-96 years of age with a mean of 61) were residents from rural counties Cochran, Palmer, and Bailey, Texas. Groundwater arsenic concentration at each subject's home was estimated with ArcGIS inverse distance weighted interpolation based on the residential location's distances to surrounding wells with known water arsenic concentrations. The estimated groundwater arsenic concentration ranged from 2.2 to 15.3 (mean 6.2) μg/L in this cohort. Logistic regression analysis showed that coronary heart disease was associated with higher arsenic exposure (p<0.05) and with AS3MT genotype GG vs. AA (p<0.05) after adjustments for age, ethnicity, gender, education, smoking status, alcoholism, and anti-hyperlipidemia medication. Hypertension was associated with higher arsenic exposure, while hyperlipidemia was associated with genotype AG vs. AA of the AS3MT gene (p<0.05). Thus, coronary heart disease and its main risk factors were associated with low-level arsenic exposure, AS3MT polymorphism or both. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    PubMed Central

    Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

    2012-01-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a six month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. PMID:22521957

  16. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.

    PubMed

    Stueckle, Todd A; Lu, Yongju; Davis, Mary E; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B; Rojanasakul, Yon

    2012-06-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A 'pro-cancer' gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment.

  17. Assessing the microbial community and functional genes in a vertical soil profile with long-term arsenic contamination.

    PubMed

    Xiong, Jinbo; He, Zhili; Van Nostrand, Joy D; Luo, Guosheng; Tu, Shuxin; Zhou, Jizhong; Wang, Gejiao

    2012-01-01

    Arsenic (As) contamination in soil and groundwater has become a serious problem to public health. To examine how microbial communities and functional genes respond to long-term arsenic contamination in vertical soil profile, soil samples were collected from the surface to the depth of 4 m (with an interval of 1 m) after 16-year arsenic downward infiltration. Integrating BioLog and functional gene microarray (GeoChip 3.0) technologies, we showed that microbial metabolic potential and diversity substantially decreased, and community structure was markedly distinct along the depth. Variations in microbial community functional genes, including genes responsible for As resistance, carbon and nitrogen cycling, phosphorus utilization and cytochrome c oxidases were detected. In particular, changes in community structures and activities were correlated with the biogeochemical features along the vertical soil profile when using the rbcL and nifH genes as biomarkers, evident for a gradual transition from aerobic to anaerobic lifestyles. The C/N showed marginally significant correlations with arsenic resistance (p = 0.069) and carbon cycling genes (p = 0.073), and significant correlation with nitrogen fixation genes (p = 0.024). The combination of C/N, NO(3) (-) and P showed the highest correlation (r = 0.779, p = 0.062) with the microbial community structure. Contradict to our hypotheses, a long-term arsenic downward infiltration was not the primary factor, while the spatial isolation and nutrient availability were the key forces in shaping the community structure. This study provides new insights about the heterogeneity of microbial community metabolic potential and future biodiversity preservation for arsenic bioremediation management.

  18. Impact of early developmental arsenic exposure on promotor CpG-island methylation of genes involved in neuronal plasticity.

    PubMed

    Martínez, Liborio; Jiménez, Verónica; García-Sepúlveda, Christian; Ceballos, Fátima; Delgado, Juan Manuel; Niño-Moreno, Perla; Doniz, Lesly; Saavedra-Alanís, Víctor; Castillo, Claudia G; Santoyo, Martha E; González-Amaro, Roberto; Jiménez-Capdeville, María E

    2011-04-01

    Epigenetic mechanisms are crucial to regulate the expression of different genes required for neuronal plasticity. Neurotoxic substances such as arsenic, which induces cognitive deficits in exposed children before any other manifestation of toxicity, could interfere with the epigenetic modulation of neuronal gene expression required for learning and memory. This study assessed in Wistar rats the effects that developmental arsenic exposure had on DNA methylation patterns in hippocampus and frontal cortex. Animals were exposed to arsenic in drinking water (3 and 36ppm) from gestation until 4 months of age, and DNA methylation in brain cells was determined by flow cytometry, immunohistochemistry and methylation-specific polymerase chain reaction (PCR) of the promoter regions of reelin (RELN) and protein phosphatase 1 (PP1) at 1, 2, 3 and 4 months of age. Immunoreactivity to 5 methyl-cytosine was significantly higher in the cortex and hippocampus of exposed animals compared to controls at 1 month, and DNA hypomethylation was observed the following months in the cortex at high arsenic exposure. Furthermore, we observed a significant increase in the non-methylated form of PP1 gene promoter at 2 and 3 months of age, either in cortex or hippocampus. In order to determine whether this exposure level is associated with memory deficits, a behavioral test was performed at the same age points, revealing progressive and dose-dependent deficits of fear memory. Our results demonstrate alterations of the methylation pattern of genes involved in neuronal plasticity in an animal model of memory deficit associated with arsenic exposure.

  19. The polymorphisms of P53 codon 72 and MDM2 SNP309 and renal cell carcinoma risk in a low arsenic exposure area

    SciTech Connect

    Huang, Chao-Yuan; Su, Chien-Tien; Chu, Jan-Show; Huang, Shu-Pin; Pu, Yeong-Shiau; Yang, Hsiu-Yuan; Chung, Chi-Jung; Wu, Chia-Chang; Hsueh, Yu-Mei

    2011-12-15

    Our recent study demonstrated the increased risk of renal cell carcinoma (RCC) associated with high urinary total arsenic levels among people living in a low arsenic exposure area. Genomic instability is important in arsenic carcinogenesis. This study evaluated the relationship between the polymorphisms of p53, p21, and MDM2, which plays a role in gene stability, and the arsenic-related RCC risk. Here, we found that p53 Pro/Pro genotype and MDM2 SNP309 GG genotype significantly increased RCC risk compared to the p53 Arg/Arg genotype and MDM2 SNP309 TT genotype. RCC patients with the p53Arg/Arg genotype had a signicantly low percentage of inorganic arsenic, a low percentage of monomethylarsonic acid (MMA), and a high percentage of dimethylarsinic acid (DMA), which indicates efcient arsenic methylation capacity. Subjects with the p53 Arg/Pro + Pro/Pro genotype or MDM2 SNP309 TG + GG genotype, in conjunction with high urinary total arsenic ({>=} 14.02 {mu}g/L), had a signicantly higher RCC risk than those with the p53 Arg/Arg or MDM2 SNP309 TT genotypes and low urinary total arsenic. Taken together, this is the first study to show that a variant genotype of p53 Arg{sup 72}Pro or MDM2 SNP309 may modify the arsenic-related RCC risk even in a non-obvious arsenic exposure area. -- Highlights: Black-Right-Pointing-Pointer Subjects with p53 Pro/Pro or MDM2 GG genotype significantly increased RCC risk. Black-Right-Pointing-Pointer A significant multiplicative joint effect of p53 and p21 on RCC risk. Black-Right-Pointing-Pointer RCC patients with p53 Arg/Arg genotype had efficient arsenic methylation capacity. Black-Right-Pointing-Pointer Joint effect of p53 or MDM2 genotype and high urinary total arsenic on RCC risk.

  20. Higher urinary heavy metal, phthalate, and arsenic but not parabens concentrations in people with high blood pressure, U.S. NHANES, 2011-2012.

    PubMed

    Shiue, Ivy

    2014-06-05

    Link between environmental chemicals and human health has emerged but not been completely examined in risk factors. Therefore, it was aimed to study the relationships of different sets of urinary environmental chemical concentrations and risk of high blood pressure (BP) in a national, population-based study. Data were retrieved from United States National Health and Nutrition Examination Surveys, 2011-2012 including demographics, BP readings, and urinary environmental chemical concentrations. Analyses included chi-square test, t-test and survey-weighted logistic regression modeling. After full adjustment (adjusting for urinary creatinine, age, sex, ethnicity, and body mass index), urinary cesium (OR 1.56, 95%CI 1.11-2.20, P = 0.014), molybden (OR 1.46, 95%CI 1.06-2.01, P = 0.023), manganese (OR 1.42, 95%CI 1.09-1.86, P = 0.012), lead (OR 1.58, 95%CI 1.28-1.96, P < 0.001), tin (OR 1.44, 95%CI 1.25-1.66, P < 0.001), antimony (OR 1.39, 95%CI 1.10-1.77, P = 0.010), and tungsten (OR 1.49, 95%CI 1.25-1.77, P < 0.001) concentrations were observed to be associated with high BP. People with higher urinary mono-2-ethyl-5-carboxypentyl phthalate (OR 1.33, 95%CI 1.00-1.62, P = 0.006), mono-n-butyl phthalate (OR 1.35, 95%CI 1.13-1.62, P = 0.002), mono-2-ethyl-5-hydroxyhexyl (OR 1.25, 95%CI 1.05-1.49, P = 0.014), mono-n-methyl phthalate (OR 1.26, 95%CI 1.07-1.48, P = 0.007), mono-2-ethyl-5-oxohexyl (OR 1.25, 95%CI 1.07-1.48, P = 0.009), and monobenzyl phthalate (OR 1.40, 95%CI 1.15-1.69, P = 0.002) tended to have high BP as well. However, there are no clear associations between environmental parabens and high BP, nor between pesticides and high BP. In addition, trimethylarsine oxide (OR 2.47, 95%CI 1.27-4.81, P = 0.011) and dimethylarsonic acid concentrations (OR 1.42, 95%CI 1.12-1.79, P = 0.006) were seen to be associated with high BP. In sum, urinary heavy metal, phthalate, and arsenic concentrations were associated with high BP, although the causal effect cannot be

  1. Higher Urinary Heavy Metal, Phthalate, and Arsenic but Not Parabens Concentrations in People with High Blood Pressure, U.S. NHANES, 2011–2012

    PubMed Central

    Shiue, Ivy

    2014-01-01

    Link between environmental chemicals and human health has emerged but not been completely examined in risk factors. Therefore, it was aimed to study the relationships of different sets of urinary environmental chemical concentrations and risk of high blood pressure (BP) in a national, population-based study. Data were retrieved from United States National Health and Nutrition Examination Surveys, 2011–2012 including demographics, BP readings, and urinary environmental chemical concentrations. Analyses included chi-square test, t-test and survey-weighted logistic regression modeling. After full adjustment (adjusting for urinary creatinine, age, sex, ethnicity, and body mass index), urinary cesium (OR 1.56, 95%CI 1.11–2.20, P = 0.014), molybden (OR 1.46, 95%CI 1.06–2.01, P = 0.023), manganese (OR 1.42, 95%CI 1.09–1.86, P = 0.012), lead (OR 1.58, 95%CI 1.28–1.96, P < 0.001), tin (OR 1.44, 95%CI 1.25–1.66, P < 0.001), antimony (OR 1.39, 95%CI 1.10–1.77, P = 0.010), and tungsten (OR 1.49, 95%CI 1.25–1.77, P < 0.001) concentrations were observed to be associated with high BP. People with higher urinary mono-2-ethyl-5-carboxypentyl phthalate (OR 1.33, 95%CI 1.00–1.62, P = 0.006), mono-n-butyl phthalate (OR 1.35, 95%CI 1.13–1.62, P = 0.002), mono-2-ethyl-5-hydroxyhexyl (OR 1.25, 95%CI 1.05–1.49, P = 0.014), mono-n-methyl phthalate (OR 1.26, 95%CI 1.07–1.48, P = 0.007), mono-2-ethyl-5-oxohexyl (OR 1.25, 95%CI 1.07–1.48, P = 0.009), and monobenzyl phthalate (OR 1.40, 95%CI 1.15–1.69, P = 0.002) tended to have high BP as well. However, there are no clear associations between environmental parabens and high BP, nor between pesticides and high BP. In addition, trimethylarsine oxide (OR 2.47, 95%CI 1.27–4.81, P = 0.011) and dimethylarsonic acid concentrations (OR 1.42, 95%CI 1.12–1.79, P = 0.006) were seen to be associated with high BP. In sum, urinary heavy metal, phthalate, and arsenic concentrations were associated with high BP, although the

  2. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water

    SciTech Connect

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V.; Costa, Max

    2015-05-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p < 0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. - Highlights: • Males and females exhibit unique gene expression changes in response to arsenic. • Only 23 genes are common among the differentially expressed genes for the sexes. • Male and female gene lists exhibit common biological

  3. Polymorphisms in maternal folate pathway genes interact with arsenic in drinking water to influence risk of myelomeningocele

    PubMed Central

    Mazumdar, Maitreyi; Valeri, Linda; Rodrigues, Ema G.; Hasan, Md Omar Sharif Ibne; Hamid, Rezina; Paul, Ligi; Selhub, Jacob; Silva, Fareesa; Mostofa, MdGolam; Quamruzzaman, Quazi; Rahman, Mahmuder; Christiani, David C.

    2015-01-01

    Background Arsenic induces neural tube defects in many animal models. Additionally, studies have shown that mice with specific genetic defects in folate metabolism and transport are more susceptible to arsenic-induced neural tube defects. We sought to determine whether 14 single-nucleotide polymorphisms in genes involved in folate metabolism modified the effect of exposure to drinking water contaminated with inorganic arsenic and posterior neural tube defect (myelomeningocele) risk. Methods Fifty-four mothers of children with myelomeningocele and 55 controls were enrolled through clinical sites in rural Bangladesh in a case-control study of the association between environmental arsenic exposure and risk of myelomeningocele. We assessed participants for level of myelomeningocele, administered questionnaires, conducted biological and environmental sample collection, and performed genotyping. Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure inorganic arsenic concentration in drinking water. Candidate single-nucleotide polymorphisms were identified through review of the literature. Results Drinking water inorganic arsenic concentration was associated with increased risk of myelomeningocele for participants with 4 of the 14 studied single-nucleotide polymorphisms in genes involved in folate metabolism: the AA/AG genotype of rs2236225 (MTHFD1), the GG genotype of rs1051266 (SLC19A1), the TT genotype of rs7560488 (DNMT3A), and the GG genotype of rs3740393 (AS3MT) with adjusted OR of 1.13, 1.31, 1.20, and 1.25 for rs2236225, rs1051266, rs7560488, and rs3740393, respectively. Conclusions Our results support the hypothesis that environmental arsenic exposure increases the risk of myelomeningocele via interaction with folate metabolic pathways. PMID:26250961

  4. Polymorphisms in maternal folate pathway genes interact with arsenic in drinking water to influence risk of myelomeningocele.

    PubMed

    Mazumdar, Maitreyi; Valeri, Linda; Rodrigues, Ema G; Ibne Hasan, Md Omar Sharif; Hamid, Rezina; Paul, Ligi; Selhub, Jacob; Silva, Fareesa; Mostofa, Md Golam; Quamruzzaman, Quazi; Rahman, Mahmuder; Christiani, David C

    2015-09-01

    Arsenic induces neural tube defects in many animal models. Additionally, studies have shown that mice with specific genetic defects in folate metabolism and transport are more susceptible to arsenic-induced neural tube defects. We sought to determine whether 14 single-nucleotide polymorphisms in genes involved in folate metabolism modified the effect of exposure to drinking water contaminated with inorganic arsenic and posterior neural tube defect (myelomeningocele) risk. Fifty-four mothers of children with myelomeningocele and 55 controls were enrolled through clinical sites in rural Bangladesh in a case-control study of the association between environmental arsenic exposure and risk of myelomeningocele. We assessed participants for level of myelomeningocele, administered questionnaires, conducted biological and environmental sample collection, and performed genotyping. Inductively coupled plasma mass spectrometry was used to measure inorganic arsenic concentration in drinking water. Candidate single-nucleotide polymorphisms were identified through review of the literature. Drinking water inorganic arsenic concentration was associated with increased risk of myelomeningocele for participants with 4 of the 14 studied single-nucleotide polymorphisms in genes involved in folate metabolism: the AA/AG genotype of rs2236225 (MTHFD1), the GG genotype of rs1051266 (SLC19A1), the TT genotype of rs7560488 (DNMT3A), and the GG genotype of rs3740393 (AS3MT) with adjusted odds ratio of 1.13, 1.31, 1.20, and 1.25 for rs2236225, rs1051266, rs7560488, and rs3740393, respectively. Our results support the hypothesis that environmental arsenic exposure increases the risk of myelomeningocele by means of interaction with folate metabolic pathways. © 2015 Wiley Periodicals, Inc.

  5. Transcriptional Modulation of the ERK1/2 MAPK and NF-kB pathways in Human Urothelial cells after trivalent arsenical exposure: Implications for urinary bladder cancer

    EPA Science Inventory

    Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk ofurinary bladder (DB) cancers in humans. Rodent models administered particular arsenicals have indicated urothelial necrosis followed by regenerative proliferation i...

  6. Transcriptional Modulation of the ERK1/2 MAPK and NF-kB pathways in Human Urothelial cells after trivalent arsenical exposure: Implications for urinary bladder cancer

    EPA Science Inventory

    Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk ofurinary bladder (DB) cancers in humans. Rodent models administered particular arsenicals have indicated urothelial necrosis followed by regenerative proliferation i...

  7. Arsenic Induces Polyadenylation of Canonical Histone mRNA by Down-regulating Stem-Loop-binding Protein Gene Expression*

    PubMed Central

    Brocato, Jason; Fang, Lei; Chervona, Yana; Chen, Danqi; Kiok, Kathrin; Sun, Hong; Tseng, Hsiang-Chi; Xu, Dazhong; Shamy, Magdy; Jin, Chunyuan; Costa, Max

    2014-01-01

    The replication-dependent histone genes are the only metazoan genes whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3′-end. Instead, the histone mRNAs display a stem-loop structure at their 3′-end. Stem-loop-binding protein (SLBP) binds the stem-loop and regulates canonical histone mRNA metabolism. Here we report that exposure to arsenic, a carcinogenic metal, decreased cellular levels of SLBP by inducing its proteasomal degradation and inhibiting SLBP transcription via epigenetic mechanisms. Notably, arsenic exposure dramatically increased polyadenylation of canonical histone H3.1 mRNA possibly through down-regulation of SLBP expression. The polyadenylated H3.1 mRNA induced by arsenic was not susceptible to normal degradation that occurs at the end of S phase, resulting in continued presence into mitosis, increased total H3.1 mRNA, and increased H3 protein levels. Excess expression of canonical histones have been shown to increase sensitivity to DNA damage as well as increase the frequency of missing chromosomes and induce genomic instability. Thus, polyadenylation of canonical histone mRNA following arsenic exposure may contribute to arsenic-induced carcinogenesis. PMID:25266719

  8. Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation.

    PubMed

    Bailey, Kathryn A; Wu, Michael C; Ward, William O; Smeester, Lisa; Rager, Julia E; García-Vargas, Gonzalo; Del Razo, Luz-Maria; Drobná, Zuzana; Stýblo, Miroslav; Fry, Rebecca C

    2013-02-01

    Biotransformation of inorganic arsenic (iAs) is one of the factors that determines the character and magnitude of the diverse detrimental health effects associated with chronic iAs exposure, but it is unknown how iAs biotransformation may impact the epigenome. Here, we integrated analyses of genome-wide, gene-specific promoter DNA methylation levels of peripheral blood leukocytes with urinary arsenical concentrations of subjects from a region of Mexico with high levels of iAs in drinking water. These analyses revealed dramatic differences in DNA methylation profiles associated with concentrations of specific urinary metabolites of arsenic (As). The majority of individuals in this study had positive indicators of As-related disease, namely pre-diabetes mellitus or diabetes mellitus (DM). Methylation patterns of genes with known associations with DM were associated with urinary concentrations of specific iAs metabolites. Future studies will determine whether these DNA methylation profiles provide mechanistic insight into the development of iAs-associated disease, predict disease risk, and/or serve as biomarkers of iAs exposure in humans. © 2013 Wiley Periodicals, Inc.

  9. Arsenic downregulates gene expression at the postsynaptic density in mouse cerebellum, including genes responsible for long-term potentiation and depression.

    PubMed

    Zhang, Cong; Li, Sheng; Sun, Yahui; Dong, Wei; Piao, Fengyuan; Piao, Yongjun; Liu, Shuang; Guan, Huai; Yu, Shengbo

    2014-08-04

    Arsenic (As) is a neurotoxin induces dysfunction of learning and memory. Research has indicated that cerebellum may be involved in arsenic-induced impairment of learning and memory. However, the molecular mechanisms that underlie these effects remain unclear. This study screened for the differentially expressed genes related to the long-term potentiation and long-term depression (LTP and LTD) at the cerebellar postsynaptic density (PSD) of mice following exposure to arsenic, and we provide evidence of the mechanism by which arsenic adversely affects the functions of learning and memory. Here, SPF mice were exposed to 1ppm, 2ppm and 4ppm As2O3 for 60 days. The ultrastructure of the synapses in cerebella of these mice was observed via transmission electron microscopy. The cerebellum global gene expression of mice exposed to 4ppm As2O3 was determined through GeneChip analysis. We used the web tool DAVID to analyze the Gene Ontology (GO) and KEGG pathways that were significantly enriched among the differentially expressed genes. Our observations of synaptic ultrastructure showed that the thickness of the cerebellar PSD was reduced in mice exposed to arsenic. Go analysis revealed the PSD as a significantly altered cellular component. KEGG pathway analysis showed that LTP and LTD were affected by arsenic with highest statistical significance, and 20 differentially expressed genes were associated with them. Among these differentially expressed genes, significant decreases in the mRNA expressions of CaMKII, Gria1, Gria2, Grin1, Itpr1, Grm1 and PLCβ4 related to the LTP and LTD were found at the PSD of mouse cerebellum exposed to arsenic. The downregulation of these genes was further confirmed via real-time reverse transcription PCR or Western blot at 1ppm, 2ppm and 4ppm As2O3. Our results indicate that the 7 genes with in cerebellar PSDs may be involved in arsenic-induced neurotoxicity, including impairment of learning and memory. Copyright © 2014 Elsevier Ireland Ltd

  10. Risk of carotid atherosclerosis associated with genetic polymorphisms of apolipoprotein E and inflammatory genes among arsenic exposed residents in Taiwan

    SciTech Connect

    Hsieh, Y.-C.; Hsieh, F.-I; Lien, L.-M.; Chou, Y.-L.; Chiou, H.-Y. Chen, C.-J.

    2008-02-15

    Arsenic had been reported to be associated with carotid atherosclerosis. However, there were few studies to evaluate the association between the susceptible gene of lipid metabolism and inflammation and carotid atherosclerosis among arsenic exposure residents. The aim of the study was to investigate the associations between the genetic polymorphisms of APOE and MCP-1 and the risk of carotid atherosclerosis among residents of Lanyang Basin in Taiwan which was a newly confirmed arsenic-endemic area. In total, 479 residents who had been genotyped of these two genes and examined the severity of carotid atherosclerosis were included in this study. The study subjects with carotid intima media thickness (IMT) {>=} 1.0 mm or with the observable plaque in the extracranial carotid artery were diagnosed as carotid atherosclerosis. A significantly age- and gender-adjusted odds ratio of 2.0 for the development of carotid atherosclerosis was observed in study subjects with {epsilon}4 allele of APOE than those without {epsilon}4 allele. Compared with study subjects who carried wild genotypes of APOE and MCP-1, those with both risk genotypes of APOE and MCP-1 had 2.5-fold risk of carotid atherosclerosis after adjustment for age and gender, revealing a significant dose-response relationship between number of risk genotypes of these genes and risk of carotid atherosclerosis. Additionally, study subjects with two risk genotypes of APOE and MCP-1 and either had ingested well water contained arsenic level > 10 {mu}g/L or had arsenic exposure > 0.22 mg/L-year would have strikingly highest risk of 10.3-fold and 15.7-fold, respectively, for the development carotid atherosclerosis, showing significant joint effect of arsenic exposure and risk genotypes of APOE and MCP-1.

  11. Arsenic and phosphate rock impacted the abundance and diversity of bacterial arsenic oxidase and reductase genes in rhizosphere of As-hyperaccumulator Pteris vittata.

    PubMed

    Han, Yong-He; Fu, Jing-Wei; Xiang, Ping; Cao, Yue; Rathinasabapathi, Bala; Chen, Yanshan; Ma, Lena Q

    2017-01-05

    Microbially-mediated arsenic (As) transformation in soils affects As speciation and plant uptake. However, little is known about the impacts of As on bacterial communities and their functional genes in the rhizosphere of As-hyperaccumulator Pteris vittata. In this study, arsenite (AsIII) oxidase genes (aroA-like) and arsenate (AsV) reductase genes (arsC) were amplified from three soils, which were amended with 50mgkg(-1) As and/or 1.5% phosphate rock (PR) and grew P. vittata for 90 d. The aroA-like genes in the rhizosphere were 50 times more abundant than arsC genes, consistent with the dominance of AsV in soils. According to functional gene alignment, most bacteria belonged to α-, β- and γ-Proteobacteria. Moreover, aroA-like genes showed a higher biodiversity than arsC genes based on clone library analysis and could be grouped into nine clusters based on terminal restriction fragment length polymorphism (T-RFLP) analysis. Besides, AsV amendment elevated aroA-like gene diversity, but decreased arsC gene diversity. Redundancy analysis indicated that soil pH, available Ca and P, and AsV concentration were key factors driving diverse compositions in aroA-like gene community. This work identified new opportunities to screen for As-oxidizing and/or -reducing bacteria to aid phytoremediation of As-contaminated soils.

  12. Bortezomib and Arsenic Trioxide Activity on a Myelodysplastic Cell Line (P39): A Gene Expression Study

    PubMed Central

    Savlı, Hakan; Galimberti, Sara; Sünnetçi, Deniz; Canestraro, Martina; Palumbo, Giuseppe; Nagy, Balint; Raimondo, Francesco Di; Petrini, Mario

    2015-01-01

    Objective: We aimed to understand the molecular pathways affected by bortezomib and arsenic trioxide treatment on myelomonocytoid cell line P39. Materials and Methods: Oligonucleotide microarray platforms were used for gene expression and pathway analysis. Confirmation studies were performed using quantitative real time PCR. Results: Bortezomib treatment has shown upregulated DIABLO and NF-κBIB (a NF-κB inhibitor) and downregulated NF-κB1, NF-κB2, and BIRC1 gene expressions. Combination treatment of the two compounds showed gene expression deregulations in concordance by the results of single bortezomib treatment. Especially, P53 was a pathway more significantly modified and a gene network centralized around the beta estradiol gene. Beta estradiol, BRCA2, and FOXA1 genes were remarkable deregulations in our findings. Conclusion: Results support the suggestions about possible use of proteasome inhibitors in the treatment of high-risk myelodysplastic syndrome (MDS). NF-κB was observed as an important modulator in leukemic transformation of MDS. PMID:25913414

  13. FOLATE DEFICIENCY ENHANCES ARSENIC EFFECTS ON EXPRESSION OF GENES INVOLVED IN EPIDERMAL DIFFERENTIATION

    EPA Science Inventory

    Chronic arsenic exposure in humans is associated with cancers of the skin, lung, and bladder. There is evidence that folate deficiency may increase susceptibility to arsenic¿s effects, including arsenic-induced skin lesions. K6/ODC mice develop skin tumors when exposed to 10 ppm ...

  14. FOLATE DEFICIENCY ENHANCES ARSENIC EFFECTS ON EXPRESSION OF GENES INVOLVED IN EPIDERMAL DIFFERENTIATION

    EPA Science Inventory

    Chronic arsenic exposure in humans is associated with cancers of the skin, lung, and bladder. There is evidence that folate deficiency may increase susceptibility to arsenic¿s effects, including arsenic-induced skin lesions. K6/ODC mice develop skin tumors when exposed to 10 ppm ...

  15. Gene Expression of Normal Human Epidermal Keratinocytes Modulated by Trivalent Arsenicals

    EPA Science Inventory

    Chronic exposure to inorganic arsenic (iAs) is associated with the development of benign and malignant human skin lesions including nonmelanoma skin cancers. The precise arsenical form(s) responsible for this carcinogenic effect are unknown, although trivalent inorganic arsenic (...

  16. GENE EXPRESSION PROFILING OF NORMAL HUMAN BRONCHIAL EPITHELIAL CELLS EXPOSED TO TRIVALENT ARSENICALS AND DIMETHYLTHIOARSINIC ACID

    EPA Science Inventory

    Lung is a major target for arsenic carcinogenesis in humans. However, the carcinogenic mode of action of arsenicals is unknown. We investigated, in human bronchial epithelial (BEAS2B) cells, the effects of inorganic arsenic (iAsIII), monomethylarsonous acid (MMAIII), dimethylarsi...

  17. Gene Expression of Normal Human Epidermal Keratinocytes Modulated by Trivalent Arsenicals

    EPA Science Inventory

    Chronic exposure to inorganic arsenic (iAs) is associated with the development of benign and malignant human skin lesions including nonmelanoma skin cancers. The precise arsenical form(s) responsible for this carcinogenic effect are unknown, although trivalent inorganic arsenic (...

  18. GENE EXPRESSION PROFILING OF NORMAL HUMAN BRONCHIAL EPITHELIAL CELLS EXPOSED TO TRIVALENT ARSENICALS AND DIMETHYLTHIOARSINIC ACID

    EPA Science Inventory

    Lung is a major target for arsenic carcinogenesis in humans. However, the carcinogenic mode of action of arsenicals is unknown. We investigated, in human bronchial epithelial (BEAS2B) cells, the effects of inorganic arsenic (iAsIII), monomethylarsonous acid (MMAIII), dimethylarsi...

  19. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    SciTech Connect

    Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

    2012-06-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6 month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. Highlights: ► Chronic As{sub 2}O

  20. Biological and behavioral factors modify biomarkers of arsenic exposure in a U.S. population.

    PubMed

    Calderon, Rebecca L; Hudgens, Edward E; Carty, Cara; He, Bin; Le, X Chris; Rogers, John; Thomas, David J

    2013-10-01

    Although consumption of drinking water contaminated with inorganic arsenic is usually considered the primary exposure route, aggregate exposure to arsenic depends on direct consumption of water, use of water in food preparation, and the presence in arsenicals in foods. To gain insight into the effects of biological and behavioral factors on arsenic exposure, we determined arsenic concentrations in urine and toenails in a U.S. population that uses public or private water supplies containing inorganic arsenic. Study participants were 904 adult residents of Churchill County, Nevada, whose home tap water supplies contained <3 to about 1200 µg of arsenic per liter. Biomarkers of exposure for this study were summed urinary concentrations of inorganic arsenic and its methylated metabolites (speciated arsenical), of all urinary arsenicals (total arsenical), and of all toenail arsenicals (total arsenical). Increased tap water arsenic concentration and consumption were associated with significant upward trends for urinary speciated and total and toenail total arsenical concentrations. Significant gender differences in concentrations of speciated and total arsenicals in urine and toenails reflected male-female difference in water intake. Both recent and higher habitual seafood consumption significantly increased urinary total but not speciated arsenical concentration. In a stepwise general linear model, seafood consumption significantly predicted urinary total arsenical but not urinary speciated or toenail total arsenical concentrations. Smoking behavior significantly predicted urinary speciated or total arsenical concentration. Gender, tap water arsenic concentration, and primary drinking water source significantly predicted urinary speciated and total concentrations and toenail total arsenical concentrations. These findings confirm the primacy of home tap water as a determinant of arsenic concentration in urine and toenails. However, biological and behavioral factors can

  1. Analysis of the functional gene structure and metabolic potential of microbial community in high arsenic groundwater.

    PubMed

    Li, Ping; Jiang, Zhou; Wang, Yanhong; Deng, Ye; Van Nostrand, Joy D; Yuan, Tong; Liu, Han; Wei, Dazhun; Zhou, Jizhong

    2017-10-15

    Microbial functional potential in high arsenic (As) groundwater ecosystems remains largely unknown. In this study, the microbial community functional composition of nineteen groundwater samples was investigated using a functional gene array (GeoChip 5.0). Samples were divided into low and high As groups based on the clustering analysis of geochemical parameters and microbial functional structures. The results showed that As related genes (arsC, arrA), sulfate related genes (dsrA and dsrB), nitrogen cycling related genes (ureC, amoA, and hzo) and methanogen genes (mcrA, hdrB) in groundwater samples were correlated with As, SO4(2-), NH4(+) or CH4 concentrations, respectively. Canonical correspondence analysis (CCA) results indicated that some geochemical parameters including As, total organic content, SO4(2-), NH4(+), oxidation-reduction potential (ORP) and pH were important factors shaping the functional microbial community structures. Alkaline and reducing conditions with relatively low SO4(2-), ORP, and high NH4(+), as well as SO4(2-) and Fe reduction and ammonification involved in microbially-mediated geochemical processes could be associated with As enrichment in groundwater. This study provides an overall picture of functional microbial communities in high As groundwater aquifers, and also provides insights into the critical role of microorganisms in As biogeochemical cycling. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Analysis of Genes Involved in Arsenic Resistance in Corynebacterium glutamicum ATCC 13032†

    PubMed Central

    Ordóñez, Efrén; Letek, Michal; Valbuena, Noelia; Gil, José A.; Mateos, Luis M.

    2005-01-01

    Corynebacterium glutamicum is able to grow in media containing up to 12 mM arsenite and 500 mM arsenate and is one of the most arsenic-resistant microorganisms described to date. Two operons (ars1 and ars2) involved in arsenate and arsenite resistance have been identified in the complete genome sequence of Corynebacterium glutamicum. The operons ars1 and ars2 are located some distance from each other in the bacterial chromosome, but they are both composed of genes encoding a regulatory protein (arsR), an arsenite permease (arsB), and an arsenate reductase (arsC); operon ars1 contains an additional arsenate reductase gene (arsC1′) located immediately downstream from arsC1. Additional arsenite permease and arsenate reductase genes (arsB3 and arsC4) scattered on the chromosome were also identified. The involvement of ars operons in arsenic resistance in C. glutamicum was confirmed by gene disruption experiments of the three arsenite permease genes present in its genome. Wild-type and arsB3 insertional mutant C. glutamicum strains were able to grow with up to 12 mM arsenite, whereas arsB1 and arsB2 C. glutamicum insertional mutants were resistant to 4 mM and 9 mM arsenite, respectively. The double arsB1-arsB2 insertional mutant was resistant to only 0.4 mM arsenite and 10 mM arsenate. Gene amplification assays of operons ars1 and ars2 in C. glutamicum revealed that the recombinant strains containing the ars1 operon were resistant to up to 60 mM arsenite, this being one of the highest levels of bacterial resistance to arsenite so far described, whereas recombinant strains containing operon ars2 were resistant to only 20 mM arsenite. Northern blot and reverse transcription-PCR analysis confirmed the presence of transcripts for all the ars genes, the expression of arsB3 and arsC4 being constitutive, and the expression of arsR1, arsB1, arsC1, arsC1′, arsR2, arsB2, and arsC2 being inducible by arsenite. PMID:16204540

  3. The immune responses and expression of metallothionein (MT) gene and heat shock protein 70 (HSP 70) in juvenile rockfish, Sebastes schlegelii, exposed to waterborne arsenic (As(3+)).

    PubMed

    Kim, Jun-Hwan; Kang, Ju-Chan

    2016-10-01

    Juvenile rockfish, Sebastes schlegelii (mean length 16.4±1.9cm, and mean weight 71.6±6.4g) were exposed for 20days with the different levels of waterborne arsenic concentration (0, 50, 100, 200 and 400μg/L). The plasma cortisol of S. schlegelii was significantly increased by the waterborne arsenit exposure. In the immune responses, the immunoglobulin M (Ig M) and lysozyme activity of S. schlegelii were significantly increased by the waterborne arsenic exposure. The acetylcholinesterase (AChE) activity of S. schlegelii was inhibited by the waterborne arsenic exposure. The substantial increases in the gene expression such as metallothionein (MT) and heat shock protein 70 (HSP 70) were observed by the waterborne arsenic exposure. The results demonstrated that waterborne arsenic exposure can induce the significant alterations in the immune responses and specific gene expression of S. schlegelii.

  4. Fetal-sex dependent genomic responses in the circulating lymphocytes of arsenic-exposed pregnant women in New Hampshire.

    PubMed

    Bommarito, Paige A; Martin, Elizabeth; Smeester, Lisa; Palys, Thomas; Baker, Emily R; Karagas, Margaret R; Fry, Rebecca C

    2017-08-06

    Exposure to inorganic arsenic (iAs) during pregnancy is associated with adverse health outcomes present both at birth and later in life. A biological mechanism may include epigenetic and genomic alterations in fetal genes involved in immune functioning. To investigate the role of the maternal immune response to in utero iAs exposure, we conducted an analysis of the expression of immune-related genes in pregnant women from the New Hampshire Birth Cohort Study. A set of 31 genes was identified with altered expression in association with levels of urinary total arsenic, urinary iAs, urinary monomethylated arsenic and urinary dimethylated arsenic. Notably, maternal gene expression signatures differed when stratified on fetal sex, with a more robust inflammatory response observed in male pregnancies. Moreover, the differentially expressed genes were also related to birth outcomes. These findings highlight the sex-dependent nature of the maternal iAs-induced inflammatory response in relationship to fetal outcomes. Copyright © 2017. Published by Elsevier Inc.

  5. Molecular detection of virulence genes as markers in Pseudomonas aeruginosa isolated from urinary tract infections.

    PubMed

    Sabharwal, Neha; Dhall, Shriya; Chhibber, Sanjay; Harjai, Kusum

    2014-01-01

    Catheter associated urinary tract infections by P. aeruginosa are related to variety of complications. Quorum sensing and related circuitry guard its virulence potential. Though P. aeruginosa accounts for an appreciable amount of virulence factors, this organism is highly unstable phenotypically. Thus, genotyping of clinical isolates of P. aeruginosa is of utmost importance for understanding the epidemiology of infection. This may contribute towards development of immunotherapeutic approaches against this multi drug resistant pathogen. Moreover, no epidemiological study has been reported yet on uroisolates of P. aeruginosa. Thus this study was planned to obtain information regarding presence, distribution and rate of occurrence of quorum sensing and some associated virulence genes at genetic level. The profiling of quorum sensing genes lasI, lasR, rhlI, rhlR and virulence genes like toxA, aprA, rhlAB, plcH, lasB and fliC of twelve strains of P. aeruginosa isolated from patients with UTIs was done by direct PCR. The results showed variable distribution of quorum sensing genes and virulence genes. Their percentage occurrence may be specifically associated with different levels of intrinsic virulence and pathogenicity in urinary tract. Such information can help in identifying these virulence genes as useful diagnostic markers for clinical P. aeruginosa strains isolated from UTIs.

  6. Evaluating long-term cellular effects of the arsenic species thio-DMA(V): qPCR-based gene expression as screening tool.

    PubMed

    Ebert, Franziska; Thomann, Marlies; Witt, Barbara; Müller, Sandra M; Meyer, Sören; Weber, Till; Christmann, Markus; Schwerdtle, Tanja

    2016-09-01

    Thio-dimethylarsinic acid (thio-DMA(V)) is a human urinary metabolite of the class 1 human carcinogen inorganic arsenic as well as of arsenosugars. Thio-DMA(V) exerts strong cellular toxicity, whereas its toxic modes of action are not fully understood. For the first time, this study characterises the impact of a long-term (21days) in vitro incubation of thio-DMA(V) on the expression of selected genes related to cell death, stress response, epigenetics and DNA repair. The observed upregulation of DNMT1 might be a cellular compensation to counterregulate the in a very recent study observed massive global DNA hypomethylation after chronic thio-DMA(V) incubation. Moreover, our data suggest that chronic exposure towards subcytotoxic, pico- to nanomolar concentrations of thio-DMA(V) causes a stress response in human urothelial cells. The upregulation of genes encoding for proteins of DNA repair (Apex1, Lig1, XRCC1, DDB2, XPG, ATR) as well as damage response (GADD45A, GADD45G, Trp53) indicate a potential genotoxic risk emanating from thio-DMA(V) after long-term incubation.

  7. Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese.

    PubMed

    Andrade, Vanda; Mateus, M Luísa; Batoréu, M Camila; Aschner, Michael; dos Santos, A P Marreilha

    2013-09-01

    Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5mg/kg), As (60mg/L), Mn (10mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture.

  8. Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese

    PubMed Central

    Andrade, Vanda; Mateus, M. Luísa; Batoréu, M. Camila; Aschner, Michael; Marreilha dos Santos, A.P.

    2013-01-01

    Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5 mg/kg), As (60 mg/L), Mn (10 mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture. PMID:23764341

  9. Bacteria and Genes Involved in Arsenic Speciation in Sediment Impacted by Long-Term Gold Mining

    PubMed Central

    Costa, Patrícia S.; Scholte, Larissa L. S.; Reis, Mariana P.; Chaves, Anderson V.; Oliveira, Pollyanna L.; Itabayana, Luiza B.; Suhadolnik, Maria Luiza S.; Barbosa, Francisco A. R.; Chartone-Souza, Edmar; Nascimento, Andréa M. A.

    2014-01-01

    The bacterial community and genes involved in geobiocycling of arsenic (As) from sediment impacted by long-term gold mining were characterized through culture-based analysis of As-transforming bacteria and metagenomic studies of the arsC, arrA, and aioA genes. Sediment was collected from the historically gold mining impacted Mina stream, located in one of the world’s largest mining regions known as the “Iron Quadrangle”. A total of 123 As-resistant bacteria were recovered from the enrichment cultures, which were phenotypically and genotypically characterized for As-transformation. A diverse As-resistant bacteria community was found through phylogenetic analyses of the 16S rRNA gene. Bacterial isolates were affiliated with Proteobacteria, Firmicutes, and Actinobacteria and were represented by 20 genera. Most were AsV-reducing (72%), whereas AsIII-oxidizing accounted for 20%. Bacteria harboring the arsC gene predominated (85%), followed by aioA (20%) and arrA (7%). Additionally, we identified two novel As-transforming genera, Thermomonas and Pannonibacter. Metagenomic analysis of arsC, aioA, and arrA sequences confirmed the presence of these genes, with arrA sequences being more closely related to uncultured organisms. Evolutionary analyses revealed high genetic similarity between some arsC and aioA sequences obtained from isolates and clone libraries, suggesting that those isolates may represent environmentally important bacteria acting in As speciation. In addition, our findings show that the diversity of arrA genes is wider than earlier described, once none arrA-OTUs were affiliated with known reference strains. Therefore, the molecular diversity of arrA genes is far from being fully explored deserving further attention. PMID:24755825

  10. Transcriptome profiling of genes and pathways associated with arsenic toxicity and tolerance in Arabidopsis

    PubMed Central

    2014-01-01

    Background Arsenic (As) is a toxic metalloid found ubiquitously in the environment and widely considered an acute poison and carcinogen. However, the molecular mechanisms of the plant response to As and ensuing tolerance have not been extensively characterized. Here, we report on transcriptional changes with As treatment in two Arabidopsis accessions, Col-0 and Ws-2. Results The root elongation rate was greater for Col-0 than Ws-2 with As exposure. Accumulation of As was lower in the more tolerant accession Col-0 than in Ws-2. We compared the effect of As exposure on genome-wide gene expression in the two accessions by comparative microarray assay. The genes related to heat response and oxidative stresses were common to both accessions, which indicates conserved As stress-associated responses for the two accessions. Most of the specific response genes encoded heat shock proteins, heat shock factors, ubiquitin and aquaporin transporters. Genes coding for ethylene-signalling components were enriched in As-tolerant Col-0 with As exposure. A tolerance-associated gene candidate encoding Leucine-Rich Repeat receptor-like kinase VIII (LRR-RLK VIII) was selected for functional characterization. Genetic loss-of-function analysis of the LRR-RLK VIII gene revealed altered As sensitivity and the metal accumulation in roots. Conclusions Thus, ethylene-related pathways, maintenance of protein structure and LRR-RLK VIII-mediated signalling may be important mechanisms for toxicity and tolerance to As in the species. Here, we provide a comprehensive survey of global transcriptional regulation for As and identify stress- and tolerance-associated genes responding to As. PMID:24734953

  11. Characterization of the ars Gene Cluster from Extremely Arsenic-Resistant Microbacterium sp. Strain A33▿ †

    PubMed Central

    Achour-Rokbani, Asma; Cordi, Audrey; Poupin, Pascal; Bauda, Pascale; Billard, Patrick

    2010-01-01

    The arsenic resistance gene cluster of Microbacterium sp. A33 contains a novel pair of genes (arsTX) encoding a thioredoxin system that are cotranscribed with an unusual arsRC2 fusion gene, ACR3, and arsC1 in an operon divergent from arsC3. The whole ars gene cluster is required to complement an Escherichia coli ars mutant. ArsRC2 negatively regulates the expression of the pentacistronic operon. ArsC1 and ArsC3 are related to thioredoxin-dependent arsenate reductases; however, ArsC3 lacks the two distal catalytic cysteine residues of this class of enzymes. PMID:19966021

  12. Inactivation of p15(INK4b) in chronic arsenic poisoning cases.

    PubMed

    Zhang, Aihua; Gao, Chen; Han, Xue; Wang, Lifang; Yu, Chun; Zeng, Xiaowen; Chen, Liping; Li, Daochuan; Chen, Wen

    2014-01-01

    Arsenic exposure from burning high arsenic-containing coal has been associated with human skin lesion and cancer. However, the mechanisms of arsenic-related carcinogenesis are not fully understood. Inactivation of critical tumor suppression genes by epigenetic regulation or genetic modification might contribute to arsenic-induced carcinogenicity. This study aims to clarify the correlation between arsenic pollution and functional defect of p15(INK4b) gene in arsenic exposure residents from a region of Guizhou Province, China. To this end, 103 arsenic exposure residents and 105 control subjects were recruited in this study. The results showed that the exposure group exhibited higher levels of urinary and hair arsenic compared with the control group (55.28 vs 28.87 μg/L, 5.16 vs 1.36 μg/g). Subjects with higher arsenic concentrations are more likely to have p15(INK4b) methylation and gene deletion (χ(2) = 4.28, P = 0.04 and χ(2) = 4.31, P = 0.04). We also found that the degree of p15(INK4b) hypermethylation and gene deletion occurred at higher incidence in the poisoning cases with skin cancer (3.7% and 14.81% in non-skin cancer group, 41.18% and 47.06 in skin cancer group), and were significantly associated with the stage of skin lesions (χ(2) = 12.82, P < 0.01 and χ(2) = 7.835, P = 0.005). These observations indicate that inactivation of p15(INK4b) through genetic alteration or epigenetic modification is a common event that is associated with arsenic exposure and the development of arsenicosis.

  13. Transplacental arsenic plus postnatal 12-O-teradecanoyl phorbol-13-acetate exposures associated with hepatocarcinogenesis induce similar aberrant gene expression patterns in male and female mouse liver

    SciTech Connect

    Liu Jie . E-mail: Liu6@niehs.nih.gov; Xie Yaxiong; Merrick, B. Alex; Shen Jun; Ducharme, Danica M.K.; Collins, Jennifer; Diwan, Bhalchandra A.; Logsdon, Daniel; Waalkes, Michael P.

    2006-06-15

    Our prior work shows that in utero arsenic exposure alone is a complete transplacental carcinogen, producing hepatocellular carcinoma in adult male offspring but not in females. In a follow-up study to potentially promote arsenic-initiated tumors, mice were exposed to arsenic (85 ppm) from gestation day 8 to 18 and then exposed to 12-O-teradecanoyl phorbol-13-acetate (TPA), a well-known tumor promoter after weaning. The dermal application of TPA (2 {mu}g/0.1 ml acetone, twice/week for 21 weeks) after transplacental arsenic did not further increase arsenic-induced liver tumor formation in adult males but significantly increased liver tumor formation in adult females. Thus, for comparison, liver tumors and normal liver samples taken from adult male and female mice at necropsy were analyzed for aberrant gene/protein expression by microarray, real-time RT-PCR and Western blot analysis. Arsenic/TPA treatment resulted in increased expression of {alpha}-fetoprotein, k-ras, c-myc, estrogen receptor-{alpha}, cyclin D1, cdk2na, plasminogen activator inhibitor-1, cytokeratin-8, cytokeratin-18, glutathione S-transferases and insulin-like growth factor binding proteins in liver and liver tumors from both male and female mice. Arsenic/TPA also decreased the expression of BRCA1, betaine-homocysteine methyltransferase, CYP7B1, CYP2F2 and insulin-like growth factor-1 in normal and cancerous livers. Alterations in these gene products were associated with arsenic/TPA-induced liver tumors, regardless of sex. Thus, transplacental arsenic plus postnatal TPA exposure induced similar aberrant gene expression patterns in male and female mouse liver, which are persistent and potentially important to the mechanism of arsenic initiation of hepatocarcinogenesis.

  14. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water.

    PubMed

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V; Costa, Max

    2015-05-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Interaction between arsenic exposure from drinking water and genetic susceptibility in carotid intima–media thickness in Bangladesh

    SciTech Connect

    Wu, Fen; Jasmine, Farzana; Kibriya, Muhammad G.; Liu, Mengling; Cheng, Xin; Parvez, Faruque; Paul-Brutus, Rachelle; Islam, Tariqul; Paul, Rina Rani; Sarwar, Golam; Ahmed, Alauddin; Jiang, Jieying; Islam, Tariqul; Slavkovich, Vesna; Rundek, Tatjana; Demmer, Ryan T.; Desvarieux, Moise; and others

    2014-05-01

    Epidemiologic studies that evaluated genetic susceptibility for the effects of arsenic exposure from drinking water on subclinical atherosclerosis are limited. We conducted a cross-sectional study of 1078 participants randomly selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh to evaluate whether the association between arsenic exposure and carotid artery intima–media thickness (cIMT) differs by 207 single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. Although not statistically significant after correcting for multiple testing, nine SNPs in APOE, AS3MT, PNP, and TNF genes had a nominally statistically significant interaction with well-water arsenic in cIMT. For instance, the joint presence of a higher level of well-water arsenic (≥ 40.4 μg/L) and the GG genotype of AS3MT rs3740392 was associated with a difference of 40.9 μm (95% CI = 14.4, 67.5) in cIMT, much greater than the difference of cIMT associated with the genotype alone (β = − 5.1 μm, 95% CI = − 31.6, 21.3) or arsenic exposure alone (β = 7.2 μm, 95% CI = − 3.1, 17.5). The pattern and magnitude of the interactions were similar when urinary arsenic was used as the exposure variable. Additionally, the at-risk genotypes of the AS3MT SNPs were positively related to the proportion of monomethylarsonic acid (MMA) in urine, which is indicative of arsenic methylation capacity. The findings provide novel evidence that genetic variants related to arsenic metabolism may play an important role in arsenic-induced subclinical atherosclerosis. Future replication studies in diverse populations are needed to confirm the findings. - Highlights: • Nine SNPs had a nominally significant interaction with well-water arsenic in cIMT. • Three SNPs in AS3MT showed nominally significant interactions with urinary arsenic. • cIMT was much higher among subjects with higher arsenic exposure and AS3MT

  16. Reduced Expression of MAPK/ERK Genes in Perinatal Arsenic-Exposed Offspring Induced by Glucocorticoid Receptor Deficits

    PubMed Central

    Martinez-Finley, Ebany J.; Goggin, Samantha L.; Labrecque, Matthew T.; Allan, Andrea M.

    2011-01-01

    Changes within the glucocorticoid receptor (GR) cellular signaling pathway were evaluated in adolescent mice exposed to 50 ppb arsenic during gestation. Previously, we reported increased basal plasma corticosterone levels, decreased hippocampal GR levels and deficits in learning and memory performance in perinatal arsenic-exposed mice. The biosynthesis of members of the mitogen-activated protein kinase (MAPK) signaling pathway, known to be involved in learning and memory, is modulated by the binding of GR to glucocorticoid response elements (GREs) in the gene promoters. Two genes of the MAPK pathway, Ras and Raf, contain GREs which are activated upon binding of GRs. We evaluated the activity of GRs at Ras and Raf promoters using chromatin immunoprecipitation and real-time PCR and report decreased binding of the GR at these promoters. An ELISA-based GR binding assay was used to explore whether this decreased binding was restricted to in vivo promoters and revealed no differences in binding of native GR to synthetic GREs. The decreased in vivo GR binding coincides with significantly decreased mRNA levels and slight reductions of protein of both H-Ras and Raf-1 in perinatally arsenic-exposed mice. Nuclear activated extracellular-signal regulated kinase (ERK), a downstream target of Ras and Raf, whose transcriptional targets also play an important role in learning and memory, was decreased in the hippocampus of arsenic-exposed animals when compared to controls. GR-mediated transcriptional deficits in the MAPK/ERK pathway could be an underlying cause of previously reported learning deficits and provide the link to arsenic-induced deficiencies in cognitive development. PMID:21784148

  17. Effect of Sodium Arsenite Dose Administered in the Drinking Water on the Urinary Bladder Epithelium of Female Arsenic (+3 oxidation state) Methyltransferase Knockout Mice

    EPA Science Inventory

    The enzyme arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions converting inorganic arsenic to methylated metabolites, some of which are highly cytotoxic. In a previous study, we evaluated whether the As3mt null genotype in mice modified cytotoxic and proli...

  18. Effect of Sodium Arsenite Dose Administered in the Drinking Water on the Urinary Bladder Epithelium of Female Arsenic (+3 oxidation state) Methyltransferase Knockout Mice

    EPA Science Inventory

    The enzyme arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions converting inorganic arsenic to methylated metabolites, some of which are highly cytotoxic. In a previous study, we evaluated whether the As3mt null genotype in mice modified cytotoxic and proli...

  19. Arsenic methylation, GSTO1 polymorphisms, and metabolic syndrome in an arseniasis endemic area of southwestern Taiwan.

    PubMed

    Chen, Jein-Wen; Wang, Shu-Li; Wang, Ya-Hui; Sun, Chien-Wen; Huang, Yeou-Lih; Chen, Chien-Jen; Li, Wan-Fen

    2012-07-01

    Previous studies have shown that hair arsenic (As) levels are associated with an increased prevalence of metabolic syndrome (MetS), which is a strong predictor for type 2 diabetes. The objective of this study was to evaluate whether urinary arsenic methylation is related to MetS in an arseniasis endemic area of southwestern Taiwan, taking genetic factors into account. Subjects were from a community-based cohort recruited in 1990 from three villages in Putai Township. In 2002-2003, we successfully followed 247 subjects and measured their urinary arsenic species including inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as the coding region polymorphisms of three genes known to involve in arsenic methylation. Results showed that subjects of MetS had a history of consuming well water of higher arsenic concentration as compared to those without MetS. We also found a significant association between urinary arsenic species and risk for MetS, where the odds ratio of MetS was increased with decreasing proportion of MMA and low rate of primary methylation (defined as MMA/inorganic As). The increased risk associated with low primary methylation rate was further modified by the GSTO1 A140D polymorphism, with the D allele carriers showing a slightly higher risk for MetS. Our results suggest that a low MMA% is associated with increased risk for MetS among As-exposed subjects and the genetic polymorphism of GSTO1, an enzyme responsible for the reduction of pentavalent arsenic species, may also play a modest modification role. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Prenatal Arsenic Exposure Alters Gene Expression in the Adult Liver to a Proinflammatory State Contributing to Accelerated Atherosclerosis

    PubMed Central

    States, J. Christopher; Singh, Amar V.; Knudsen, Thomas B.; Rouchka, Eric C.; Ngalame, Ntube O.; Arteel, Gavin E.; Piao, Yulan; Ko, Minoru S. H.

    2012-01-01

    The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE−/−) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE−/− mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing

  1. Gene expression of the arsenic resistance operon in Chromobacterium violaceum ATCC 12472.

    PubMed

    Azevedo, Juliana Simão Nina de; Silva-Rocha, Rafael; Silva, Artur; Peixe Carepo, Marta Sofia; Cruz Schneider, Maria Paula

    2008-02-01

    Chromobacterium violaceum ATCC 12472 presents an arsRCB-type operon, which is involved in arsenic resistance. The regulating protein of this resistance system (ArsR) does not have the small conserved site (ELCVDCL) to link to the metalloid, as observed in Escherichia coli, and is thus considered to be an atypical ArsR protein, like that observed in Acidithiobacillus ferrooxidans. In the present study, the gene expression profile of the ars operon under induction at different concentrations of arsenite - As(III) - was obtained via real-time PCR (TaqMan), by correlating the threshold cycle (Ct) values of induced and uninduced (control) samples. Through linear regression analysis (R2 = 0.9926), the gene expression profile of the ars operon showed clearly that the 0.125 micromol/L concentration of As(III) was sufficient to provoke a 4-fold increase in the resistance system, and a further increase in concentration resulted in an increase of up to 53-fold in transcription rates. The relation between resistance and induction of the ars operon indicates that the increased resistance to As(III) is associated with the increase in the number of transcripts.

  2. GENE EXPRESSION PROFILING OF HYPERKERATOTIC SKIN FROM INNER MONGOLIANS CHRONICALLY EXPOSED TO ARSENIC

    EPA Science Inventory

    Millions of people worldwide have been chronically exposed to arsenic levels in drinking water that greatly exceed the current World Health Organization¿s recommended limit of 10 µg/ml. The skin is a major target of arsenic toxicity, and some of the first clinical signs of chroni...

  3. GENE EXPRESSION PROFILING OF HYPERKERATOTIC SKIN FROM INNER MONGOLIANS CHRONICALLY EXPOSED TO ARSENIC

    EPA Science Inventory

    Millions of people worldwide have been chronically exposed to arsenic levels in drinking water that greatly exceed the current World Health Organization¿s recommended limit of 10 µg/ml. The skin is a major target of arsenic toxicity, and some of the first clinical signs of chroni...

  4. Arsenic as an endocrine disruptor: arsenic disrupts retinoic acid receptor-and thyroid hormone receptor-mediated gene regulation and thyroid hormone-mediated amphibian tail metamorphosis.

    PubMed

    Davey, Jennifer C; Nomikos, Athena P; Wungjiranirun, Manida; Sherman, Jenna R; Ingram, Liam; Batki, Cavus; Lariviere, Jean P; Hamilton, Joshua W

    2008-02-01

    Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01-5 microM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element-luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element-luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1- 4.0 microM As. As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult

  5. Trichoderma inoculation ameliorates arsenic induced phytotoxic changes in gene expression and stem anatomy of chickpea (Cicer arietinum).

    PubMed

    Tripathi, Pratibha; Singh, Poonam C; Mishra, Aradhana; Chaudhry, Vasvi; Mishra, Sandhya; Tripathi, Rudra D; Nautiyal, Chandra S

    2013-03-01

    Arsenic, a carcinogenic metalloid severely affects plant growth in contaminated areas. Present study shows role of Trichoderma reesei NBRI 0716 (NBRI 0716) in ameliorating arsenic (As) stress on chickpea under greenhouse conditions. Arsenic stress adversely affected seed germination (25%), chlorophyll content (44%) and almost eliminated nodule formation that were significantly restored on NBRI 0716 inoculation. It also restored stem anomalies like reduced trichome turgidity and density, deformation in collenchymatous and sclerenchymatous cells induced by As stress. Semi-quantitative RT-PCR of stress responsive genes showed differential expression of genes involved in synthesis of cell wall degrading enzymes, dormancy termination and abiotic stress. Upregulation of drought responsive genes (DRE, EREBP, T6PS, MIPS, and PGIP), enhanced proline content and shrunken cortex cells in the presence of As suggests that it creates water deficiency in plants and these responses were modulated by NBRI 0716 which provides a protective role. NBRI0716 mediated production of As reductase enzyme in chickpea and thus contributed in As metabolism. The study suggests a multifarious role of NBRI0716 in mediating stress tolerance in chickpea towards As. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Metagenomic approach reveals variation of microbes with arsenic and antimony metabolism genes from highly contaminated soil.

    PubMed

    Luo, Jinming; Bai, Yaohui; Liang, Jinsong; Qu, Jiuhui

    2014-01-01

    Microbes have great potential for arsenic (As) and antimony (Sb) bioremediation in heavily contaminated soil because they have the ability to biotransform As and Sb to species that have less toxicity or are more easily removed. In this study, we integrated a metagenomic method with physicochemical characterization to elucidate the composition of microbial community and functional genes (related to As and Sb) in a high As (range from 34.11 to 821.23 mg kg-1) and Sb (range from 226.67 to 3923.07 mg kg-1) contaminated mine field. Metagenomic analysis revealed that microbes from 18 phyla were present in the 5 samples of soil contaminated with high As and Sb. Moreover, redundancy analysis (RDA) of the relationship between the 18 phyla and the concentration of As and Sb demonstrated that 5 phyla of microbes, i.e. Actinobacteria, Firmicutes, Nitrospirae, Tenericutes and Gemmatimonadetes were positively correlated with As and Sb concentration. The distribution, diversity and abundance of functional genes (including arsC, arrA, aioA, arsB and ACR3) were much higher for the samples containing higher As and Sb concentrations. Based on correlation analysis, the results showed a positive relationship between arsC-like (R2 = 0.871) and aioA-like (R2 = 0.675) gene abundance and As concentration, and indicated that intracellular As(V) reduction and As(III) oxidation could be the dominant As detoxification mechanism enabling the microbes to survive in the environment. This study provides a direct and reliable reference on the diversity of microbial community and functional genes in an extremely high concentration As- and Sb-contaminated environment.

  7. Metagenomic Approach Reveals Variation of Microbes with Arsenic and Antimony Metabolism Genes from Highly Contaminated Soil

    PubMed Central

    Luo, Jinming; Bai, Yaohui; Liang, Jinsong; Qu, Jiuhui

    2014-01-01

    Microbes have great potential for arsenic (As) and antimony (Sb) bioremediation in heavily contaminated soil because they have the ability to biotransform As and Sb to species that have less toxicity or are more easily removed. In this study, we integrated a metagenomic method with physicochemical characterization to elucidate the composition of microbial community and functional genes (related to As and Sb) in a high As (range from 34.11 to 821.23 mg kg−1) and Sb (range from 226.67 to 3923.07 mg kg−1) contaminated mine field. Metagenomic analysis revealed that microbes from 18 phyla were present in the 5 samples of soil contaminated with high As and Sb. Moreover, redundancy analysis (RDA) of the relationship between the 18 phyla and the concentration of As and Sb demonstrated that 5 phyla of microbes, i.e. Actinobacteria, Firmicutes, Nitrospirae, Tenericutes and Gemmatimonadetes were positively correlated with As and Sb concentration. The distribution, diversity and abundance of functional genes (including arsC, arrA, aioA, arsB and ACR3) were much higher for the samples containing higher As and Sb concentrations. Based on correlation analysis, the results showed a positive relationship between arsC-like (R2 = 0.871) and aioA-like (R2 = 0.675) gene abundance and As concentration, and indicated that intracellular As(V) reduction and As(III) oxidation could be the dominant As detoxification mechanism enabling the microbes to survive in the environment. This study provides a direct and reliable reference on the diversity of microbial community and functional genes in an extremely high concentration As- and Sb-contaminated environment. PMID:25299175

  8. GSTM1 and APE1 genotypes affect arsenic-induced oxidative stress: a repeated measures study

    PubMed Central

    Breton, Carrie V; Kile, Molly L; Catalano, Paul J; Hoffman, Elaine; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Christiani, David C

    2007-01-01

    Background Chronic arsenic exposure is associated with an increased risk of skin, bladder and lung cancers. Generation of oxidative stress may contribute to arsenic carcinogenesis. Methods To investigate the association between arsenic exposure and oxidative stress, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was evaluated in a cohort of 97 women recruited from an arsenic-endemic region of Bangladesh in 2003. Arsenic exposure was measured in urine, toenails, and drinking water. Drinking water and urine samples were collected on three consecutive days. Susceptibility to oxidative stress was evaluated by genotyping relevant polymorphisms in glutathione-s transferase mu (GSTM1), human 8-oxoguanine glycosylase (hOGG1) and apurinic/apyrimidinic endonuclease (APE1) genes using the Taqman method. Data were analyzed using random effects Tobit regression to account for repeated measures and 8-OHdG values below the detection limit. Results A consistent negative effect for APE1 was observed across water, toenail and urinary arsenic models. APE1 148 glu/glu + asp/glu genotype was associated with a decrease in logged 8-OHdG of 0.40 (95%CI -0.73, -0.07) compared to APE1 148 asp/asp. An association between total urinary arsenic and 8-OHdG was observed among women with the GSTM1 null genotype but not in women with GSTM1 positive. Among women with GSTM1 null, a comparison of the second, third, and fourth quartiles of total urinary arsenic to the first quartile resulted in a 0.84 increase (95% CI 0.27, 1.42), a 0.98 increase (95% CI 033, 1.66) and a 0.85 increase (95% CI 0.27, 1.44) in logged 8-OHdG, respectively. No effects between 8-OHdG and toenail arsenic or drinking water arsenic were observed. Conclusion These results suggest the APE1 variant genotype decreases repair of 8-OHdG and that arsenic exposure is associated with oxidative stress in women who lack a functional GSTM1 detoxification enzyme. PMID:18053222

  9. Characterization and transcription of arsenic respiration and resistance genes during in situ uranium bioremediation

    PubMed Central

    Giloteaux, Ludovic; Holmes, Dawn E; Williams, Kenneth H; Wrighton, Kelly C; Wilkins, Michael J; Montgomery, Alison P; Smith, Jessica A; Orellana, Roberto; Thompson, Courtney A; Roper, Thomas J; Long, Philip E; Lovley, Derek R

    2013-01-01

    The possibility of arsenic release and the potential role of Geobacter in arsenic biogeochemistry during in situ uranium bioremediation was investigated because increased availability of organic matter has been associated with substantial releases of arsenic in other subsurface environments. In a field experiment conducted at the Rifle, CO study site, groundwater arsenic concentrations increased when acetate was added. The number of transcripts from arrA, which codes for the α-subunit of dissimilatory As(V) reductase, and acr3, which codes for the arsenic pump protein Acr3, were determined with quantitative reverse transcription-PCR. Most of the arrA (>60%) and acr3-1 (>90%) sequences that were recovered were most similar to Geobacter species, while the majority of acr3-2 (>50%) sequences were most closely related to Rhodoferax ferrireducens. Analysis of transcript abundance demonstrated that transcription of acr3-1 by the subsurface Geobacter community was correlated with arsenic concentrations in the groundwater. In contrast, Geobacter arrA transcript numbers lagged behind the major arsenic release and remained high even after arsenic concentrations declined. This suggested that factors other than As(V) availability regulated the transcription of arrA in situ, even though the presence of As(V) increased the transcription of arrA in cultures of Geobacter lovleyi, which was capable of As(V) reduction. These results demonstrate that subsurface Geobacter species can tightly regulate their physiological response to changes in groundwater arsenic concentrations. The transcriptomic approach developed here should be useful for the study of a diversity of other environments in which Geobacter species are considered to have an important influence on arsenic biogeochemistry. PMID:23038171

  10. Characterization and Transcription of Arsenic Respiration and Resistance Genes During In Situ Uranium Bioremediation

    SciTech Connect

    Giloteaux, L.; Holmes, Dawn E.; Williams, Kenneth H.; Wrighton, Kelly C.; Wilkins, Michael J.; Montgomery, Alison P.; Smith, Jessica A.; Orellana, Roberto; Thompson, Courtney A.; Roper, Thomas J.; Long, Philip E.; Lovley, Derek R.

    2013-02-04

    The possibility of arsenic release and the potential role of Geobacter in arsenic biogeochemistry during in situ uranium bioremediation was investigated because increased availability of organic matter has been associated with substantial releases of arsenic in other subsurface environments. In a field experiment conducted at the Rifle, CO study site, groundwater arsenic concentrations increased when acetate was added. The number of transcripts from arrA, which codes for the alpha subunit of dissimilatory As(V) reductase, and acr3, which codes for the arsenic pump protein Acr3, were determined with quantitative RT-PCR. Most of the arrA (> 60%) and acr3-1 (> 90%) sequences that were recovered were most similar to Geobacter species, while the majority of acr3-2 (>50%) sequences were most closely related to Rhodoferax ferrireducens. Analysis of transcript abundance demonstrated that transcription of acr3-1 by the subsurface Geobacter community was correlated with arsenic concentrations in the groundwater. In contrast, Geobacter arrA transcript numbers lagged behind the major arsenic release and remained high even after arsenic concentrations declined. This suggested that factors other than As(V) availability regulated transcription of arrA in situ even though the presence of As(V) increased transcription of arrA in cultures of G. lovleyi, which was capable of As(V) reduction. These results demonstrate that subsurface Geobacter species can tightly regulate their physiological response to changes in groundwater arsenic concentrations. The transcriptomic approach developed here should be useful for the study of a diversity of other environments in which Geobacter species are considered to have an important influence on arsenic biogeochemistry.

  11. A review on environmental factors regulating arsenic methylation in humans

    SciTech Connect

    Tseng, C.-H.

    2009-03-15

    Subjects exposed to arsenic show significant inter-individual variation in urinary patterns of arsenic metabolites but insignificant day-to-day intra-individual variation. The inter-individual variation in arsenic methylation can be partly responsible for the variation in susceptibility to arsenic toxicity. Wide inter-ethnic variation and family correlation in urinary arsenic profile suggest a genetic effect on arsenic metabolism. In this paper the environmental factors affecting arsenic metabolism are reviewed. Methylation capacity might reduce with increasing dosage of arsenic exposure. Furthermore, women, especially at pregnancy, have better methylation capacity than their men counterparts, probably due to the effect of estrogen. Children might have better methylation capacity than adults and age shows inconsistent relevance in adults. Smoking and alcohol consumption might be associated with a poorer methylation capacity. Nutritional status is important in the methylation capacity and folate may facilitate the methylation and excretion of arsenic. Besides, general health conditions and medications might influence the arsenic methylation capacity; and technical problems can cause biased estimates. The consumption of seafood, seaweed, rice and other food with high arsenic contents and the extent of cooking and arsenic-containing water used in food preparation may also interfere with the presentation of the urinary arsenic profile. Future studies are necessary to clarify the effects of the various arsenic metabolites including the trivalent methylated forms on the development of arsenic-induced human diseases with the consideration of the effects of confounding factors and the interactions with other effect modifiers.

  12. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water1

    PubMed Central

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V.; Costa, Max

    2015-01-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50–1000 µg/ L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic’s possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. PMID:25759245

  13. Micronucleus frequency in copper-mine workers exposed to arsenic is modulated by the AS3MT Met287Thr polymorphism.

    PubMed

    Hernández, Alba; Paiva, Leiliane; Creus, Amadeu; Quinteros, Domingo; Marcos, Ricard

    2014-01-01

    Arsenic(III)methyltransferase (AS3MT) has been demonstrated to be the key enzyme in the metabolism of arsenic as it catalyses the methylation of arsenite and monomethylarsonic acid (MMA) to form methylated arsenic species, which have higher toxic and genotoxic potential than the parent compounds. The aim of this study is to evaluate if genetic variation in the AS3MT gene influences arsenic-induced cytogenetic damage, measured by the micronucleus (MN) assay. AS3MT Met287Thr allele frequencies and MN values were determined for 207 subjects working in the copper-mine industry, who were exposed to variable levels of arsenic. The urinary arsenic profile was used as individual biomarker of arsenic exposure. Results indicate that the MN frequencies found in peripheral blood lymphocytes of the exposed population poorly correlate with the levels of total arsenic content in urine. Nevertheless, when workers were classified according to their AS3MT Met287Thr genotypes, significantly higher MN values were observed for those carrying the variant allele [odds ratio (OR), 3.4 (1.6-5.2); P=0.0003)]. To our knowledge, these results are the first to show that genetic variation in AS3MT, especially the Met287Thr polymorphism, may play a role in modulating the levels of arsenic-induced cytogenetic damage among individuals chronically exposed to arsenic.

  14. In utero arsenic exposure and fetal immune repertoire in a US pregnancy cohort

    PubMed Central

    Nadeau, Kari C.; Li, Zhigang; Farzan, Shohreh; Koestler, Devin; Robbins, David; Fei, Dennis Liang; Malipatlolla, Meena; Maecker, Holden; Enelow, Richard; Korrick, Susan; Karagas, Margaret R.

    2014-01-01

    Arsenic has wide-ranging effects on human health and there is evidence that it alters the immune response by influencing CD4+/CD8+ T cell ratios, IL-2 cytokine levels, and the expression of immune-response genes. We investigated the impact of in utero environmental arsenic exposure on immune development and function in newborns participating in a pregnancy cohort in New Hampshire, U.S., where arsenic levels have exceeded the current EPA maximum contaminant level of 10 μg/L. Our results showed that maternal urinary arsenic concentrations were inversely related to absolute total CD45RA+ CD4+ cord blood CD69+ T cell counts (N=116, p=0.04) and positively associated with CD45RA+ CD69− CD294+ cell counts (p=0.01). In placental samples (N=70), higher in utero urinary arsenic concentrations were positively associated with expression of IL1β (p=0.03). These data provide evidence that relatively low-level arsenic exposure in utero may alter the fetal immune system and lead to immune dysregulation. PMID:25229165

  15. Polymorphisms in the TNF-α and IL10 Gene Promoters and Risk of Arsenic-Induced Skin Lesions and Other Nondermatological Health Effects

    PubMed Central

    Banerjee, Nilanjana; Nandy, Sujay; Kearns, James K.; Bandyopadhyay, Apurba K.; Das, Jayanta K.; Majumder, Papiya; Basu, Santanu; Banerjee, Saptarshi; Sau, Tanmoy Jyoti; States, J. Christopher; Giri, Ashok K.

    2011-01-01

    In West Bengal, India, at present, more than 26 million people are exposed to arsenic through drinking water. Among them, only 15–20% manifest arsenic-induced noncancerous, precancerous, and cancerous skin lesions, indicating that genetic variants play important role in arsenic susceptibility. Chronic arsenic exposure has been associated with impairment of immune systems in the exposed individuals. Because cytokines are important immune mediators, alteration in expression of these gene products may lead to arsenic-specific disease manifestations. The aim of the present work was to investigate the association between the TNF-α−308G>A (rs1800629) and IL10 −3575T>A (rs1800890) polymorphisms and arsenic-induced dermatological and nondermatological health outcomes. A case-control study was conducted in West Bengal, India, involving 207 cases with arsenic-induced skin lesions and 190 controls without skin lesions having similar arsenic exposure. The polymorphisms were determined using conventional PCR-sequencing method. ELISA was done to determine the serum levels of the two cytokines tumor necrosis factor α (TNF-α) and interleukin 10 (IL10). Associations between the polymorphisms studied and nondermatological health effects in the study subjects were determined from our epidemiological survey data. Individuals with GA/AA (−308 TNF-α) and TA/AA (−3575 IL10) genotypes were at higher risk of developing arsenic-induced skin lesions, ocular, and respiratory diseases. Also the −308 TNF A allele corresponded to a higher production of TNF-α, and −3575 IL10 A allele corresponded to a lower production of IL10. Thus, the polymorphisms studied impart significant risk toward development of arsenic-induced dermatological and nondermatological health effects in the chronically exposed population of West Bengal, India. PMID:21357384

  16. Vitamin D receptor gene Alw I, Fok I, Apa I, and Taq I polymorphisms in patients with urinary stone.

    PubMed

    Seo, Ill Young; Kang, In-Hong; Chae, Soo-Cheon; Park, Seung Chol; Lee, Young-Jin; Yang, Yun Sik; Ryu, Soo Bang; Rim, Joung Sik

    2010-04-01

    To evaluate vitamin D receptor (VDR) gene polymorphisms in Korean patients so as to identify the candidate genes associated with urinary stones. Urinary stones are a multifactorial disease that includes various genetic factors. A normal control group of 535 healthy subjects and 278 patients with urinary stones was evaluated. Of 125 patients who presented stone samples, 102 had calcium stones on chemical analysis. The VDR gene Alw I, Fok I, Apa I, and Taq I polymorphisms were evaluated using the polymerase chain reaction-restriction fragment length polymorphism analysis. Allelic and genotypic frequencies were calculated to identify associations in both groups. The haplotype frequencies of the VDR gene polymorphisms for multiple loci were also determined. For the VDR gene Alw I, Fok I, Apa I, and Taq I polymorphisms, there was no statistically significant difference between the patients with urinary stones and the healthy controls. There was also no statistically significant difference between the patients with calcium stones and the healthy controls. A novel haplotype (Ht 4; CTTT) was identified in 13.5% of the patients with urinary stones and in 8.3% of the controls (P = .001). The haplotype frequencies were significantly different between the patients with calcium stones and the controls (P = .004). The VDR gene Alw I, Fok I, Apa I, and Taq I polymorphisms does not seem to be candidate genetic markers for urinary stones in Korean patients. However, 1 novel haplotype of the VDR gene polymorphisms for multiple loci might be a candidate genetic marker. Copyright 2010 Elsevier Inc. All rights reserved.

  17. Nuclear factor erythroid 2-related factor gene variants and susceptibility of arsenic-related skin lesions.

    PubMed

    Cordova, E J; Valenzuela, O L; Sánchez-Peña, L C; Escamilla-Guerrero, G; Hernández-Zavala, A; Orozco, L; Del Razo, L M

    2014-06-01

    Inorganic arsenic (iAs) is an important pollutant associated with various chronic-degenerative diseases. The cytoprotective protein nuclear factor erythroid 2-related factor (NRF2) has been proposed as an important responsive mechanism against iAs exposure. The aim of this study was to determine whether the risk of skin lesions in people exposed to iAs-contaminated water could be modified by the presence of single nucleotide polymorphisms in the NRF2 coding gene. We studied 117 individuals with long-term iAs exposure and 120 nonexposed individuals. Total As was determined in water, meanwhile iAs and its metabolites were measured in urine. The iAs-induced skin lesion status was evaluated by expert dermatologists. We sequenced the promoter region of NRF2 in a sample of 120 healthy donors. We found four polymorphisms previously reported and one novel polymorphism in the 5' regulatory region of the NRF2. In this study, we did not find allelic and genotype association of NRF2 polymorphisms with iAs-related skin lesion. However, the analysis of haplotypes composed by -653GA, and -617CA NRF2 single nucleotide polymorphisms showed a significant association with protection against skin lesions in the low-As exposure group. This is the first report studying the association between NRF2 polymorphisms and susceptibility of As-related skin lesions. Increasing the sample size will allow us to confirm this data. © The Author(s) 2014.

  18. Colorimetric TMPRSS2-ERG Gene Fusion Detection in Prostate Cancer Urinary Samples via Recombinase Polymerase Amplification.

    PubMed

    Koo, Kevin M; Wee, Eugene J H; Trau, Matt

    2016-01-01

    TMPRSS2 (Exon 1)-ERG (Exon 4) is the most frequent gene fusion event in prostate cancer (PC), and is highly PC-specific unlike the current serum prostate specific antigen (PSA) biomarker. However, TMPRSS2-ERG levels are currently measured with quantitative reverse-transcription PCR (RT-qPCR) which is time-consuming and requires costly equipment, thus limiting its use in clinical diagnostics. Herein, we report a novel rapid, cost-efficient and minimal-equipment assay named "FusBLU" for detecting TMPRSS2-ERG gene fusions from urine. TMPRSS2-ERG mRNA was amplified by isothermal reverse transcription-recombinase polymerase amplification (RT-RPA), magnetically-isolated, and detected through horseradish peroxidase (HRP)-catalyzed colorimetric reaction. FusBLU was specific for TMPRSS2-ERG mRNA with a low visual detection limit of 10(5) copies. We also demonstrated assay readout versatility on 3 potentially useful platforms. The colorimetric readout was detectable by naked eye for a quick yes/no evaluation of gene fusion presence. On the other hand, a more quantitative TMPRSS2-ERG detection was achievable by absorbance/electrochemical measurements. FusBLU was successfully applied to 12 urinary samples and results were validated by gold-standard RT-qPCR. We also showed that sediment RNA was likely the main source of TMPRSS2-ERG mRNA in urinary samples. We believe that our assay is a potential clinical screening tool for PC and could also have wide applications for other disease-related fusion genes.

  19. Colorimetric TMPRSS2-ERG Gene Fusion Detection in Prostate Cancer Urinary Samples via Recombinase Polymerase Amplification

    PubMed Central

    Koo, Kevin M.; Wee, Eugene J.H.; Trau, Matt

    2016-01-01

    TMPRSS2 (Exon 1)-ERG (Exon 4) is the most frequent gene fusion event in prostate cancer (PC), and is highly PC-specific unlike the current serum prostate specific antigen (PSA) biomarker. However, TMPRSS2-ERG levels are currently measured with quantitative reverse-transcription PCR (RT-qPCR) which is time-consuming and requires costly equipment, thus limiting its use in clinical diagnostics. Herein, we report a novel rapid, cost-efficient and minimal-equipment assay named “FusBLU” for detecting TMPRSS2-ERG gene fusions from urine. TMPRSS2-ERG mRNA was amplified by isothermal reverse transcription-recombinase polymerase amplification (RT-RPA), magnetically-isolated, and detected through horseradish peroxidase (HRP)-catalyzed colorimetric reaction. FusBLU was specific for TMPRSS2-ERG mRNA with a low visual detection limit of 105 copies. We also demonstrated assay readout versatility on 3 potentially useful platforms. The colorimetric readout was detectable by naked eye for a quick yes/no evaluation of gene fusion presence. On the other hand, a more quantitative TMPRSS2-ERG detection was achievable by absorbance/electrochemical measurements. FusBLU was successfully applied to 12 urinary samples and results were validated by gold-standard RT-qPCR. We also showed that sediment RNA was likely the main source of TMPRSS2-ERG mRNA in urinary samples. We believe that our assay is a potential clinical screening tool for PC and could also have wide applications for other disease-related fusion genes. PMID:27375789

  20. Individual differences in arsenic metabolism and lung cancer in a case-control study in Cordoba, Argentina

    SciTech Connect

    Steinmaus, Craig; Yuan Yan; Kalman, Dave; Rey, Omar A.; Skibola, Christine F.; Dauphine, Dave; Basu, Anamika; Porter, Kristin E.; Hubbard, Alan; Bates, Michael N.; Smith, Martyn T.; Smith, Allan H.

    2010-09-01

    In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although in most people this process is not complete. Previous studies have identified associations between the proportion of urinary MMA (%MMA) and increased risks of several arsenic-related diseases, although none of these reported on lung cancer. In this study, urinary arsenic metabolites were assessed in 45 lung cancer cases and 75 controls from arsenic-exposed areas in Cordoba, Argentina. Folate has also been linked to arsenic-disease susceptibility, thus an exploratory assessment of associations between single nucleotide polymorphisms in folate metabolizing genes, arsenic methylation, and lung cancer was also conducted. In analyses limited to subjects with metabolite concentrations above detection limits, the mean %MMA was higher in cases than in controls (17.5% versus 14.3%, p = 0.01). The lung cancer odds ratio for subjects with %MMA in the upper tertile compared to those in the lowest tertile was 3.09 (95% CI, 1.08-8.81). Although the study size was too small for a definitive conclusion, there was an indication that lung cancer risks might be highest in those with a high %MMA who also carried cystathionine {beta}-synthase (CBS) rs234709 and rs4920037 variant alleles. This study is the first to report an association between individual differences in arsenic metabolism and lung cancer, a leading cause of arsenic-related mortality. These results add to the increasing body of evidence that variation in arsenic metabolism plays an important role in arsenic-disease susceptibility.

  1. Individual Differences in Arsenic Metabolism and Lung Cancer in a Case-Control Study in Cordoba, Argentina

    PubMed Central

    Steinmaus, Craig; Yuan, Yan; Kalman, Dave; Rey, Omar A.; Skibola, Christine F.; Dauphine, Dave; Basu, Anamika; Porter, Kristin E.; Hubbard, Alan; Bates, Michael N.; Smith, Martyn T.; Smith, Allan H.

    2013-01-01

    In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although in most people this process is not complete. Previous studies have identified associations between the proportion of urinary MMA (%MMA) and increased risks of several arsenic-related diseases, although none of these reported on lung cancer. In this study, urinary arsenic metabolites were assessed in 45 lung cancer cases and 75 controls from arsenic-exposed areas in Cordoba, Argentina. Folate has also been linked to arsenic-disease susceptibility, thus an exploratory assessment of associations between single nucleotide polymorphisms in folate metabolizing genes, arsenic methylation, and lung cancer was also conducted. In analyses limited to subjects with metabolite concentrations above detection limits, the mean %MMA was higher in cases than in controls (17.5% versus 14.3%, p = 0.01). The lung cancer odds ratios for subjects with %MMA in the upper tertile compared to those in the lowest tertile was 3.09 (95% CI, 1.08–8.81). Although the study size was too small for a definitive conclusion, there was an indication that lung cancer risks might be highest in those with a high %MMA who also carried cystathionine β-synthase (CBS) rs234709 and rs4920037 variant alleles. This study is the first to report an association between individual differences in arsenic metabolism and lung cancer, a leading cause of arsenic-related mortality. These results add to the increasing body of evidence that variation in arsenic metabolism plays an important role in arsenic-disease susceptibility. PMID:20600216

  2. Isolation of a cDNA Clone for Mouse Urinary Proteins: Age- And Sex-Related Expression of Mouse Urinary Protein Genes is Transcriptionally Controlled

    NASA Astrophysics Data System (ADS)

    Derman, Eva

    1981-09-01

    A recombinant cDNA plasmid derived from mouse urinary protein (MUP) mRNA was isolated and used to determine the level of control of the developmentally regulated and the sex-linked expression of MUP genes by monitoring the transcription of MUP mRNA sequences in isolated liver nuclei. No transcription of MUP genes could be detected in liver nuclei of prepubescent animals whose livers do not contain measurable MUP mRNA. Transcription of MUP genes in the livers of adult male mice was 6-fold higher than in the livers of adult female mice, proportional to the difference in MUP mRNA concentrations. Transcriptional control mechanisms are therefore implicated as responsible for both the developmentally and the sex-linked changes in the expression of MUP genes.

  3. Ethnic differences in five intronic polymorphisms associated with arsenic metabolism within human arsenic (+ 3 oxidation state) methyltransferase (AS3MT) gene

    SciTech Connect

    Fujihara, Junko; Fujii, Yoshimi; Agusa, Tetsuro; Kunito, Takashi; Yasuda, Toshihiro; Moritani, Tamami; Takeshita, Haruo

    2009-01-01

    Human arsenic (+ 3 oxidation state) methyltransferase (AS3MT) is known to catalyze the methylation of arsenite, and intronic single-nucleotide polymorphisms (SNPs: G7395A, G12390C, T14215C, T35587C, and G35991A) in the AS3MT gene were shown to be related to inter-individual variation in the arsenic metabolism. In the present study, the genotyping for these SNPs was developed using the polymerase chain reaction and restriction fragment length polymorphism technique. Applying this method, the genotype distribution among the Ovambo, Turkish, Mongolian, Korean, and Japanese populations was investigated, and our results were compared with those from other studies. G7395, G12390, T35587, and A35991 were predominant among the five populations in our study. However, a previous study in Argentina, C12390 and G35991 showed the highest allele frequency among the eight populations studied in other studies. The dominant allele of T14215C differed among populations: the T14215 allele was predominant in Argentina, the allele frequency of C14215 was higher than that of T14215 among Turks, Mongolians, Europeans, and American ancestry. In Korea and Japan, similar allele frequencies were observed in T14215 and C14215. Higher allele frequencies were observed in haplotype G7395/G12390/C14215/T35587 with frequencies of 0.40 (Turks), 0.28 (Mongolians), and 0.23 (Koreans). On the other hand, the allele frequency for G7395/G14215/T35587/A35991 was the highest among the Ovambos (0.32), and the frequency for G7395/G12390/C35587/G35991 was the highest among the Japanese (0.27). It is noteworthy that the Japanese haplotype differs from that of the Koreans and Mongolians, which indicates the importance of investigating other intronic polymorphisms in AS3MT, especially in Asians.

  4. Gene-arsenic interaction in longitudinal changes of blood pressure: Findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh.

    PubMed

    Farzan, Shohreh F; Karagas, Margaret R; Jiang, Jieying; Wu, Fen; Liu, Mengling; Newman, Jonathan D; Jasmine, Farzana; Kibriya, Muhammad G; Paul-Brutus, Rachelle; Parvez, Faruque; Argos, Maria; Scannell Bryan, Molly; Eunus, Mahbub; Ahmed, Alauddin; Islam, Tariqul; Rakibuz-Zaman, Muhammad; Hasan, Rabiul; Sarwar, Golam; Slavkovich, Vesna; Graziano, Joseph; Ahsan, Habibul; Chen, Yu

    2015-10-01

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and mounting evidence indicates that toxicant exposures can profoundly impact on CVD risk. Epidemiologic studies have suggested that arsenic (As) exposure is positively related to increases in blood pressure (BP), a primary CVD risk factor. However, evidence of whether genetic susceptibility can modify the association between As and BP is lacking. In this study, we used mixed effect models adjusted for potential confounders to examine the interaction between As exposure from well water and potential genetic modifiers on longitudinal change in BP over approximately 7years of follow-up in 1137 subjects selected from the Health Effects of Arsenic Longitudinal Study (HEALS) cohort in Bangladesh. Genotyping was conducted for 235 SNPs in 18 genes related to As metabolism, oxidative stress and endothelial function. We observed interactions between 44 SNPs with well water As for one or more BP outcome measures (systolic, diastolic, or pulse pressure (PP)) over the course of follow-up. The interaction between CYBA rs3794624 and well water As on annual PP remained statistically significant after correction for multiple comparisons (FDR-adjusted p for interaction=0.05). Among individuals with the rs3794624 variant genotype, well water As was associated with a 2.23mmHg (95% CI: 1.14-3.32) greater annual increase in PP, while among those with the wild type, well water As was associated with a 0.13mmHg (95% CI: 0.02-0.23) greater annual increase in PP. Our results suggest that genetic variability may contribute to As-associated increases in BP over time.

  5. GT-repeat polymorphism in the heme oxygenase-1 gene promoter and the risk of carotid atherosclerosis related to arsenic exposure

    PubMed Central

    2010-01-01

    Background Arsenic is a strong stimulus of heme oxygenase (HO)-1 expression in experimental studies in response to oxidative stress caused by a stimulus. A functional GT-repeat polymorphism in the HO-1 gene promoter was inversely correlated to the development of coronary artery disease in diabetics and development of restenosis following angioplasty in patients. The role of this potential vascular protective factor in carotid atherosclerosis remains unclear. We previously reported a graded association of arsenic exposure in drinking water with an increased risk of carotid atherosclerosis. In this study, we investigated the relationship between HO-1 genetic polymorphism and the risk of atherosclerosis related to arsenic. Methods Three-hundred and sixty-seven participants with an indication of carotid atherosclerosis and an additional 420 participants without the indication, which served as the controls, from two arsenic exposure areas in Taiwan, a low arsenic-exposed Lanyang cohort and a high arsenic-exposed LMN cohort, were studied. Carotid atherosclerosis was evaluated using a duplex ultrasonographic assessment of the extracranial carotid arteries. Allelic variants of (GT)n repeats in the 5'-flanking region of the HO-1 gene were identified and grouped into a short (S) allele (< 27 repeats) and long (L) allele (≥ 27 repeats). The association of atherosclerosis and the HO-1 genetic variants was assessed by a logistic regression analysis, adjusted for cardiovascular risk factors. Results Analysis results showed that arsenic's effect on carotid atherosclerosis differed between carriers of the class S allele (OR 1.39; 95% CI 0.86-2.25; p = 0.181) and non-carriers (OR 2.65; 95% CI 1.03-6.82; p = 0.044) in the high-exposure LMN cohort. At arsenic exposure levels exceeding 750 μg/L, difference in OR estimates between class S allele carriers and non-carriers was borderline significant (p = 0.051). In contrast, no such results were found in the low-exposure Lanyang

  6. Global Gene Expression Profiling of Hyperkeratotic Skin Lesions from Inner Mongolians Chronically Exposed to Arsenic

    EPA Science Inventory

    The skin is an organ that is highly sensitive to chronic arsenic exposure. Skin lesions such as hyperkeratoses (HKs), which are characterized by hyperproliferation and aberrations in terminal epidermal differentiation, are common early manifestations of arsenicosis in humans. H...

  7. Global Gene Expression Profiling of Hyperkeratotic Skin Lesions from Inner Mongolians Chronically Exposed to Arsenic

    EPA Science Inventory

    The skin is an organ that is highly sensitive to chronic arsenic exposure. Skin lesions such as hyperkeratoses (HKs), which are characterized by hyperproliferation and aberrations in terminal epidermal differentiation, are common early manifestations of arsenicosis in humans. H...

  8. Pattern of expression of apoptosis and inflammatory genes in humans exposed to arsenic and/or fluoride.

    PubMed

    Salgado-Bustamante, Mariana; Ortiz-Pérez, María D; Calderón-Aranda, Emma; Estrada-Capetillo, Lizbeth; Niño-Moreno, Perla; González-Amaro, Roberto; Portales-Pérez, Diana

    2010-01-15

    We have assessed whether the combined exposure to arsenic (As) and fluoride (F) exerts a different effect than the exposure to As alone on the pattern of expression of apoptosis and inflammatory genes by immune cells. RNA was extracted from peripheral blood mononuclear cells from twenty individuals exposed or not to As or F or both. Then, cDNA was isolated, and the expression of 180 genes related to apoptosis and inflammation was tested by a cDNA array test. We found significant differences in the expression of 9 apoptosis and 15 inflammation genes in the three exposed groups compared to non-exposed individuals. In addition, subjects exposed to As or F or both showed different patterns of expression of at least 19 genes. Our data indicate that the combined exposure to As and F has a different effect on gene expression than the exposure to As or F alone.

  9. Interaction between arsenic exposure from drinking water and genetic susceptibility in carotid intima-media thickness in Bangladesh.

    PubMed

    Wu, Fen; Jasmine, Farzana; Kibriya, Muhammad G; Liu, Mengling; Cheng, Xin; Parvez, Faruque; Paul-Brutus, Rachelle; Paul, Rina Rani; Sarwar, Golam; Ahmed, Alauddin; Jiang, Jieying; Islam, Tariqul; Slavkovich, Vesna; Rundek, Tatjana; Demmer, Ryan T; Desvarieux, Moise; Ahsan, Habibul; Chen, Yu

    2014-05-01

    Epidemiologic studies that evaluated genetic susceptibility for the effects of arsenic exposure from drinking water on subclinical atherosclerosis are limited. We conducted a cross-sectional study of 1078 participants randomly selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh to evaluate whether the association between arsenic exposure and carotid artery intima-media thickness (cIMT) differs by 207 single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. Although not statistically significant after correcting for multiple testing, nine SNPs in APOE, AS3MT, PNP, and TNF genes had a nominally statistically significant interaction with well-water arsenic in cIMT. For instance, the joint presence of a higher level of well-water arsenic (≥ 40.4 μg/L) and the GG genotype of AS3MT rs3740392 was associated with a difference of 40.9 μm (95% CI = 14.4, 67.5) in cIMT, much greater than the difference of cIMT associated with the genotype alone (β = -5.1 μm, 95% CI = -31.6, 21.3) or arsenic exposure alone (β = 7.2 μm, 95% CI = -3.1, 17.5). The pattern and magnitude of the interactions were similar when urinary arsenic was used as the exposure variable. Additionally, the at-risk genotypes of the AS3MT SNPs were positively related to the proportion of monomethylarsonic acid (MMA) in urine, which is indicative of arsenic methylation capacity. The findings provide novel evidence that genetic variants related to arsenic metabolism may play an important role in arsenic-induced subclinical atherosclerosis. Future replication studies in diverse populations are needed to confirm the findings. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism.

    PubMed

    Liu, Jie; Xie, Yaxiong; Cooper, Ryan; Ducharme, Danica M K; Tennant, Raymond; Diwan, Bhalchandra A; Waalkes, Michael P

    2007-05-01

    Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood.

  11. A Distinct and Replicable Squamous Cell Carcinoma Gene INPPA5 Variant Modifies Susceptibility of Arsenic-Associated Skin Lesions in Bangladesh

    PubMed Central

    Seow, Wei Jie; Pan, Wen-Chi; Kile, Molly L.; Lin, Tong; Baccarelli, Andrea; Quamruzzaman, Quazi; Rahman, Mahmuder; Mostofa, Golam; Rakibuz-Zaman, Muhammad; Kibriya, Muhammad; Ahsan, Habibul; Lin, Xihong; Christiani, David C.

    2015-01-01

    Background Single nucleotide polymorphisms (SNPs) in inflammation, one-carbon metabolism and skin cancer genes might influence susceptibility to arsenic-induced skin lesions. Methods A case-control study was conducted in Pabna, Bangladesh (2001-2003) and drinking water arsenic concentration was measured for each participant. A panel of twenty-five candidate SNPs was analyzed in 540 cases and 400 controls. Logistic regression was used to estimate the association between each SNP and the potential for gene-environment interactions in skin lesion risk adjusting for relevant covariates. Replication testing was conducted in an independent Bangladesh population with 488 cases and 2,794 controls. Results In the discovery population, genetic variants in the one-carbon metabolism genes PEMT (rs2278952, P for interaction = 0.004; rs897453, P for interaction = 0.05) and DHFR (rs1650697, P for interaction = 0.02), inflammation gene IL10 (rs3024496, P for interaction = 0.04), and skin cancer genes INPP5A (rs1133400, P for interaction = 0.03) and XPC (rs2228000, P for interaction = 0.01) significantly modified the association between arsenic and skin lesions after adjusting for multiple comparisons. The significant gene-environment interaction between a SNP in INPP5A gene (rs1133400) and water arsenic on skin lesion risk was successfully replicated in an independent population (P for interaction = 0.03). Conclusion Minor allele carriers of skin cancer gene INPP5A modified odds of arsenic-induced skin lesions in both main and replicative populations. Genetic variation in INPP5A appears to have a role in susceptibility to arsenic toxicity. PMID:25759212

  12. Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism

    SciTech Connect

    Liu Jie . E-mail: Liu6@niehs.nih.gov; Xie Yaxiong; Cooper, Ryan; Ducharme, Danica M.K.; Tennant, Raymond; Diwan, Bhalchandra A.; Waalkes, Michael P.

    2007-05-01

    Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p < 0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17{beta}-hydroxysteroid dehydrogenase-7 (HSD17{beta}7; involved in estradiol production) and decreased expression of HSD17{beta}5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood.

  13. Blood Pressure Associated with Arsenic Methylation and Arsenic Metabolism Caused by Chronic Exposure to Arsenic in Tube Well Water.

    PubMed

    Wei, Bing Gan; Ye, Bi Xiong; Yu, Jiang Ping; Yang, Lin Sheng; Li, Hai Rong; Xia, Ya Juan; Wu, Ke Gong

    2017-05-01

    The effects of arsenic exposure from drinking water, arsenic metabolism, and arsenic methylation on blood pressure (BP) were observed in this study. The BP and arsenic species of 560 participants were determined. Logistic regression analysis was applied to estimate the odds ratios of BP associated with arsenic metabolites and arsenic methylation capability. BP was positively associated with cumulative arsenic exposure (CAE). Subjects with abnormal diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) usually had higher urinary iAs (inorganic arsenic), MMA (monomethylated arsenic), DMA (dimethylated arsenic), and TAs (total arsenic) than subjects with normal DBP, SBP, and PP. The iAs%, MMA%, and DMA% differed slightly between subjects with abnormal BP and those with normal BP. The PMI and SMI were slightly higher in subjects with abnormal PP than in those with normal PP. Our findings suggest that higher CAE may elevate BP. Males may have a higher risk of abnormal DBP, whereas females have a higher risk of abnormal SBP and PP. Higher urinary iAs may increase the risk of abnormal BP. Lower PMI may elevate the BP. However, higher SMI may increase the DBP and SBP, and lower SMI may elevate the PP. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  14. THE REACTIVE OXYGEN SPECIES (ROS) THEORY OF ARSENIC CARCINOGENESIS

    EPA Science Inventory



    Arsenic is a human carcinogen in skin, lung, liver, urinary bladder
    and kidney. At this time, there is not a scientific consensus on the
    mechanisms/modes of action for arsenic carcinogenesis. Proposed
    mechanisms/modes of action for arsenic carcinogenesi...

  15. THE REACTIVE OXYGEN SPECIES (ROS) THEORY OF ARSENIC CARCINOGENESIS

    EPA Science Inventory



    Arsenic is a human carcinogen in skin, lung, liver, urinary bladder
    and kidney. At this time, there is not a scientific consensus on the
    mechanisms/modes of action for arsenic carcinogenesis. Proposed
    mechanisms/modes of action for arsenic carcinogenesi...

  16. Identification of genes conferring arsenic resistance to Escherichia coli from an effluent treatment plant sludge metagenomic library.

    PubMed

    Chauhan, Nar Singh; Ranjan, Ravi; Purohit, Hemant J; Kalia, Vipin C; Sharma, Rakesh

    2009-01-01

    The majority of bacteria elude culture in the laboratory. A metagenomic approach provides culture-independent access to the gene pool of the whole bacterial community. A metagenomic library was constructed from an industrial effluent treatment plant sludge containing about 1.25 Gb of microbial community DNA. Two arsenic-resistant clones were selected from the metagenomic library. Clones MT3 and MT6 had eight- and 18-fold higher resistance to sodium arsenate in comparison with the parent strain, respectively. The clones also showed increased resistance to arsenite but not to antimony. Sequence analysis of the clones revealed genes encoding for putative arsenate reductases and arsenite efflux pumps. A novel arsenate resistance gene (arsN) encoding a protein with similarity to acetyltransferases was identified from clone MT6. ArsN homologues were found to be closely associated with arsenic resistance genes in many bacterial genomes. ArsN homologues were found fused to putative arsenate reductases in Methylibium petroleiphilum PM1 and Anaeromyxobacter dehalogenans 2CP-C and with a putative arsenite chaperone in Burkholderia vietnamiensis G4. ArsN alone resulted in an approximately sixfold higher resistance to sodium arsenate in wild-type Escherichia coli W3110.

  17. Thyroid hormone related gene transcription in southern sand flathead (Platycephalus bassensis) is associated with environmental mercury and arsenic exposure.

    PubMed

    Fu, Dingkun; Leef, Melanie; Nowak, Barbara; Bridle, Andrew

    2017-07-01

    Arsenic (As) and mercury (Hg) are ubiquitous elements known to disrupt thyroid function in vertebrates. To explore the underlying mechanisms of Hg and As on the fish thyroid system, we investigated the associations between muscle concentrations of Hg and As with thyroid-related gene transcription in flathead (Platycephalus bassensis) from a contaminated estuary. We sampled fish at several sites to determine the hepatic expression of genes including deiodinases (D1 and D2), transthyretin (TTR), thyroid hormone receptors (TRα and TRβ) and related them to Hg and As levels in the same individuals. Negative correlations were observed between Hg levels and D2, TTR, TRα and TRβ, whereas positive associations were found between As concentrations and TTR and TRβ. These results suggest that Hg and As exposures from environmental pollution affect the regulation of genes important for normal thyroid function in fish. These thyroid-related genes could be used as biomarkers for monitoring environmental thyroid-hormone disrupting chemicals.

  18. PEPTIDE BINDING AS A MODE OF ACTION FOR THE CARCINOGENICITY AND TOXICITY OF ARSENIC

    EPA Science Inventory

    Arsenic exposure leads to tumors in human skin, lung, urinary bladder, kidney and liver. Three likely initial stages of arsenical-macromolecular interaction are (1) binding of trivalent arsenicals to the sulfhydryl groups of peptides and proteins, (2) arsenical-induced generation...

  19. PEPTIDE BINDING AS A MODE OF ACTION FOR THE CARCINOGENICITY AND TOXICITY OF ARSENIC

    EPA Science Inventory

    Arsenic exposure leads to tumors in human skin, lung, urinary bladder, kidney and liver. Three likely initial stages of arsenical-macromolecular interaction are (1) binding of trivalent arsenicals to the sulfhydryl groups of peptides and proteins, (2) arsenical-induced generation...

  20. Escherichia coli Global Gene Expression in Urine from Women with Urinary Tract Infection

    PubMed Central

    Rasko, David A.; Faerber, Gary J.; Mobley, Harry L. T.

    2010-01-01

    Murine models of urinary tract infection (UTI) have provided substantial data identifying uropathogenic E. coli (UPEC) virulence factors and assessing their expression in vivo. However, it is unclear how gene expression in these animal models compares to UPEC gene expression during UTI in humans. To address this, we used a UPEC strain CFT073-specific microarray to measure global gene expression in eight E. coli isolates monitored directly from the urine of eight women presenting at a clinic with bacteriuria. The resulting gene expression profiles were compared to those of the same E. coli isolates cultured statically to exponential phase in pooled, sterilized human urine ex vivo. Known fitness factors, including iron acquisition and peptide transport systems, were highly expressed during human UTI and support a model in which UPEC replicates rapidly in vivo. While these findings were often consistent with previous data obtained from the murine UTI model, host-specific differences were observed. Most strikingly, expression of type 1 fimbrial genes, which are among the most highly expressed genes during murine experimental UTI and encode an essential virulence factor for this experimental model, was undetectable in six of the eight E. coli strains from women with UTI. Despite the lack of type 1 fimbrial expression in the urine samples, these E. coli isolates were generally capable of expressing type 1 fimbriae in vitro and highly upregulated fimA upon experimental murine infection. The findings presented here provide insight into the metabolic and pathogenic profile of UPEC in urine from women with UTI and represent the first transcriptome analysis for any pathogenic E. coli during a naturally occurring infection in humans. PMID:21085611

  1. Environmental arsenic exposure and serum matrix metalloproteinase-9

    PubMed Central

    Burgess, Jefferey L.; Kurzius-Spencer, Margaret; O’Rourke, Mary Kay; Littau, Sally R.; Roberge, Jason; Meza-Montenegro, Maria Mercedes; Gutiérrez-Millán, Luis Enrique; Harris, Robin B.

    2014-01-01

    The objective of this study was to evaluate the relationship between environmental arsenic exposure and serum matrix metalloproteinase (MMP)-9, a biomarker associated with cardiovascular disease and cancer. In a cross-sectional study of residents of Arizona, USA (n=215) and Sonora, Mexico (n=163), drinking water was assayed for total arsenic, and daily drinking water arsenic intake estimated. Urine was speciated for arsenic and concentrations were adjusted for specific gravity. Serum was analyzed for MMP-9 using ELISA. Mixed model linear regression was used to assess the relation among drinking water arsenic concentration, drinking water arsenic intake, urinary arsenic sum of species (the sum of arsenite, arsenate, monomethylarsonic acid and dimethylarsinic acid), and MMP-9, controlling for autocorrelation within households. Drinking water arsenic concentration and intake were positively associated with MMP-9, both in crude analysis and after adjustment for gender, country/ethnicity, age, body mass index, current smoking and diabetes. Urinary arsenic sum of species was positively associated with MMP-9 in multivariable analysis only. Using Akaike’s Information Criterion, arsenic concentration in drinking water provided a better fitting model of MMP-9, than either urinary arsenic or drinking water arsenic intake. In conclusion, arsenic exposure was positively associated with MMP-9 using all three exposure metrics evaluated. PMID:23232971

  2. Further studies on aberrant gene expression associated with arsenic-induced malignant transformation in rat liver TRL1215 cells

    SciTech Connect

    Liu Jie . E-mail: Liu6@niehs.nih.gov; Benbrahim-Tallaa, Lamia; Qian Xun; Yu, Limei; Xie Yaxiong; Boos, Jennifer; Qu Wei; Waalkes, Michael P.

    2006-11-01

    Chronic arsenic exposure of rat liver epithelial TRL1215 cells induced malignant transformation in a concentration-dependent manner. To further define the molecular events of these arsenic-transformed cells (termed CAsE cells), gene expressions associated with arsenic carcinogenesis or influenced by methylation were examined. Real-time RT-PCR showed that at carcinogenic concentrations (500 nM, and to a less extent 250 nM of arsenite), the expressions of {alpha}-fetoprotein (AFP), Wilm's tumor protein-1 (WT-1), c-jun, c-myc, H-ras, c-met and hepatocyte growth factor, heme oxygenase-1, superoxide dismutase-1, glutathione-S-transferase-{pi} and metallothionein-1 (MT) were increased between 3 to 12-fold, while expressions of insulin-like growth factor II (IGF-II) and fibroblast growth factor receptor (FGFR1) were essentially abolished. These changes were not significant at the non-carcinogenic concentration (125 nM), except for IGF-II. The positive cell-cycle regulators cyclin D1 and PCNA were overexpressed in CAsE cells, while the negative regulators p21 and p16 were suppressed. Western-blot confirmed increases in AFP, WT-1, cyclin D1 and decreases in p16 and p21 protein in CAsE cells. The CAsE cells over-expressed MT but the demethylating agent 5-aza-deoxycytidine (5-aza-dC, 2.5 {mu}M, 72 h) stimulated further MT expression. 5-Aza-deoxycytidine restored the loss of expression of p21 in CAsE cells to control levels, but did not restore the expression of p16, IGF-II, or FGFR1, indicating the loss of expression of these genes is due to factors other than DNA methylation changes. Overall, an intricate variety of gene expression changes occur in arsenic-induced malignant transformation of liver cells including oncogene activation and alterations in expression of genes critical to growth regulation.

  3. Effects of arsenic exposure from drinking water on spatial memory, ultra-structures and NMDAR gene expression of hippocampus in rats.

    PubMed

    Luo, Jiao-hua; Qiu, Zhi-qun; Shu, Wei-qun; Zhang, Yong-yan; Zhang, Liang; Chen, Ji-an

    2009-01-30

    Epidemiological investigations indicate that chronic arsenic exposure can damage neurobehavioral function in children. The present study was aimed to study the effects of arsenic exposure from drinking water on the spatial memory, and hippocampal ultra-structures and N-methyl-d-aspartate receptor (NMDAR) gene expression in rats. Sprague-Dawley rats were assigned to four groups: rats in control group drank regular water, rats in other groups drank water with final arsenic concentration of 2.72 mg/L (group A), 13.6 mg/L (group B) and 68 mg/L (group C), respectively, for 3 months. The levels of arsenic in blood serum and hippocampus were monitored. Rats were tested in Morris water maze (MWM) for memory status. Samples of hippocampus were collected from two rats in each group for transmission electron microscopic study and the detection of NMDAR expression by RT-PCR. The rats in group C showed a significant delay in hidden platform acquisition. Neurons and endothelial cells presented pathological changes and the expression of NR2A was down-regulated in hippocampus in arsenic exposed rats. Our data indicated that arsenic exposure of 68 mg/L caused spatial memory damage, of which the morphological and biochemical bases could be the ultra-structure changes and reduced NR2A expression in hippocampus.

  4. Tissue, Dosimetry, Metabolism and Excretion of Pentavalent and Trivalent Dimethylated Arsenic in Mice after Oral Administration

    EPA Science Inventory

    Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic inmice after acute oral administration. Adult fema...

  5. Tissue, Dosimetry, Metabolism and Excretion of Pentavalent and Trivalent Dimethylated Arsenic in Mice after Oral Administration

    EPA Science Inventory

    Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic inmice after acute oral administration. Adult fema...

  6. Metabolic profile in workers occupationally exposed to arsenic: role of GST polymorphisms.

    PubMed

    Marcos, Ricardo; Martínez, Valeria; Hernández, Alba; Creus, Amadeu; Sekaran, Chandra; Tokunaga, Hiroshi; Quinteros, Domingo

    2006-03-01

    Arsenic is a well-known human carcinogen with a ubiquitous distribution in the natural environment. Chronic exposure to inorganic arsenic involves a biotransformation process that leds to the main excretion of organic methylated metabolites, such as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as the parental inorganic species. Interindividual variation in arsenic metabolism has been extensively reported, and polymorphisms in genes involved in such process could be related to changes in the arsenic excretion profile and the response to chronic exposures. Our analysis of the metabolic profiles in three groups of workers exposed to different arsenic exposure levels showed high amounts of inorganic arsenic and MMA in the most-exposed workers versus the least-exposed workers, in whom high amounts of DMA were observed. With respect to the role of different genetic polymorphisms in the glutathione S-transferase (GST) genes in the modulation of the urinary profiles, for the overall population only a tendency was just observed between GSTM1 null and MMA excretion as well as between GSTP1 val/val and DMA excretion.

  7. GLUTATHIONE MODULATES RECOMBINANT RAT ARSENIC (+3 OXIDATION STATE) METHYLTRANSFERASE-CATALYZED FORMATION OF TRIMETHYLARSINE OXIDE AND TRIMETHYLARSINE

    EPA Science Inventory


    Humans and other species enzymatically convert inorganic arsenic into methylated metabolites. Although the major metabolites are mono- and dimethylated arsenicals, trimethylated arsenicals have been detected in urine following exposure to inorganic arsenic. The AS3MT gene e...

  8. Measurements of Arsenic in the Urine and Nails of Individuals Exposed to Low Concentrations of Arsenic in Drinking Water From Private Wells in a Rural Region of Québec, Canada.

    PubMed

    Gagnon, Fabien; Lampron-Goulet, Eric; Normandin, Louise; Langlois, Marie-France

    2016-01-01

    Chronic exposure to inorganic arsenic leads to an increased risk of cancer. A biological measurement was conducted in 153 private well owners and their families consuming water contaminated by inorganic arsenic at concentrations that straddle 10 μg/L. The relationship between the external dose indicators (concentration of inorganic arsenic in wells and daily well water inorganic arsenic intake) and the internal doses (urinary arsenic--sum of As(III), DMA, and MMA, adjusted for creatinine--and total arsenic in toenails) was evaluated using multiple linear regressions, controlling for age, gender, dietary sources of arsenic, and number of cigarettes smoked. It showed that urinary arsenic was associated with concentration of inorganic arsenic in wells (p < .001) and daily well water inorganic arsenic intake (p < .001) in adults, and with daily well water inorganic arsenic intake (p = .017) and rice consumption (p = .022) in children (n = 43). The authors' study reinforces the drinking-water quality guidelines for inorganic arsenic.

  9. The polymorphism XRCC1 Arg194Trp and 8-hydroxydeoxyguanosine increased susceptibility to arsenic-related renal cell carcinoma.

    PubMed

    Hsueh, Yu-Mei; Lin, Ying-Chin; Chen, Wei-Jen; Huang, Chao-Yuan; Shiue, Horng-Sheng; Pu, Yeong-Shiau; Chen, Chi-Hung; Su, Chien-Tien

    2017-10-01

    This study was designed to explore the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms and renal cell carcinoma (RCC) and to investigate whether individuals with an XRCC1 risk genotype, a high level of 8-OHdG or a high urinary total arsenic concentration have a modified odds ratio (OR) of RCC. We recruited 180 RCC patients and 360 age- and sex-matched controls from a hospital-based pool. Image-guided biopsy or surgical resection of renal tumors was performed on RCC patients for pathological verification. Genomic DNA was used to examine the genotype of XRCC1(Arg399Gln), XRCC1(Arg194Trp), XRCC3(Thr241Met) and XPD(Lys751Gln) by PCR-RFLP. Liquid chromatography with tandem mass spectrometry was used to determine urinary 8-OHdG levels. A HPLC-HG-AAS was used to determine the concentrations of urinary arsenic species. Participants with the genotype XRCC1(Arg194Trp) Arg/Trp+Trp/Trp had a significantly higher OR of RCC than those with the Arg/Arg genotype; the OR and 95% confidence interval was 0.66 (0.45-0.97) after multivariate adjustment. The OR of RCC for the combined effect of high urinary 8-OHdG levels and high urinary total arsenic concentration in individuals with a XRCC1(Arg194Trp) Arg/Trp+Trp/Trp genotype was higher than in patients with an Arg/Arg genotype, which was evident in a dose response manner. In conclusion, this is the first study to show that the XRCC1 Arg194 allele is a predicting factor for RCC. The more risk factors (high urinary 8-OHdG levels, high urinary total arsenic concentrations, and XRCC1 Arg194 allele) that were present, the higher the OR of RCC. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Characterization of gene expression changes associated with MNNG, arsenic, or metal mixture treatment in human keratinocytes: application of cDNA microarray technology.

    PubMed Central

    Bae, Dong-Soon; Hanneman, William H; Yang, Raymond S H; Campain, Julie A

    2002-01-01

    The identification of molecular markers related to critical biological processes during carcinogenesis may aid in the evaluation of carcinogenic potentials of chemicals and chemical mixtures. Work from our laboratory demonstrated that a single treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) enhanced spontaneous malignant transformation of the human keratinocyte cell line RHEK-1. In contrast, chronic low-level exposure of cells to arsenic alone or in a mixture containing arsenic, cadmium, chromium, and lead inhibited malignant conversion. To identify changes in gene expression that influence these different outcomes, cDNA microarray technology was used. Analysis of multiple human arrays in MNNG-transformed RHEK-1 cells, designated OM3, and those treated with arsenic or the arsenic-containing metal mixture showed unique patterns of gene expression. Genes that were overexpressed in OM3 included oncogenes, cell cycle regulators, and those involved in signal transduction, whereas genes for DNA repair enzymes and inhibitors of transformation and metastasis were suppressed. In arsenic-treated cells, multiple DNA repair proteins were overexpressed. Mixture-treated cells showed increased expression of a variety of genes including metallothioneins and integrin 4. These cells showed decreased expression of oncogenes, DNA repair proteins, and genes involved in the mitogen-activated protein kinase pathway. For comparison we are currently analyzing gene expression changes in RHEK-1 cells transformed by other means. The goal of these studies is to identify common batteries of genes affected by chemical modulators of the carcinogenic process. Mechanistic studies may allow us to correlate alterations in their expression with sequential stages in the carcinogenic process and may aid in the risk assessment of other xenobiotics. PMID:12634122

  11. Differential expression of genes encoding phosphate transporters contributes to arsenic accumulation in shrub willow (Salix spp.)

    Treesearch

    Emily E. Puckett; Michelle J. Serpiglia; Alyssa M. DeLeon; Stephanie Long; Rakesh Minocha; Lawrence B. Smart

    2012-01-01

    Studies of arsenate and phosphate uptake by plants in hydroponic and soil systems indicate a common transport mechanism via the phosphate transporters (PHTs) due to structural similarity of the anions. Typically, the presence of phosphate decreases plant uptake and translocation of arsenate in hydroponic solution. This study quantified arsenic (As) uptake related to...

  12. Identification of genes and physiological factors that reduce accumulation of arsenic in rice grain

    USDA-ARS?s Scientific Manuscript database

    The arsenic (As) levels in rice grains and food products can reach toxic levels when produced under certain growing conditions. The World Health Organization (WHO) recently set a CODEX limit of 0.2 ppm inorganic As in milled white rice, and lower limits may be set for baby food products. While studi...

  13. Hydrogen peroxide triggers a novel alternative splicing of arsenic (+3 oxidation state) methyltransferase gene.

    PubMed

    Sumi, Daigo; Takeda, Chieri; Yasuoka, Daiki; Himeno, Seiichiro

    2016-11-04

    We previously reported that two splicing variants of human AS3MT mRNA, exon-3 skipping form (Δ3) and exons-4 and -5 skipping form (Δ4,5), were detected in HepG2 cells and that both variants lacked arsenic methylation activity (Sumi et al., 2011). Here we studied whether hydrogen peroxide (H2O2) triggers alternative splicing of AS3MT mRNA. The results showed that exposure of HepG2 cells to H2O2 resulted in increased levels of a novel spliced form skipping exon-3 to exon-10 (Δ3-10) in an H2O2-concentration-dependent manner, although no change was detected in the mRNA levels of Δ3 AS3MT. We found decreased protein levels of serine/arginine-rich 40 (SRp40), which we determined to be a candidate splice factor for controlling the splicing of AS3MT mRNA. We next compared the amounts of methylated arsenic metabolites between control and H2O2-exposed HepG2 cells after the addition of arsenite as a substance. The results showed lower levels of methylated arsenic metabolites in HepG2 cells exposed to H2O2. These data suggest that the splicing of AS3MT pre-mRNA was disconcerted by oxidative stress and that abnormal alternative splicing of AS3MT mRNA may affect arsenic methylation ability.

  14. Transcriptome of Proteus mirabilis in the Murine Urinary Tract: Virulence and Nitrogen Assimilation Gene Expression▿†

    PubMed Central

    Pearson, Melanie M.; Yep, Alejandra; Smith, Sara N.; Mobley, Harry L. T.

    2011-01-01

    The enteric bacterium Proteus mirabilis is a common cause of complicated urinary tract infections. In this study, microarrays were used to analyze P. mirabilis gene expression in vivo from experimentally infected mice. Urine was collected at 1, 3, and 7 days postinfection, and RNA was isolated from bacteria in the urine for transcriptional analysis. Across nine microarrays, 471 genes were upregulated and 82 were downregulated in vivo compared to in vitro broth culture. Genes upregulated in vivo encoded mannose-resistant Proteus-like (MR/P) fimbriae, urease, iron uptake systems, amino acid and peptide transporters, pyruvate metabolism enzymes, and a portion of the tricarboxylic acid (TCA) cycle enzymes. Flagella were downregulated. Ammonia assimilation gene glnA (glutamine synthetase) was repressed in vivo, while gdhA (glutamate dehydrogenase) was upregulated in vivo. Contrary to our expectations, ammonia availability due to urease activity in P. mirabilis did not drive this gene expression. A gdhA mutant was growth deficient in minimal medium with citrate as the sole carbon source, and loss of gdhA resulted in a significant fitness defect in the mouse model of urinary tract infection. Unlike Escherichia coli, which represses gdhA and upregulates glnA in vivo and cannot utilize citrate, the data suggest that P. mirabilis uses glutamate dehydrogenase to monitor carbon-nitrogen balance, and this ability contributes to the pathogenic potential of P. mirabilis in the urinary tract. PMID:21505083

  15. Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh

    PubMed Central

    Pierce, Brandon L.; Kibriya, Muhammad G.; Tong, Lin; Jasmine, Farzana; Argos, Maria; Roy, Shantanu; Paul-Brutus, Rachelle; Rahaman, Ronald; Rakibuz-Zaman, Muhammad; Parvez, Faruque; Ahmed, Alauddin; Quasem, Iftekhar; Hore, Samar K.; Alam, Shafiul; Islam, Tariqul; Slavkovich, Vesna; Gamble, Mary V.; Yunus, Md; Rahman, Mahfuzar; Baron, John A.; Graziano, Joseph H.; Ahsan, Habibul

    2012-01-01

    Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin

  16. Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

    PubMed

    Pierce, Brandon L; Kibriya, Muhammad G; Tong, Lin; Jasmine, Farzana; Argos, Maria; Roy, Shantanu; Paul-Brutus, Rachelle; Rahaman, Ronald; Rakibuz-Zaman, Muhammad; Parvez, Faruque; Ahmed, Alauddin; Quasem, Iftekhar; Hore, Samar K; Alam, Shafiul; Islam, Tariqul; Slavkovich, Vesna; Gamble, Mary V; Yunus, Md; Rahman, Mahfuzar; Baron, John A; Graziano, Joseph H; Ahsan, Habibul

    2012-01-01

    Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8)) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12)) and neighboring gene C10orf32 (P = 10(-44)), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin

  17. Inverse association between toenail arsenic and body mass index in a population of welders.

    PubMed

    Grashow, Rachel; Zhang, Jinming; Fang, Shona C; Weisskopf, Marc G; Christiani, David C; Kile, Molly L; Cavallari, Jennifer M

    2014-05-01

    Recent data show that arsenic may play a role in obesity-related diseases. However, urinary arsenic studies report an inverse association between arsenic level and body mass index (BMI). We explored whether toenail arsenic, a long-term exposure measure, was associated with BMI in 74 welders with known arsenic exposure. BMI showed significant inverse associations with toenail arsenic (p=0.01), which persisted in models adjusted for demographics, diet and work history. It is unclear whether low arsenic biomarker concentrations in high BMI subjects truly reflect lower exposures, or instead reflect internal or metabolic changes that alter arsenic metabolism and tissue deposition.

  18. Inverse association between toenail arsenic and body mass index in a population of welders

    PubMed Central

    Grashow, Rachel; Zhang, Jinming; Fang, Shona C.; Weisskopf, Marc G.; Christiani, David C.; Kile, Molly L.; Cavallari, Jennifer M.

    2014-01-01

    Recent data show that arsenic may play a role in obesity-related diseases. However, urinary arsenic studies report an inverse association between arsenic level and body mass index (BMI). We explored whether toenail arsenic, a long-term exposure measure, was associated with BMI in 74 welders with known arsenic exposure. BMI showed significant inverse associations with toenail arsenic (p=0.01), which persisted in models adjusted for demographics, diet and work history. It is unclear whether low arsenic biomarker concentrations in high BMI subjects truly reflect lower exposures, or instead reflect internal or metabolic changes that alter arsenic metabolism and tissue deposition. PMID:24721130

  19. Efficient arsenic metabolism--the AS3MT haplotype is associated with DNA methylation and expression of multiple genes around AS3MT.

    PubMed

    Engström, Karin S; Hossain, Mohammad Bakhtiar; Lauss, Martin; Ahmed, Sultan; Raqib, Rubhana; Vahter, Marie; Broberg, Karin

    2013-01-01

    Arsenic is a very potent toxicant. One major susceptibility factor for arsenic-related toxicity is the efficiency of arsenic metabolism. The efficiency, in turn, is associated with non-coding single nucleotide polymorphisms (SNPs) in the arsenic methyltransferase AS3MT on chromosome 10q24. However, the mechanism of action for these SNPs is not yet clarified. Here, we assessed the influence of genetic variation in AS3MT on DNA methylation and gene expression within 10q24, in people exposed to arsenic in drinking water. DNA was extracted from peripheral blood from women in the Argentinean Andes (N = 103) and from cord blood from new-borns in Bangladesh (N = 127). AS3MT SNPs were analyzed with Sequenom or Taqman assays. Whole genome epigenetic analysis with Infinium HumanMethylation450 BeadChip was performed on bisulphite-treated DNA. Whole genome gene expression analysis was performed with Illumina DirectHyb HumanHT-12 v4.0 on RNA from peripheral blood. Arsenic exposure was assessed by HPLC-ICPMS. In the Argentinean women, the major AS3MT haplotype, associated with more efficient arsenic metabolism, showed increased methylation of AS3MT (p = 10(-6)) and also differential methylation of several other genes within about 800 kilobasepairs: CNNM2 (p<10(-16)), NT5C2 (p<10(-16)), C10orf26 (p = 10(-8)), USMG5 (p = 10(-5)), TRIM8 (p = 10(-4)), and CALHM2 (p = 0.038) (adjusted for multiple comparisons). Similar, but weaker, associations between AS3MT haplotype and DNA methylation in 10q24 were observed in cord blood (Bangladesh). The haplotype-associated altered CpG methylation was correlated with reduced expression of AS3MT and CNNM2 (r(s) = -0.22 to -0.54), and with increased expression of NT5C2 and USMG5 (r(s) = 0.25 to 0.58). Taking other possibly influential variables into account in multivariable linear models did only to a minor extent alter the strength of the associations. In conclusion, the AS3MT haplotype status strongly

  20. Unusual arsenic metabolism in Giant Pandas.

    PubMed

    Braeuer, Simone; Dungl, Eveline; Hoffmann, Wiebke; Li, Desheng; Wang, Chengdong; Zhang, Hemin; Goessler, Walter

    2017-09-18

    The total arsenic concentration and the arsenic speciation in urine and feces samples of the two Giant Pandas living at Vienna zoo and of their feed, bamboo, were determined with ICPMS and HPLC-ICPMS. Urine was the main excretion route and accounted for around 90% of the ingested arsenic. The urinary arsenic concentrations were very high, namely up to 179 μg/L. Dimethylarsinic acid (DMA) was the dominating arsenic compound in the urine samples and ranged from 73 to 92% of the total arsenic, which is unusually high for a terrestrial mammal. The feces samples contained around 70% inorganic arsenic and 30% DMA. The arsenic concentrations in the bamboo samples were between 16 and 920 μg/kg dry mass. The main arsenic species in the bamboo extracts was inorganic arsenic. This indicates that the Giant Panda possesses a unique way of very efficiently methylating and excreting the provided inorganic arsenic. This could be essential for the survival of the animal in its natural habitat, because parts of this area are contaminated with arsenic. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Folic acid supplementation lowers blood arsenic2

    PubMed Central

    Gamble, Mary V; Liu, Xinhua; Slavkovich, Vesna; Pilsner, J Richard; Ilievski, Vesna; Factor-Litvak, Pam; Levy, Diane; Alam, Shafiul; Islam, Mominul; Parvez, Faruque; Ahsan, Habibul; Graziano, Joseph H

    2007-01-01

    Background Chronic arsenic exposure currently affects >100 million persons worldwide. Methylation of ingested inorganic arsenic (InAs) to monomethylarsonic (MMAs) and dimethylarsinic (DMAs) acids relies on folate-dependent one-carbon metabolism and facilitates urinary arsenic elimination. Objective We hypothesized that folic acid supplementation to arsenic-exposed Bangladeshi adults would increase arsenic methylation and thereby lower total blood arsenic. Design In this randomized, double-blind, placebo-controlled trial, we evaluated blood concentrations of total arsenic, InAs, MMAs, and DMAs in 130 participants with low plasma folate (<9 nmol/L) before and after 12 wk of supplementation with folic acid (400 μg/d) or placebo. Results MMAs in blood was reduced by a mean ± SE of 22.24 ± 2.86% in the folic acid supplementation group and by 1.24 ± 3.59% in the placebe group (P < 0.0001). There was no change in DMAs in blood; DMAs is rapidly excreted in urine as evidenced by an increase in urinary DMAs (P = 0.0099). Total blood arsenic was reduced by 13.62% in the folic acid supplementation group and by 2.49% in the placebo group (P = 0.0199). Conclusions Folic acid supplementation to participants with low plasma concentrations of folate lowered blood arsenic concentrations, primarily by decreasing blood MMAs and increasing urinary DMAs. Therapeutic strategies to facilitate arsenic methylation, particularly in populations with folate deficiency or hyperhomocysteinemia or both, may lower blood arsenic concentrations and thereby contribute to the prevention of arsenic-induced illnesses. PMID:17921403

  2. RECENT ADVANCES IN ARSENIC CARCINOGENESIS: MODES OF ACTION, ANIMAL MODEL SYSTEMS AND METHYLATED ARSENIC METABOLITES

    EPA Science Inventory


    Abstract:

    Recent advances in our knowledge of arsenic carcinogenesis include the development of rat or mouse models for all human organs in which inorganic arsenic is known to cause cancer -skin, lung, urinary bladder, liver and kidney. Tumors can be produced from eit...

  3. RECENT ADVANCES IN ARSENIC CARCINOGENESIS: MODES OF ACTION, ANIMAL MODEL SYSTEMS AND METHYLATED ARSENIC METABOLITES

    EPA Science Inventory


    Abstract:

    Recent advances in our knowledge of arsenic carcinogenesis include the development of rat or mouse models for all human organs in which inorganic arsenic is known to cause cancer -skin, lung, urinary bladder, liver and kidney. Tumors can be produced from eit...

  4. Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population.

    PubMed

    de la Rosa, Rosemarie; Steinmaus, Craig; Akers, Nicholas K; Conde, Lucia; Ferreccio, Catterina; Kalman, David; Zhang, Kevin R; Skibola, Christine F; Smith, Allan H; Zhang, Luoping; Smith, Martyn T

    2017-07-01

    Inter-individual differences in arsenic metabolism have been linked to arsenic-related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic inorganic arsenic (iAs) metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = -1.9%, 95% CI: -3.3, -0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR = 0.3; 95% CI: 0.1-0.6) and lung cancer (OR = 0.6; 95% CI: 0.2-1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease. Environ. Mol. Mutagen. 58:411-422, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  5. Intrarenal and Urinary Th9 and Th22 Cytokine Gene Expression in Lupus Nephritis.

    PubMed

    Luk, Cathy Choi-Wan; Tam, Lai-Shan; Kwan, Bonnie Ching-Ha; Wong, Priscilla Ching-Han; Ma, Terry King-Wing; Chow, Kai-Ming; Lai, Fernand Mac-Moune; Li, Philip Kam-Tao; Szeto, Cheuk-Chun

    2015-07-01

    We studied the urinary sediment mRNA level of Th9- and Th22-related cytokines in patients with systemic lupus erythematosus (SLE). We quantified urinary mRNA levels of interleukin (IL) 9, IL-10, IL-22, and their corresponding transcription factors in 73 patients with active lupus nephritis, 13 patients with hypertensive nephrosclerosis (HTN), and 25 healthy subjects. There was no detectable IL-9 mRNA in all samples. Patients with proliferative lupus nephritis had significantly lower urinary IL-22 mRNA levels than those with nonproliferative nephritis (2.2 ± 5.4 vs 8.6 ± 20.0 copies, p = 0.019), and urinary IL-22 mRNA level inversely correlated with the histological activity index (r = -0.427, p < 0.0001). In contrast, patients with lupus nephritis had significantly higher urinary IL-10 mRNA levels than patients with HTN (7.8 ± 18.5 vs 1.9 ± 4.0 copies, p = 0.012), and urinary IL-10 mRNA levels correlated with its intrarenal mRNA levels (r = 0.337, p = 0.004) and SLE disease activity index (r = 0.277, p = 0.018). Urinary IL-10 mRNA level was significantly lower among patients who achieved complete remission than those with partial remission or no response (4.1 ± 6.5 vs 14.1 ± 28.0 copies, p = 0.036). Urinary IL-22 mRNA level is decreased in patients with SLE with proliferative nephritis, while urinary IL-10 mRNA levels correlates with its intrarenal mRNA level and disease activity. Urinary IL-10 mRNA levels may also predict treatment response. These results suggest that urinary mRNA levels of IL-10 and IL-22 might be used as biomarkers for assessing disease activity and risk stratification in lupus nephritis.

  6. GENE EXPRESSION PROFILES IN ARSENIC-TREATED MCF-7 BREAST CANCER CELLS EXPRESSING DIFFERENT LEVELS OF HSP70

    EPA Science Inventory

    Gene expression profiles in arsenic-treated MCF-7 breast cancer cells expressing different levels of HSP70

    Gail Nelson, Susan Hester, Ernest Winkfield, Jill Barnes, James Allen
    Environmental Carcinogenesis Division, NHEERL, ORD, US Environmental Protection Agency, Rese...

  7. GENE EXPRESSION PROFILES IN ARSENIC-TREATED MCF-7 BREAST CANCER CELLS EXPRESSING DIFFERENT LEVELS OF HSP70

    EPA Science Inventory

    Gene expression profiles in arsenic-treated MCF-7 breast cancer cells expressing different levels of HSP70

    Gail Nelson, Susan Hester, Ernest Winkfield, Jill Barnes, James Allen
    Environmental Carcinogenesis Division, NHEERL, ORD, US Environmental Protection Agency, Rese...

  8. Arsenic detoxification potential of aox genes in arsenite-oxidizing bacteria isolated from natural and constructed wetlands in the Republic of Korea.

    PubMed

    Chang, Jin-Soo; Yoon, In-Ho; Lee, Ji-Hoon; Kim, Ki-Rak; An, Jeongyi; Kim, Kyoung-Woong

    2010-04-01

    Arsenic is subject to microbial interactions, which support a wide range of biogeochemical transformations of elements in natural environments such as wetlands. The arsenic detoxification potential of the bacterial strains was investigated with the arsenite oxidation gene, aox genotype, which were isolated from the natural and constructed wetlands. The isolates were able to grow in the presence of 10 mM of sodium arsenite (As(III) as NaAsO(2)) and 1 mM of D: +glucose. Phylogenetic analysis based on 16S rRNA gene sequencing indicated that these isolated strains resembled members of the genus that have arsenic-resistant systems (Acinetobacter sp., Aeromonas sp., Agrobacterium sp., Comamonas sp., Enterobacter sp., Pantoea sp., and Pseudomonas sp.) with sequence similarities of 81-98%. One bacterial isolate identified as Pseudomonas stutzeri strain GIST-BDan2 (EF429003) showed the activity of arsenite oxidation and existence of aoxB and aoxR gene, which could play an important role in arsenite oxidation to arsenate. This reaction may be considered as arsenic detoxification process. The results of a batch test showed that P. stutzeri GIST-BDan2 (EF429003) completely oxidized in 1 mM of As(III) to As(V) within 25-30 h. In this study, microbial activity was evaluated to provide a better understanding of arsenic biogeochemical cycle in both natural and constructed wetlands, where ecological niches for microorganisms could be different, with a specific focus on arsenic oxidation/reduction and detoxification.

  9. [Relationship between CYP1A1 gene polymorphisms and urinary 1-hydroxypyrene levels in coke oven workers].

    PubMed

    Nie, Ji-sheng; Zhang, Hong-mei; Sun, Jian-ya; Zeng, Ping; Zhang, Ling; Niu, Qiao

    2009-05-01

    To study the associations of CYP1A1 gene polymorphisms with levels of urinary 1-hydroxypyrene among coke oven workers. 223 male workers from a coke plant (76, 82 and 65 workers in oven top group, oven-side group and oven-bottom group respectively) and 119 controls without occupational polycyclic aromatic hydrocarbons exposure were selected. The MspI gene polymorphism in CYP1A1 3' flanking region and the genotypes at I462V site in exon 7 of CYP1A1 were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific amplification (ASA). The urinary 1-hydroxypyrene of coke oven workers in oven-top, oven-side and oven-bottom (3.77+/-0.64, 3.57+/-0.49, 3.26+/-0.80 micromol/mol Cr) were significantly higher than controls (2.80+/-1.02 micromol/mol Cr) (P<0.01). The urinary 1-hydroxypyrene was not significantly different among MspI genotypes in CYP1A1 3' flanking region (P>0.05). In oven-top group and oven-side group, the subjects with Val/Val genotype in exon 7 of CYP1A1 had significantly higher urinary 1-hydroxypyrene levels than those with Ile/Val or Ile/Ile genotype, and urinary 1-hydroxypyrene of Ile-Val genotype were also significantly higher than Ile/Ile genotype (P<0.01). Multivariate logistic regression analysis showed that the coke oven workers (OR in oven top group, oven-side group and oven-bottom group was 24.926, 4.226 and 6.729 respectively) and subjects with m2/m2 genotype in CYP1A1 3' flanking region (OR=4.031) or with Val/Val or Ile/Val genotype in exon 7 of CYP1A1 (OR were 5.524 and 3.811) had elevated urinary 1-hydroxypyrene (greater than 95 percentile of control group, 3.876 micromol/mol Cr). BAP concentration of work environment contributes to the elevated urinary 1-hydroxypyrene levels, and the exposed BAP levels were regulated by the CYP1A1 MspI and I462V genotypes. Genetic polymorphism of CYP1A1 gene could be a susceptible biomarker in coke oven workers which was involved in the individual susceptibility

  10. Transformation and characterization of an arsenic gene operon from urease-positive thermophilic Campylobacter (UPTC) in Escherichia coli.

    PubMed

    Matsuda, M; Kuribayashi, T; Yamamoto, S; Millar, B C; Moore, J E

    2016-01-01

    An arsenate susceptibility test was performed with transformed and cultured Escherichia coli DH5α cells, which carried recombinant DNA of full-length arsenic (ars) operon, namely a putative membrane permease, ArsP; a transcriptional repressor, ArsR; an arsenate reductase, ArsC; and an arsenical-resistance membrane transporter, Acr3, from the Japanese urease-positive thermophilic Campylobacter lari (UPTC) CF89-12. The E. coli DH5α transformant showed reduced susceptibility to arsenate (~1536 μg/mL), compared to the control. Thus, these ars four-genes from the UPTC CF89-12 strain cells could confer a reduced susceptibility to arsenate in the transformed and E. coli DH5α cells. E. coli transformants with truncated ars operons, acr3 (acr3) and arsC-acr3 (∆arsC-acr3), of the ars operon, showed an MIC value of 384 μg/mL (~384 μg/mL), similar to the E. coli cells which carried the pGEM-T vector (control). Reverse transcription PCR confirmed in vivo transcription of recombinant full-length ars operon and deletion variants (∆acr3 and ∆arsC-acr3) in the transformed E. coli cells.

  11. Herpes simplex virus vector-mediated gene delivery for the treatment of lower urinary tract pain

    PubMed Central

    Goins, WF; Goss, JR; Chancellor, MB; de Groat, WC; Glorioso, JC; Yoshimura, N

    2009-01-01

    Interstitial cystitis (IC)/painful bladder syndrome (PBS) is a painful debilitating chronic visceral pain disorder of unknown etiology that affects an estimated 1 million people in the, United States alone. It is characterized by inflammation of the bladder that results in chronic pelvic pain associated with bladder symptoms of urinary frequency and urgency. Regardless of the etiology, IC/PBS involves either increased and/or abnormal activity in afferent nociceptive sensory neurons. Pain-related symptoms in patients with IC/PBS are often very difficult to treat. Both medical and surgical therapies have had limited clinical utility in this debilitating disease and numerous drug treatments, such as heparin, dimethylsulfoxide and amitriptyline, have proven to be palliative at best, and in some IC/PBS patients provide no relief whatsoever. Although opiate narcotics have been employed to help alleviate IC/PBS pain, this strategy is fraught with problems as systemic narcotic administration causes multiple unwanted side effects including mental status change and constipation. Moreover, chronic systemic narcotic use leads to dependency and need for dose escalation due to tolerance: therefore, new therapies are desperately needed to treat refractory IC/PBS. This has led our group to develop a gene therapy strategy that could potentially alleviate chronic pelvic pain using the herpes simplex virus-directed delivery of analgesic proteins to the bladder. PMID:19242523

  12. MODES OF ACTION FOR THE CARCINOGENICITY AND TOXICITY OF ARSENIC - MOVING TOWARDS A MORE QUANTITATIVE RISK ASSESSMENT

    EPA Science Inventory

    Arsenic exposures can lead to human tumors in skin, lung, urinary bladder, kidney and liver. Three likely initial stages of arsenical¬macromolecular interaction are (1) binding of trivalent arsenicals to sulfhydryl groups of peptides and proteins, (2) arsenical-induced generation...

  13. MODES OF ACTION FOR THE CARCINOGENICITY AND TOXICITY OF ARSENIC - MOVING TOWARDS A MORE QUANTITATIVE RISK ASSESSMENT

    EPA Science Inventory

    Arsenic exposures can lead to human tumors in skin, lung, urinary bladder, kidney and liver. Three likely initial stages of arsenical¬macromolecular interaction are (1) binding of trivalent arsenicals to sulfhydryl groups of peptides and proteins, (2) arsenical-induced generation...

  14. Quantification of DNA in urinary porcine bladder matrix using the ACTB gene.

    PubMed

    Silva-Benítez, Erika; Soto-Sáinz, Eduardo; Pozos-Guillen, Amaury; Romero-Quintana, José Geovanni; Aguilar-Medina, Maribel; Ayala-Ham, Alfredo; Peña-Martínez, Eri; Ramos-Payán, Rosalío; Flores, Héctor

    2015-11-01

    Extracellular matrix (ECM) is a rich network of proteins and proteoglycans that has proved to be very useful in tissue regeneration. Porcine ECM has been proposed as a biological scaffold, and urinary bladder matrix (UBM) has demonstrated superior biological properties; however, its use in human treatment requires ensuring that it is DNA free. Several protocols have been used for decellularization and to demonstrate the absence of DNA, but until now, a porcine housekeeping gene for quantifying DNA by real-time quantitative PCR (qPCR) has been limiting. The aim of this study was to propose a protocol to quantify the DNA content of decellularized UBM by qPCR for the beta-actin gene (ACTB). A total of 20 porcine bladders were used, and each bladder was divided into three pieces: one as a control and the others decellularized with either SDS or Triton X-100 detergent. The presence of DNA was assessed by histology, spectrophotometry, conventional PCR, and qPCR for the ACTB. Histological analysis demonstrated the absence of nuclei using both protocols. Spectrophotometrical evaluation resulted in DNA concentrations of 1561.4 ± 357.1 and 1211.9 ± 635.2 ng of DNA/mg dry weight after the SDS and Triton X-100 protocols, respectively. DNA was not detected in any protocol by conventional PCR. In contrast, using qPCR, we found 3.9 ± 2.8 ng of DNA/mg dry weight in the Triton X-100 protocol. Therefore, the use of qPCR is a reliable method to quantify residual DNA content after decellularization procedures.

  15. Association of urinary bladder paragangliomas with germline mutations in the SDHB and VHL genes

    PubMed Central

    Martucci, Victoria L.; Lorenzo, Zarina G.; Weintraub, Michael; del Rivero, Jaydira; Ling, Alexander; Merino, Maria; Siddiqui, Minhaj; Shuch, Brian; Vourganti, Srinivas; Linehan, W. Marston; Agarwal, Piyush K.; Pacak, Karel

    2015-01-01

    Objective Our primary goal was to examine the clinical characteristics of a series of patients with urinary bladder paragangliomas (UBPGLs), focusing particularly on their genetic backgrounds. Materials and methods We analyzed the medical records of patients who presented to the National Institutes of Health with UBPGL from 2000 to 2013 to determine their clinical characteristics and outcomes, biochemical phenotype, tumor size, and genetic background. Results Of the 27 patients with UBPGLs who were identified, 17 (63%) had underlying genetic mutations. Overall, 14 (51.9%) patients had a germline mutation in the succinate dehydrogenase subunit B gene (SDHB), and 3 (11.1%) had in the von Hippel-Lindau gene (VHL). Of the 21 patients who had biochemical data available before their first operation, 19 (90.5%) presented with a noradrenergic biochemical phenotype; 7 (33.3%) patients had tumors that also secreted dopamine. In addition, 1 patient (4.8%) had elevated metanephrine levels, and 2 (9.5%) had normal biochemical data. In total, 13 (48.1%) patients in the series were diagnosed with metastatic disease, at either first presentation or follow-up; 6 of these patients (46.1%) had SDHB mutations. Conclusions UBPGLs typically present with a noradrenergic phenotype and are frequently associated with underlying germline mutations. Patients presenting with these rare neuroendocrine tumors should be screened for these mutations. In addition, patients with UBPGLs should be followed up closely for metastatic development regardless of genetic background, as almost half of the patients in this series presented with metastatic disease and less than half of them had SDHB mutations. PMID:25683602

  16. Liver is a target of arsenic carcinogenesis.

    PubMed

    Liu, Jie; Waalkes, Michael P

    2008-09-01

    Inorganic arsenic is clearly a human carcinogen causing tumors of the skin, lung, urinary bladder, and possibly liver (IARC, 2004). At the time of construction of this monograph, the evidence for arsenic as a hepatocarcinogen in humans was considered controversial and in rodents considered insufficient. However, recent data has accumulated indicating hepatocarcinogenicity of arsenic. This forum reevaluates epidemiology studies, rodent studies together with in vitro models, and focuses on the liver as a target organ of arsenic toxicity and carcinogenesis. Hepatocellular carcinoma and hepatic angiosarcoma, have been frequently associated with environmental or medicinal exposure to arsenicals. Preneoplastic lesions, including hepatomegaly, hepatoportal sclerosis, fibrosis, and cirrhosis often occur after chronic arsenic exposure. Recent work in mice clearly shows that exposure to inorganic arsenic during gestation induces tumors, including hepatocellular adenoma and carcinoma, in offspring when they reach adulthood. In rats, the methylated arsenicals, dimethylarsinic acid promotes diethylnitrosamine-initiated liver tumors, whereas trimethylarsine oxide induces liver adenomas. Chronic exposure of rat liver epithelial cells to low concentrations of inorganic arsenic induces malignant transformation, producing aggressive, undifferentiated epithelial tumors when inoculated into the Nude mice. There are a variety of potential mechanisms for arsenical-induced hepatocarcinogenesis, such as oxidative DNA damage, impaired DNA damage repair, acquired apoptotic tolerance, hyperproliferation, altered DNA methylation, and aberrant estrogen signaling. Some of these mechanisms may be liver specific/selective. Overall, accumulating evidence clearly indicates that the liver could be an important target of arsenic carcinogenesis.

  17. Arsenic and bladder cancer: observations and suggestions.

    PubMed

    Radosavljević, Vladan; Jakovljević, Branko

    2008-10-01

    Arsenic from drinking water is a well-known risk factor for bladder cancer. The purpose of this paper is to systematize some important yet often overlooked facts considering the relationship between arsenic exposure and the occurrence of bladder cancer. Since the exposure to inorganic arsenic from food, inhaled air, and skin absorption as well as arsenic methylation ability are not fully investigated, our assumption is that the exposure of arsenic only from drinking water is underestimated and its role as a risk factor is highly overestimated. This paper proposes some qualitative and quantitative parameters of arsenic as a risk factor for bladder cancer. The recommended qualitative parameters of arsenic intake are first, pathways of exposure, and second, toxicity and metabolism. The suggested quantitative parameters of arsenic intake include amounts of arsenic absorbed in the body, duration of arsenic exposure, and duration of arsenic presence in the urinary bladder. This approach can be implemented in a systematic classification and explanation of various risk factors and their mutual interactions for other types of cancer or diseases in general.

  18. Arsenic Methylation and its Relationship to Abundance and Diversity of arsM Genes in Composting Manure

    NASA Astrophysics Data System (ADS)

    Zhai, Weiwei; Wong, Mabel T.; Luo, Fei; Hashmi, Muhammad Z.; Liu, Xingmei; Edwards, Elizabeth A.; Tang, Xianjin; Xu, Jianming

    2017-03-01

    Although methylation is regarded as one of the main detoxification pathways for arsenic (As), current knowledge about this process during manure composting remains limited. In this study, two pilot-scale compost piles were established to treat manure contaminated with As. An overall accumulation of methylated As occurred during 60 day-composting time. The concentration of monomethylarsonic acid (MMA) increased from 6 to 190 μg kg-1 within 15 days and decreased to 35 μg kg-1 at the end of the maturing phase; while the concentration of dimethylarsinic acid (DMA) continuously increased from 33 to 595 μg kg-1 over the composting time. The arsM gene copies increased gradually from 0.08 × 109 to 6.82 × 109 copies g-1 dry mass over time and correlated positively to the concentrations of methylated As. 16S rRNA gene sequencing and arsM clone library analysis confirmed the high abundance and diversity of arsM genes. Many of these genes were related to those from known As-methylating microbes, including Streptomyces sp., Amycolatopsis mediterranei and Sphaerobacter thermophiles. These results demonstrated that As methylation during manure composting is significant and, for the first time, established a linkage between As biomethylation and the abundance and diversity of the arsM functional genes in composting manure.

  19. Prenatal exposure to arsenic and cadmium impacts infectious disease-related genes within the glucocorticoid receptor signal transduction pathway.

    PubMed

    Rager, Julia E; Yosim, Andrew; Fry, Rebecca C

    2014-12-03

    There is increasing evidence that environmental agents mediate susceptibility to infectious disease. Studies support the impact of prenatal/early life exposure to the environmental metals inorganic arsenic (iAs) and cadmium (Cd) on increased risk for susceptibility to infection. The specific biological mechanisms that underlie such exposure-mediated effects remain understudied. This research aimed to identify key genes/signal transduction pathways that associate prenatal exposure to these toxic metals with changes in infectious disease susceptibility using a Comparative Genomic Enrichment Method (CGEM). Using CGEM an infectious disease gene (IDG) database was developed comprising 1085 genes with known roles in viral, bacterial, and parasitic disease pathways. Subsequently, datasets collected from human pregnancy cohorts exposed to iAs or Cd were examined in relationship to the IDGs, specifically focusing on data representing epigenetic modifications (5-methyl cytosine), genomic perturbations (mRNA expression), and proteomic shifts (protein expression). A set of 82 infection and exposure-related genes was identified and found to be enriched for their role in the glucocorticoid receptor signal transduction pathway. Given their common identification across numerous human cohorts and their known toxicological role in disease, the identified genes within the glucocorticoid signal transduction pathway may underlie altered infectious disease susceptibility associated with prenatal exposures to the toxic metals iAs and Cd in humans.

  20. Arsenic Methylation and its Relationship to Abundance and Diversity of arsM Genes in Composting Manure

    PubMed Central

    Zhai, Weiwei; Wong, Mabel T.; Luo, Fei; Hashmi, Muhammad Z.; Liu, Xingmei; Edwards, Elizabeth A.; Tang, Xianjin; Xu, Jianming

    2017-01-01

    Although methylation is regarded as one of the main detoxification pathways for arsenic (As), current knowledge about this process during manure composting remains limited. In this study, two pilot-scale compost piles were established to treat manure contaminated with As. An overall accumulation of methylated As occurred during 60 day-composting time. The concentration of monomethylarsonic acid (MMA) increased from 6 to 190 μg kg−1 within 15 days and decreased to 35 μg kg−1 at the end of the maturing phase; while the concentration of dimethylarsinic acid (DMA) continuously increased from 33 to 595 μg kg−1 over the composting time. The arsM gene copies increased gradually from 0.08 × 109 to 6.82 × 109 copies g−1 dry mass over time and correlated positively to the concentrations of methylated As. 16S rRNA gene sequencing and arsM clone library analysis confirmed the high abundance and diversity of arsM genes. Many of these genes were related to those from known As-methylating microbes, including Streptomyces sp., Amycolatopsis mediterranei and Sphaerobacter thermophiles. These results demonstrated that As methylation during manure composting is significant and, for the first time, established a linkage between As biomethylation and the abundance and diversity of the arsM functional genes in composting manure. PMID:28266584

  1. Prenatal Exposure to Arsenic and Cadmium Impacts Infectious Disease-Related Genes within the Glucocorticoid Receptor Signal Transduction Pathway

    PubMed Central

    Rager, Julia E.; Yosim, Andrew; Fry, Rebecca C.

    2014-01-01

    There is increasing evidence that environmental agents mediate susceptibility to infectious disease. Studies support the impact of prenatal/early life exposure to the environmental metals inorganic arsenic (iAs) and cadmium (Cd) on increased risk for susceptibility to infection. The specific biological mechanisms that underlie such exposure-mediated effects remain understudied. This research aimed to identify key genes/signal transduction pathways that associate prenatal exposure to these toxic metals with changes in infectious disease susceptibility using a Comparative Genomic Enrichment Method (CGEM). Using CGEM an infectious disease gene (IDG) database was developed comprising 1085 genes with known roles in viral, bacterial, and parasitic disease pathways. Subsequently, datasets collected from human pregnancy cohorts exposed to iAs or Cd were examined in relationship to the IDGs, specifically focusing on data representing epigenetic modifications (5-methyl cytosine), genomic perturbations (mRNA expression), and proteomic shifts (protein expression). A set of 82 infection and exposure-related genes was identified and found to be enriched for their role in the glucocorticoid receptor signal transduction pathway. Given their common identification across numerous human cohorts and their known toxicological role in disease, the identified genes within the glucocorticoid signal transduction pathway may underlie altered infectious disease susceptibility associated with prenatal exposures to the toxic metals iAs and Cd in humans. PMID:25479081

  2. Clinical manifestations and arsenic methylation after a rare subacute arsenic poisoning accident.

    PubMed

    Xu, Yuanyuan; Wang, Yi; Zheng, Quanmei; Li, Bing; Li, Xin; Jin, Yaping; Lv, Xiuqiang; Qu, Guang; Sun, Guifan

    2008-06-01

    One hundred and four workers ingested excessive levels of arsenic in an accident caused by leakage of pipeline in a copper-smelting factory. Clinical examinations were performed by physicians in a local hospital. Excreted urinary arsenic species were determined by cold trap hydride generation atomic absorption spectrometry. In the initial toxic phase, gastrointestinal symptoms were predominant (83 people, 79.8%). Most patients showed leucopenia (72 people, 69.2%), and increased serum alanine aminotransferase (84 people, 80.8%) and aspartate aminotransferase (58 people, 55.8%). Thirty-five patients (33.6%) had elevated red blood cells in urine. After 17 days of admission, many subjects (45 people, 43.3%) developed peripheral neuropathy and 25 of these 45 patients (24.0%) showed a decrease in motor and sensory nerve conduction velocity. In the comparison of urinary arsenic metabolites among subacute arsenic-poisoned, chronic high arsenic-exposed and control subjects, we found that subacute arsenic-poisoned patients had significantly elevated proportions of urinary inorganic arsenic (iAs) and methylarsonic acid (MMA) but reduced proportion of urinary dimethylarsinic acid (DMA) compared with chronic high arsenic-exposed and control subjects. Chronic exposed subjects excreted higher proportions of iAs and MMA but lower proportions of DMA in urine compared with control subjects. These results suggest that gastrointestinal symptoms, leucopenia, and hepatic and urinary injury are predominant in the initial phase of subacute arsenic poisoning. Peripheral neuropathy is the most frequent manifestation after the initial phase. The biomethylation of arsenic decreases in a dose rate-dependent manner.

  3. Arsenic Methyltransferase

    EPA Science Inventory

    The metalloid arsenic enters the environment by natural processes (volcanic activity, weathering of rocks) and by human activity (mining, smelting, herbicides and pesticides). Although arsenic has been exploited for homicidal and suicidal purposes since antiquity, its significan...

  4. Arsenic Methyltransferase

    EPA Science Inventory

    The metalloid arsenic enters the environment by natural processes (volcanic activity, weathering of rocks) and by human activity (mining, smelting, herbicides and pesticides). Although arsenic has been exploited for homicidal and suicidal purposes since antiquity, its significan...

  5. Effectiveness of arsenic mitigation program in Bangladesh--relationship between arsenic concentrations in well water and urine.

    PubMed

    Habib, Ahsan; Hayashi, Tomoshige; Sato, Kyoko Kogawa; Hata, Akihisa; Ikebe, Maiko; Rahman, Fashiur; Hassan, Parvez; Endo, Yoko; Endo, Ginji

    2007-12-01

    Arsenic in drinking water remains a major public problem in Bangladesh, although arsenic mitigation programs began there a decade ago. The purpose of this study was to examine the effectiveness of this program by determining the relationship between current arsenic levels in well water and the high level of urinary arsenic excretion. A community-based cross-sectional study was conducted in the Pabna district of Bangladesh between May and July 2005. We included 174 married couples and collected their drinking water from 138 wells. The allowable limit for arsenic in drinking water is 50 microg/L in Bangladesh, while the normal level of urinary arsenic is < or =40 microg x 1.5 L(-1) x day(-1) by Dhaka Community Hospital. Of 348 subjects, 304 exceeded the urinary arsenic level of 40 microg x 1.5 L(-1) x day(-1). Of all wells, 44.2% had arsenic levels >50 microg/L. Multiple-adjusted odds ratios of urinary arsenic level >40 microg x 1.5 L(-1) x day(-1) were 8.90 (95% CI: 3.31-23.93) for the arsenic level in well water of 11-50 microg/L, and 53.07 (11.91-236.46) for that of 51-332 microg/L, compared with < or =10 microg/L. When the Bangladeshi standard arsenic level in drinking water of 50 microg/L was used, the sensitivity in detecting subjects with a urinary arsenic level >40 microg x 1.5 L(-1) x day(-1) was 50%, although when the World Health Organization (WHO) guideline value of 10 microg/L was used, it was 76.3%. Green marked wells, which the Bangladesh government regards as safe, are not always safe. The mitigation programs should use the WHO guideline arsenic level to determine the safety of well water for drinking.

  6. Gene expression profiling analysis reveals arsenic-induced cell cycle arrest and apoptosis in p53-proficient and p53-deficient cells through differential gene pathways

    SciTech Connect

    Yu Xiaozhong Robinson, Joshua F.; Gribble, Elizabeth; Hong, Sung Woo; Sidhu, Jaspreet S.; Faustman, Elaine M.

    2008-12-15

    Arsenic (As) is a well-known environmental toxicant and carcinogen as well as an effective chemotherapeutic agent. The underlying mechanism of this dual capability, however, is not fully understood. Tumor suppressor gene p53, a pivotal cell cycle checkpoint signaling protein, has been hypothesized to play a possible role in mediating As-induced toxicity and therapeutic efficiency. In this study, we found that arsenite (As{sup 3+}) induced apoptosis and cell cycle arrest in a dose-dependent manner in both p53{sup +/+} and p53{sup -/-} mouse embryonic fibroblasts (MEFs). There was, however, a distinction between genotypes in the apoptotic response, with a more prominent induction of caspase-3 in the p53{sup -/-} cells than in the p53{sup +/+} cells. To examine this difference further, a systems-based genomic analysis was conducted comparing the critical molecular mechanisms between the p53 genotypes in response to As{sup 3+}. A significant alteration in the Nrf2-mediated oxidative stress response pathway was found in both genotypes. In p53{sup +/+} MEFs, As{sup 3+} induced p53-dependent gene expression alterations in DNA damage and cell cycle regulation genes. However, in the p53{sup -/-} MEFs, As{sup 3+} induced a significant up-regulation of pro-apoptotic genes (Noxa) and down-regulation of genes in immune modulation. Our findings demonstrate that As-induced cell death occurs through a p53-independent pathway in p53 deficient cells while apoptosis induction occurs through p53-dependent pathway in normal tissue. This difference in the mechanism of apoptotic responses between the genotypes provides important information regarding the apparent dichotomy of arsenic's dual mechanisms, and potentially leads to further advancement of its utility as a chemotherapeutic agent.

  7. ARSENIC REMOVAL

    EPA Science Inventory

    Presentation covered five topics; arsenic chemistry, best available technology (BAT), surface water technology, ground water technology and case studies of arsenic removal. The discussion on arsenic chemistry focused on the need and method of speciation for AsIII and AsV. BAT me...

  8. Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

    SciTech Connect

    Pelch, Katherine E.; Tokar, Erik J.; Merrick, B. Alex; Waalkes, Michael P.

    2015-08-01

    Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10 μM Cd for 11 weeks (CTPE) or 5 μM iAs for 29 weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for an in-depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (> 25-fold) and S100P (> 40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (> 15-fold) and NTM (> 1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status. - Highlights: • Cd and iAs are known human carcinogens, yet neither appears directly mutagenic. • Prior data suggest epigenetic modification plays a role in Cd or iAs induced cancer. • Altered methylation of four misregulated genes was found in Cd or iAs transformants. • The resulting altered gene expression may be relevant to cellular

  9. XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation capacity are associated with urothelial carcinoma

    SciTech Connect

    Chiang, Chien-I; Huang, Ya-Li; Chen, Wei-Jen; Shiue, Horng-Sheng; Huang, Chao-Yuan; Pu, Yeong-Shiau; Lin, Ying-Chin; Hsueh, Yu-Mei

    2014-09-15

    The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case–control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03–2.75) and 0.66 (0.48–0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G-C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas. - Highlights: • The XRCC1 399Gln/Gln genotype was significantly associated with increased OR of UC. • The XRCC1 194 Arg/Trp and Trp/Trp genotype had a significantly decreased OR of UC. • Combined effect of the XRCC1 genotypes and poor arsenic methylation capacity on

  10. Urinary leukotriene and Bcl I polymorphism of glucocorticoid receptor gene in preschoolers with recurrent wheezing and high risk of asthma.

    PubMed

    Morales, M; Flores, C; Pino, K; Angulo, J; López-Lastra, M; Castro-Rodriguez, J A

    2016-01-01

    Urinary leukotriene (LTE4) is an important marker of airway inflammation presence. A relationship between single nucleotide polymorphism in the glucocorticoid receptor (GCR) gene promoter (Bcl I polymorphism), development of asthma and sensitivity to glucocorticoids has been hypothesised. To explore the possible association between the Bcl I polymorphism and baseline levels of urinary LTE4 in preschoolers with recurrent wheezing episodes. We prospectively enrolled and classified 86 preschoolers based on the risk of developing asthma (by the Asthma Predictive Index [API]). At admission standardised questionnaires for demographics and respiratory illness characteristics were completed. The Bcl I polymorphism of the GCR was determined by a PCR-RFLP assay from blood samples, and urinary leukotriene was assessed from urine samples by an enzyme immunoassay. We enrolled 86 preschoolers (46 with positive API and 40 with negative API). There were no statistical differences in demographic, respiratory illnesses and wheezing episodes characteristics between both groups. Also, the prevalence of Bcl I polymorphism was similar between positive vs. negative API groups (34.8% vs. 38.9% for homozygote GG, 56.5% vs. 52.8% for heterozygote GC, 8.7% vs. 8.3% for homozygote CC, respectively, p=0.94). However, urinary LTE4 (median [IQR]) was higher in preschoolers with positive than negative API (7.18 [5.57-8.96pg/ml] vs. 6.42 [3.96-8.07pg/ml], p=0.02, respectively). In our population, wheezing preschoolers with positive API exhibit higher levels of urinary LTE4 than those with negative API; but there were no differences in Bcl I polymorphism of the GCR. Copyright © 2015 SEICAP. Published by Elsevier Espana. All rights reserved.

  11. Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes.

    PubMed

    Rojas, Daniel; Rager, Julia E; Smeester, Lisa; Bailey, Kathryn A; Drobná, Zuzana; Rubio-Andrade, Marisela; Stýblo, Miroslav; García-Vargas, Gonzalo; Fry, Rebecca C

    2015-01-01

    Prenatal exposure to inorganic arsenic (iAs) is detrimental to the health of newborns and increases the risk of disease development later in life. Here we examined a subset of newborn cord blood leukocyte samples collected from subjects enrolled in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Gómez Palacio, Mexico, who were exposed to a range of drinking water arsenic concentrations (0.456-236 µg/l). Changes in iAs-associated DNA 5-methylcytosine methylation were assessed across 424,935 CpG sites representing 18,761 genes and compared with corresponding mRNA expression levels and birth outcomes. In the context of arsenic exposure, a total of 2919 genes were identified with iAs-associated differences in DNA methylation. Site-specific analyses identified DNA methylation changes that were most predictive of gene expression levels where CpG methylation within CpG islands positioned within the first exon, the 5' untranslated region and 200 bp upstream of the transcription start site yielded the most significant association with gene expression levels. A set of 16 genes was identified with correlated iAs-associated changes in DNA methylation and mRNA expression and all were highly enriched for binding sites of the early growth response (EGR) and CCCTC-binding factor (CTCF) transcription factors. Furthermore, DNA methylation levels of 7 of these genes were associated with differences in birth outcomes including gestational age and head circumference.These data highlight the complex interplay between DNA methylation, functional changes in gene expression and health outcomes and underscore the need for functional analyses coupled to epigenetic assessments. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Engineering the Soil Bacterium Pseudomonas putida for Arsenic Methylation

    PubMed Central

    Chen, Jian; Qin, Jie; Zhu, Yong-Guan; de Lorenzo, Víctor

    2013-01-01

    Accumulation of arsenic has potential health risks through consumption of food. Here, we inserted the arsenite [As(III)] S-adenosylmethionine methyltransferase (ArsM) gene into the chromosome of Pseudomonas putida KT2440. Recombinant bacteria methylate inorganic arsenic into less toxic organoarsenicals. This has the potential for bioremediation of environmental arsenic and reducing arsenic contamination in food. PMID:23645194

  13. ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.

    PubMed

    Zhang, Rong; Knapp, Michael; Suzuki, Kentaro; Kajioka, Daiki; Schmidt, Johanna M; Winkler, Jonas; Yilmaz, Öznur; Pleschka, Michael; Cao, Jia; Kockum, Christina Clementson; Barker, Gillian; Holmdahl, Gundela; Beaman, Glenda; Keene, David; Woolf, Adrian S; Cervellione, Raimondo M; Cheng, Wei; Wilkins, Simon; Gearhart, John P; Sirchia, Fabio; Di Grazia, Massimo; Ebert, Anne-Karolin; Rösch, Wolfgang; Ellinger, Jörg; Jenetzky, Ekkehart; Zwink, Nadine; Feitz, Wout F; Marcelis, Carlo; Schumacher, Johannes; Martinón-Torres, Federico; Hibberd, Martin Lloyd; Khor, Chiea Chuen; Heilmann-Heimbach, Stefanie; Barth, Sandra; Boyadjiev, Simeon A; Brusco, Alfredo; Ludwig, Michael; Newman, William; Nordenskjöld, Agneta; Yamada, Gen; Odermatt, Benjamin; Reutter, Heiko

    2017-02-08

    Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10(-08)). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10(-19). Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

  14. ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development

    PubMed Central

    Zhang, Rong; Knapp, Michael; Suzuki, Kentaro; Kajioka, Daiki; Schmidt, Johanna M.; Winkler, Jonas; Yilmaz, Öznur; Pleschka, Michael; Cao, Jia; Kockum, Christina Clementson; Barker, Gillian; Holmdahl, Gundela; Beaman, Glenda; Keene, David; Woolf, Adrian S.; Cervellione, Raimondo M.; Cheng, Wei; Wilkins, Simon; Gearhart, John P.; Sirchia, Fabio; Di Grazia, Massimo; Ebert, Anne-Karolin; Rösch, Wolfgang; Ellinger, Jörg; Jenetzky, Ekkehart; Zwink, Nadine; Feitz, Wout F.; Marcelis, Carlo; Schumacher, Johannes; Martinón-Torres, Federico; Hibberd, Martin Lloyd; Khor, Chiea Chuen; Heilmann-Heimbach, Stefanie; Barth, Sandra; Boyadjiev, Simeon A.; Brusco, Alfredo; Ludwig, Michael; Newman, William; Nordenskjöld, Agneta; Yamada, Gen; Odermatt, Benjamin; Reutter, Heiko

    2017-01-01

    Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10−08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10−19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development. PMID:28176844

  15. Arsenic resistance genes of As-resistant purple nonsulfur bacteria isolated from As-contaminated sites for bioremediation application.

    PubMed

    Nookongbut, Phitthaya; Kantachote, Duangporn; Krishnan, Kannan; Megharaj, Mallavarapu

    2017-04-01

    This study aimed to identify arsenic resistant mechanisms in As-resistant purple nonsulfur bacteria (PNSB) by screening them for presence of As-resistance genes and related enzymes. Resistance to As(III) and As(V) of four As-resistant PNSB determined in terms of median inhibition concentration (IC50 values) were in the order of strains Rhodopseudomonas palustris C1 > R. palustris AB3 > Rubrivivax benzoatilyticus C31 > R. palustris L28 which corresponded to the presence of As-resistance genes in these bacteria. The strain C1 showed all As-marker genes; arsC, arsM, aioA, and acr3, while aioA was not detected in strain AB3. Strains C31 and L28 had only Arsenite-transporter gene, acr3. Translation of all these detected gene sequences of strain C1 to amino acid sequences showed that these proteins have vicinal cysteine; Cys126, Cys105, and Cys178 of Acr3, ArsC, AioA, respectively. Tertiary structure of proteins Acr3, ArsC, AioA, and ArsM showed strain C1 exhibits the high activities of arsenite oxidase and arsenate reductase enzymes that are encoded by aioA and arsC genes, respectively. Moreover, strain C1 with arsM gene produced volatile-methylated As-compounds; monomethylarsonic acid (MMA), dimethylarsenic acid (DMA), and arsenobetaine (AsB) in the presence of either As(III) or As(V). In conclusion, the strain C1 has great potential for its application in bioremediation of As-contaminated sites.

  16. In Vivo Effect of Arsenic Trioxide on Keap1-p62-Nrf2 Signaling Pathway in Mouse Liver: Expression of Antioxidant Responsive Element-Driven Genes Related to Glutathione Metabolism

    PubMed Central

    Srivastava, Ritu; Sengupta, Archya; Mukherjee, Sandip; Chatterjee, Sarmishtha; Sudarshan, Muthammal; Chakraborty, Anindita; Bhattacharya, Shelley; Chattopadhyay, Ansuman

    2013-01-01

    Arsenic is a Group I human carcinogen, and chronic arsenic exposure through drinking water is a major threat to human population. Liver is one of the major organs for the detoxification of arsenic. The present study was carried out in mice in vivo after arsenic treatment through drinking water at different doses and time of exposure. Arsenic toxicity is found to be mediated by reactive oxygen species. Nuclear factor (erythroid-2 related) factor 2 (Nrf2)/Keap1 (Kelch-like ECH-associated protein 1)/ARE (antioxidant response element)—driven target gene system protects cells against oxidative stress and maintains cellular oxidative homeostasis. Our result showed 0.4 ppm, 2 ppm, and 4 ppm arsenic trioxide treatment through drinking water for 30 days and 90 days induced damages in the liver of Swiss albino mice as evidenced by histopathology, disturbances in liver function, induction of heat shock protein 70, modulation of trace elements, alteration in reduced glutathione level, glutathione-s-transferase and catalase activity, malondialdehyde production, and induction of apoptosis. Cellular Nrf2 protein level and mRNA level increased in all treatment groups. Keap1 protein as well as mRNA level decreased concomitantly in arsenic treated mice. Our study clearly indicates the important role of Nrf2 in activating ARE driven genes related to GSH metabolic pathway and also the adaptive response mechanisms in arsenic induced hepatotoxicity. PMID:27335833

  17. In Vivo Effect of Arsenic Trioxide on Keap1-p62-Nrf2 Signaling Pathway in Mouse Liver: Expression of Antioxidant Responsive Element-Driven Genes Related to Glutathione Metabolism.

    PubMed

    Srivastava, Ritu; Sengupta, Archya; Mukherjee, Sandip; Chatterjee, Sarmishtha; Sudarshan, Muthammal; Chakraborty, Anindita; Bhattacharya, Shelley; Chattopadhyay, Ansuman

    2013-01-01

    Arsenic is a Group I human carcinogen, and chronic arsenic exposure through drinking water is a major threat to human population. Liver is one of the major organs for the detoxification of arsenic. The present study was carried out in mice in vivo after arsenic treatment through drinking water at different doses and time of exposure. Arsenic toxicity is found to be mediated by reactive oxygen species. Nuclear factor (erythroid-2 related) factor 2 (Nrf2)/Keap1 (Kelch-like ECH-associated protein 1)/ARE (antioxidant response element)-driven target gene system protects cells against oxidative stress and maintains cellular oxidative homeostasis. Our result showed 0.4 ppm, 2 ppm, and 4 ppm arsenic trioxide treatment through drinking water for 30 days and 90 days induced damages in the liver of Swiss albino mice as evidenced by histopathology, disturbances in liver function, induction of heat shock protein 70, modulation of trace elements, alteration in reduced glutathione level, glutathione-s-transferase and catalase activity, malondialdehyde production, and induction of apoptosis. Cellular Nrf2 protein level and mRNA level increased in all treatment groups. Keap1 protein as well as mRNA level decreased concomitantly in arsenic treated mice. Our study clearly indicates the important role of Nrf2 in activating ARE driven genes related to GSH metabolic pathway and also the adaptive response mechanisms in arsenic induced hepatotoxicity.

  18. [Lower urinary tract dysfunction and neuropathological findings of the neural circuits controlling micturition in familial amyotrophic lateral sclerosis with L106V mutation in the SOD1 gene].

    PubMed

    Hineno, Akiyo; Oyanagi, Kiyomitsu; Nakamura, Akinori; Shimojima, Yoshio; Yoshida, Kunihiro; Ikeda, Shu-Ichi

    2016-01-01

    We report lower urinary tract dysfunction and neuropathological findings of the neural circuits controlling micturition in the patients with familial amyotrophic lateral sclerosis having L106V mutation in the SOD1 gene. Ten of 20 patients showed lower urinary tract dysfunction and 5 patients developed within 1 year after the onset of weakness. In 8 patients with an artificial respirator, 6 patients showed lower urinary tract dysfunction. Lower urinary tract dysfunction and respiratory failure requiring an artificial respirator occurred simultaneously in 3 patients. Neuronal loss and gliosis were observed in the neural circuits controlling micturition, such as frontal lobe, thalamus, hypothalamus, striatum, periaqueductal gray, ascending spinal tract, lateral corticospinal tract, intermediolateral nucleus and Onufrowicz' nucleus. Lower urinary tract dysfunction, especially storage symptoms, developed about 1 year after the onset of weakness, and the dysfunction occurred simultaneously with artificial respirator use in the patients.

  19. Prenatal Arsenic Exposure and DNA Methylation in Maternal and Umbilical Cord Blood Leukocytes

    PubMed Central

    Baccarelli, Andrea; Hoffman, Elaine; Tarantini, Letizia; Quamruzzaman, Quazi; Rahman, Mahmuder; Mahiuddin, Golam; Mostofa, Golam; Hsueh, Yu-Mei; Wright, Robert O.; Christiani, David C.

    2012-01-01

    Background: Arsenic is an epigenetic toxicant and could influence fetal developmental programming. Objectives: We evaluated the association between arsenic exposure and DNA methylation in maternal and umbilical cord leukocytes. Methods: Drinking-water and urine samples were collected when women were at ≤ 28 weeks gestation; the samples were analyzed for arsenic using inductively coupled plasma mass spectrometry. DNA methylation at CpG sites in p16 (n = 7) and p53 (n = 4), and in LINE-1 and Alu repetitive elements (3 CpG sites in each), was quantified using pyrosequencing in 113 pairs of maternal and umbilical blood samples. We used general linear models to evaluate the relationship between DNA methylation and tertiles of arsenic exposure. Results: Mean (± SD) drinking-water arsenic concentration was 14.8 ± 36.2 μg/L (range: < 1–230 μg/L). Methylation in LINE-1 increased by 1.36% [95% confidence interval (CI): 0.52, 2.21%] and 1.08% (95% CI: 0.07, 2.10%) in umbilical cord and maternal leukocytes, respectively, in association with the highest versus lowest tertile of total urinary arsenic per gram creatinine. Arsenic exposure was also associated with higher methylation of some of the tested CpG sites in the promoter region of p16 in umbilical cord and maternal leukocytes. No associations were observed for Alu or p53 methylation. Conclusions: Exposure to higher levels of arsenic was positively associated with DNA methylation in LINE-1 repeated elements, and to a lesser degree at CpG sites within the promoter region of the tumor suppressor gene p16. Associations were observed in both maternal and fetal leukocytes. Future research is needed to confirm these results and determine if these small increases in methylation are associated with any health effects. PMID:22466225

  20. Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium.

    PubMed

    Pelch, Katherine E; Tokar, Erik J; Merrick, B Alex; Waalkes, Michael P

    2015-08-01

    Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10μM Cd for 11weeks (CTPE) or 5μM iAs for 29weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for an in-depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (>25-fold) and S100P (>40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (>15-fold) and NTM (>1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status. Published by Elsevier Inc.

  1. Assessing arsenic exposure in households using bottled water or point-of-use treatment systems to mitigate well water contamination.

    PubMed

    Smith, Andrew E; Lincoln, Rebecca A; Paulu, Chris; Simones, Thomas L; Caldwell, Kathleen L; Jones, Robert L; Backer, Lorraine C

    2016-02-15

    There is little published literature on the efficacy of strategies to reduce exposure to residential well water arsenic. The objectives of our study were to: 1) determine if water arsenic remained a significant exposure source in households using bottled water or point-of-use treatment systems; and 2) evaluate the major sources and routes of any remaining arsenic exposure. We conducted a cross-sectional study of 167 households in Maine using one of these two strategies to prevent exposure to arsenic. Most households included one adult and at least one child. Untreated well water arsenic concentrations ranged from <10 μg/L to 640 μg/L. Urine samples, water samples, daily diet and bathing diaries, and household dietary and water use habit surveys were collected. Generalized estimating equations were used to model the relationship between urinary arsenic and untreated well water arsenic concentration, while accounting for documented consumption of untreated water and dietary sources. If mitigation strategies were fully effective, there should be no relationship between urinary arsenic and well water arsenic. To the contrary, we found that untreated arsenic water concentration remained a significant (p ≤ 0.001) predictor of urinary arsenic levels. When untreated water arsenic concentrations were <40 μg/L, untreated water arsenic was no longer a significant predictor of urinary arsenic. Time spent bathing (alone or in combination with water arsenic concentration) was not associated with urinary arsenic. A predictive analysis of the average study participant suggested that when untreated water arsenic ranged from 100 to 500 μg/L, elimination of any untreated water use would result in an 8%-32% reduction in urinary arsenic for young children, and a 14%-59% reduction for adults. These results demonstrate the importance of complying with a point-of-use or bottled water exposure reduction strategy. However, there remained unexplained, water-related routes of exposure

  2. Evaluation of Exposure to Arsenic in Residential Soil

    SciTech Connect

    Tsuji, Joyce S.; Van Kerkhove, Maria D.; Kaetzel, Rhonda; Scrafford, Carolyn; Mink, Pamela; Barraj, Leila M.; Crecelius, Eric A.; Goodman, Michael

    2005-12-01

    In response to concerns regarding arsenic in soil from a pesticide manufacturing plant, we conducted a biomonitoring study on children younger than 7 years of age, the age category of children most exposed to soil. Urine samples from 77 children (47% participation rate) were analyzed for total arsenic and arsenic species related to ingestion of inorganic arsenic. Older individuals also provided urine (n = 362) and toenail (n = 67) samples. Speciated urinary arsenic levels were similar between children (geometric mean, geometric SD, and range: 4.0, 2.2, and 0.89?17.7 ?g/L, respectively) and older participants (3.8, 1.9, 0.91?19.9 ?g/L) and consistent with unexposed populations. Toenail samples were < 1 mg/kg. Correlations between speciated urinary arsenic and arsenic in soil (r = 0.137, p = 0.39; n = 41) or house dust (r = 0.049, p = 0.73; n = 52) were not significant for children. Similarly, questionnaire responses indicating soil exposure were not associated with increased urinary arsenic levels. Relatively low soil arsenic exposure likely precluded quantification of arsenic exposure above background.

  3. Urinary heavy metals, phthalates, phenols, thiocyanate, parabens, pesticides, polyaromatic hydrocarbons but not arsenic or polyfluorinated compounds are associated with adult oral health: USA NHANES, 2011-2012.

    PubMed

    Shiue, Ivy

    2015-10-01

    Links between environmental chemicals and human health have emerged over the last few decades, but the effects on oral health have been less studied. Therefore, it was aimed to study the relationships of different sets of urinary chemical concentrations and adult oral health conditions in a national and population-based setting. Data was retrieved from the United States National Health and Nutrition Examination Surveys, 2011-2012 including demographics, self-reported oral health conditions and urinary environmental chemical concentrations (one third representative sample of the study population). Chi-square test, t test, and survey-weighted logistic and multi-nominal regression modeling were performed. Of 4566 American adults aged 30-80, 541 adults (11.9 %) reported poor teeth health while 1020 adults (22.4 %) reported fair teeth. Eight hundred fifty-five people (19.1 %) claimed to have gum disease, presented with higher levels of urinary cadmium, cobalt and polyaromatic hydrocarbons. Six hundred three adults (13.3 %) had bone loss around the mouth, presented with higher levels of cadmium, nitrate, thiocyanate, propyl paraben and polyaromatic hydrocarbons. Eight hundred forty-five adults (18.5 %) had tooth loose not due to injury, presented with higher level of cadmium, thiocyanate and polyaromatic hydrocarbons. Eight hundred forty-five adults (18.5 %) with higher levels of lead, uranium, polyaromatic hydrocarbons but lower level of triclosan noticed their teeth did not look right. Three hundred fifty-one adults (7.7 %) often had aching in the mouth and 650 (14.3 %) had it occasionally, presented with higher levels of phthalates, pesticides and polyaromatic hydrocarbons. Benzophenone-3 and triclosan elicited protective effects. Regulation of environmental chemicals in prevention of adult oral health might need to be considered in future health and environmental policies.

  4. Arsenic exposure from drinking water, arsenic methylation capacity, and carotid intima-media thickness in Bangladesh.

    PubMed

    Chen, Yu; Wu, Fen; Graziano, Joseph H; Parvez, Faruque; Liu, Mengling; Paul, Rina Rani; Shaheen, Ishrat; Sarwar, Golam; Ahmed, Alauddin; Islam, Tariqul; Slavkovich, Vesna; Rundek, Tatjana; Demmer, Ryan T; Desvarieux, Moise; Ahsan, Habibul

    2013-08-01

    We conducted a cross-sectional study to evaluate the interrelationships between past arsenic exposure, biomarkers specific for susceptibility to arsenic exposure, and carotid intima-media thickness (cIMT) in 959 subjects from the Health Effects of Arsenic Longitudinal Study in Bangladesh. We measured cIMT levels on average 7.2 years after baseline during 2010-2011. Arsenic exposure was measured in well water at baseline and in urine samples collected at baseline and during follow-up. Every 1-standard-deviation increase in urinary arsenic (357.9 µg/g creatinine) and well-water arsenic (102.0 µg/L) concentration was related to a 11.7-µm (95% confidence interval (CI): 1.8, 21.6) and 5.1-µm (95% CI: -0.2, 10.3) increase in cIMT, respectively. For every 10% increase in monomethylarsonic acid (MMA) percentage, there was an increase of 12.1 µm (95% CI: 0.4, 23.8) in cIMT. Among participants with a higher urinary MMA percentage, a higher ratio of urinary MMA to inorganic arsenic, and a lower ratio of dimethylarsinic acid to MMA, the association between well-water arsenic and cIMT was stronger. The findings indicate an effect of past long-term arsenic exposure on cIMT, which may be potentiated by suboptimal or incomplete arsenic methylation capacity. Future prospective studies are needed to confirm the association between arsenic methylation capacity and atherosclerosis-related outcomes.

  5. Arsenic Exposure From Drinking Water, Arsenic Methylation Capacity, and Carotid Intima-Media Thickness in Bangladesh

    PubMed Central

    Chen, Yu; Wu, Fen; Graziano, Joseph H.; Parvez, Faruque; Liu, Mengling; Paul, Rina Rani; Shaheen, Ishrat; Sarwar, Golam; Ahmed, Alauddin; Islam, Tariqul; Slavkovich, Vesna; Rundek, Tatjana; Demmer, Ryan T.; Desvarieux, Moise; Ahsan, Habibul

    2013-01-01

    We conducted a cross-sectional study to evaluate the interrelationships between past arsenic exposure, biomarkers specific for susceptibility to arsenic exposure, and carotid intima-media thickness (cIMT) in 959 subjects from the Health Effects of Arsenic Longitudinal Study in Bangladesh. We measured cIMT levels on average 7.2 years after baseline during 2010–2011. Arsenic exposure was measured in well water at baseline and in urine samples collected at baseline and during follow-up. Every 1-standard-deviation increase in urinary arsenic (357.9 µg/g creatinine) and well-water arsenic (102.0 µg/L) concentration was related to a 11.7-µm (95% confidence interval (CI): 1.8, 21.6) and 5.1-µm (95% CI: −0.2, 10.3) increase in cIMT, respectively. For every 10% increase in monomethylarsonic acid (MMA) percentage, there was an increase of 12.1 µm (95% CI: 0.4, 23.8) in cIMT. Among participants with a higher urinary MMA percentage, a higher ratio of urinary MMA to inorganic arsenic, and a lower ratio of dimethylarsinic acid to MMA, the association between well-water arsenic and cIMT was stronger. The findings indicate an effect of past long-term arsenic exposure on cIMT, which may be potentiated by suboptimal or incomplete arsenic methylation capacity. Future prospective studies are needed to confirm the association between arsenic methylation capacity and atherosclerosis-related outcomes. PMID:23788675

  6. PLASMID DNA DAMAGE CAUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITIN

    EPA Science Inventory

    Plasmid DNA damage caused by methylated arsenicals, ascorbic acid and human liver ferritin.

    Arsenic causes cancer in human skin, urinary bladder, lung, liver and kidney and is a significant world-wide public health problem. Although the metabolism of inorganic arsenic is ...

  7. PLASMID DNA DAMAGE CAUSED BY METHYLATED ARSENICALS, ASCORBIC ACID AND HUMAN LIVER FERRITIN

    EPA Science Inventory

    Plasmid DNA damage caused by methylated arsenicals, ascorbic acid and human liver ferritin.

    Arsenic causes cancer in human skin, urinary bladder, lung, liver and kidney and is a significant world-wide public health problem. Although the metabolism of inorganic arsenic is ...

  8. Antibiotic resistance and detection of the sul2 gene in urinary isolates of Escherichia coli in patients from Brazil.

    PubMed

    Teichmann, Aline; Agra, Homero Neto de Cunha; Nunes, Luciana de Souza; da Rocha, Marion Pereira; Renner, Jane Dagmar Pollo; Possuelo, Lia Gonçalves; Carneiro, Marcelo; Rieger, Alexandre; Benitez, Lisianne Brittes; Valim, Andréia Rosane de Moura

    2014-01-15

    The present study aimed to assess the antibiotic resistance profiles and detect the presence of the sul2 gene in sulfamethoxazole-susceptible and resistant isolates of Escherichia coli obtained from outpatients and inpatients with urinary tract infections. The resistance profiles of 739 strains were assessed and the presence of the sul2 gene in 100 isolates was tested. The antibiotics with the highest resistance rates were ampicillin (57.4%) and trimethoprim-sulfamethoxazole (44.7%). The presence of the gene sul2 was detected in 66.7% of outpatient samples and 67.9% of inpatient samples. Our results demonstrate that E. coli isolates exhibit high resistance to various classes of antibiotics, highlighting the need for developing strategies to help in prescribing antibiotics.

  9. Arsenic (+ 3 oxidation state) methyltransferase genotype affects steady-state distribution and clearance of arsenic in arsenate-treated mice

    SciTech Connect

    Hughes, Michael F.; Edwards, Brenda C.; Herbin-Davis, Karen M.; Saunders, Jesse; Styblo, Miroslav; Thomas, David J.

    2010-12-15

    Arsenic (+ 3 oxidation state) methyltransferase (As3mt) catalyzes formation of mono-, di-, and tri-methylated metabolites of inorganic arsenic. Distribution and retention of arsenic were compared in adult female As3mt knockout mice and wild-type C57BL/6 mice using a regimen in which mice received daily oral doses of 0.5 mg of arsenic as arsenate per kilogram of body weight. Regardless of genotype, arsenic body burdens attained steady state after 10 daily doses. At steady state, arsenic body burdens in As3mt knockout mice were 16 to 20 times greater than in wild-type mice. During the post dosing clearance period, arsenic body burdens declined in As3mt knockout mice to {approx} 35% and in wild-type mice to {approx} 10% of steady-state levels. Urinary concentration of arsenic was significantly lower in As3mt knockout mice than in wild-type mice. At steady state, As3mt knockout mice had significantly higher fractions of the body burden of arsenic in liver, kidney, and urinary bladder than did wild-type mice. These organs and lung had significantly higher arsenic concentrations than did corresponding organs from wild-type mice. Inorganic arsenic was the predominant species in tissues of As3mt knockout mice; tissues from wild-type mice contained mixtures of inorganic arsenic and its methylated metabolites. Diminished capacity for arsenic methylation in As3mt knockout mice prolongs retention of inorganic arsenic in tissues and affects whole body clearance of arsenic. Altered retention and tissue tropism of arsenic in As3mt knockout mice could affect the toxic or carcinogenic effects associated with exposure to this metalloid or its methylated metabolites.

  10. Arsenic trioxide regulates adipogenic and osteogenic differentiation in bone marrow MSCs of aplastic anemia patients through BMP4 gene.

    PubMed

    Cheng, Huan Chen; Liu, Sheng Wei; Li, Wei; Zhao, Xue Fei; Zhao, Xu; Cheng, Mei; Qiu, Lin; Ma, Jun

    2015-09-01

    The typical pathological feature of aplastic anemia (AA) is the rise in the number of fat cells and the reduction of osteoblasts in bone marrow. However, both fat cells and osteobalsts in bone marrow are derived from the mesenchymal stem cells (MSCs). Generally, the adipogenic and osteogenic differentiation is a dynamic and balanceable process. The imbalance of the adipogenic and osteogenic differentiation may participate in the occurrence and progress of many diseases. Arsenic trioxide (ATO) could induce differentiation and apoptosis in tumor cells. In this study, Oil Red-O and Alizarin red were used to detect the adipogenic and osteogenic differentiation. The ability of adipogenic differentiation is much higher, whereas the osteogenic differentiation is much lower in the MSCs of AA patients compared with healthy controls. ATO inhibits adipogenic differentiation and promotes osteogenic differentiation in the MSC of AA patients. The expression of BMP4 is increased with ATO treatment. The ability of adipogenic differentiation is decreased, whereas the osteogenic differentiation is increased after transfection of BMP4 gene into the MSCs of AA patients. This study shows that ATO regulates the adipogenic and osteogenic differentiation balance of MSCs in AA, which provides a theoretical basis for the adjunctive therapy of ATO on AA. The BMP4 gene is involved in the ATO regulation of adipogenic and osteogenic differentiation balance, which provides a new target for the treatment of AA.

  11. GENE EXPRESSION DOSE-RESPONSE IN THE BLADDERS OF MICE EXPOSED TO ARSENIC IN DRINKING WATER FOR 13 WEEKS

    EPA Science Inventory

    The association between drinking water exposures to inorganic arsenic and life-threatening tumors in the human is strongest for bladder cancer. To investigate the mode of action for inorganic arsenic carcinogenicity in the bladder, a study was conducted to characterize the dose-r...

  12. GENE EXPRESSION DOSE-RESPONSE IN THE BLADDERS OF MICE EXPOSED TO ARSENIC IN DRINKING WATER FOR 13 WEEKS

    EPA Science Inventory

    The association between drinking water exposures to inorganic arsenic and life-threatening tumors in the human is strongest for bladder cancer. To investigate the mode of action for inorganic arsenic carcinogenicity in the bladder, a study was conducted to characterize the dose-r...

  13. Arsenic poisoning.

    PubMed

    Schoolmeester, W L; White, D R

    1980-02-01

    Arsenic poisoning continues to require awareness of its diverse clinical manifestations. Industry is the major source of arsenic exposure. Although epidemiologic studies strongly contend that arsenic is carcinogenic, there are little supportive research data. Arsenic poisoning, both acute and chronic, is often overlooked initially in the evaluation of the patient with multisystem disease, but once it is suspected, many accurate methods are available to quantitate the amount and duration of exposure. Treatment with dimercaprol remains the mainstay of therapy, and early treatment is necessary to prevent irreversible complications.

  14. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract.

    PubMed

    Kohl, Stefan; Hwang, Daw-Yang; Dworschak, Gabriel C; Hilger, Alina C; Saisawat, Pawaree; Vivante, Asaf; Stajic, Natasa; Bogdanovic, Radovan; Reutter, Heiko M; Kehinde, Elijah O; Tasic, Velibor; Hildebrandt, Friedhelm

    2014-09-01

    Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study. Copyright © 2014 by the American Society of Nephrology.

  15. Arsenic exposure and prevalence of diabetes mellitus in Korean adults.

    PubMed

    Rhee, Sang Youl; Hwang, You-Cheol; Woo, Jeong-taek; Chin, Sang Ouk; Chon, Suk; Kim, Young Seol

    2013-06-01

    It has been suggested that there is an association between environmental, low-level arsenic exposure and the risk of diabetes mellitus (DM), but little research has been conducted. Here, the glucose tolerance status and urinary creatinine adjusted total arsenic concentrations were analyzed in 3,602 subjects ≥ 20 yr of age who were registered for the Korea National Health and Nutrition Examination Survey, 2008-2009. Various demographic parameters were associated with urinary arsenic concentrations. After adjusting for these variables, urinary arsenic concentrations in subjects with DM were significantly higher than those in subjects with normal glucose tolerance and those with impaired fasting glucose (P < 0.001). Compared with the lowest quartile ( < 70.7 µg/g creatinine), the odds ratios and 95% confidence intervals for DM were 1.11 (0.73-1.68), 1.42 (0.94-2.13), and 1.56 (1.03-2.36) for urinary arsenic concentrations of 70.7 to < 117.7, 117.7 to < 193.4, and ≥ 193.4 µg/g creatinine, respectively, following multivariate adjustment. Furthermore, the urinary total arsenic concentration was inversely associated with the insulin secretion index, HOMA2 %B (β = -0.033, P = 0.032). These findings suggest that arsenic exposure, possibly involving beta cell dysfunction, is associated with an increased risk of DM in the Korean population.

  16. Arsenic Methylation, Oxidative Stress and Cancer - Is there a Link?

    EPA Science Inventory

    Arsenic is a multiorgan human carcinogen. The best-known example of this effect occurred in subgroups of the Taiwanese population who were chronically exposed to high levels of naturally occurring arsenic in drinking water and developed cancers of the skin, lung, urinary bladde...

  17. Arsenic Methylation, Oxidative Stress and Cancer - Is there a Link?

    EPA Science Inventory

    Arsenic is a multiorgan human carcinogen. The best-known example of this effect occurred in subgroups of the Taiwanese population who were chronically exposed to high levels of naturally occurring arsenic in drinking water and developed cancers of the skin, lung, urinary bladde...

  18. [Study progress of adverse effects of arsenic on health].

    PubMed

    Kang, Jiaqi; Jin, Yinlong

    2004-05-01

    Adverse effects on health of high arsenic in drinking water and contaminated environment are currently of great concern. This review focuses on metabolism of arsenic and it's impairments to skin, blood circle system, nervous system, reproductive-and-urinary system, digestive system, respiratory system and immune system.

  19. Site-specific data confirm arsenic exposure predicted by the U.S. Environmental Protection Agency.

    PubMed Central

    Walker, S; Griffin, S

    1998-01-01

    The EPA uses an exposure assessment model to estimate daily intake to chemicals of potential concern. At the Anaconda Superfund site in Montana, the EPA exposure assessment model was used to predict total and speciated urinary arsenic concentrations. Predicted concentrations were then compared to concentrations measured in children living near the site. When site-specific information on concentrations of arsenic in soil, interior dust, and diet, site-specific ingestion rates, and arsenic absorption rates were used, measured and predicted urinary arsenic concentrations were in reasonable agreement. The central tendency exposure assessment model successfully described the measured urinary arsenic concentration for the majority of children at the site. The reasonable maximum exposure assessment model successfully identified the uppermost exposed population. While the agreement between measured and predicted urinary arsenic is good, it is not exact. The variables that were identified which influenced agreement included soil and dust sample collection methodology, daily urinary volume, soil ingestion rate, and the ability to define the exposure unit. The concentration of arsenic in food affected agreement between measured and predicted total urinary arsenic, but was not considered when comparing measured and predicted speciated urinary arsenic. Speciated urinary arsenic is the recommended biomarker for recent inorganic arsenic exposure. By using site-specific data in the exposure assessment model, predicted risks from exposure to arsenic were less than predicted risks would have been if the EPA's default values had been used in the exposure assessment model. This difference resulted in reduced magnitude and cost of remediation while still protecting human health. Images Figure 1 PMID:9452415

  20. A Phytoremediation Strategy for Arsenic

    SciTech Connect

    Meagher, Richard B.

    2005-06-01

    A Phytoremediation Strategy for Arsenic Progress Report May, 2005 Richard B. Meagher Principal Investigator Arsenic pollution affects the health of several hundred millions of people world wide, and an estimated 10 million Americans have unsafe levels of arsenic in their drinking water. However, few environmentally sound remedies for cleaning up arsenic contaminated soil and water have been proposed. Phytoremediation, the use of plants to extract and sequester environmental pollutants, is one new technology that offers an ecologically sound solution to a devastating problem. We propose that it is less disruptive to the environment to harvest and dispose of several thousand pounds per acre of contaminated aboveground plant material, than to excavate and dispose of 1 to 5 million pounds of contaminated soil per acre (assumes contamination runs 3 ft deep). Our objective is to develop a genetics-based phytoremediation strategy for arsenic removal that can be used in any plant species. This strategy requires the enhanced expression of several transgenes from diverse sources. Our working hypothesis is that organ-specific expression of several genes controlling the transport, electrochemical state, and binding of arsenic will result in the efficient extraction and hyperaccumulation of arsenic into aboveground plant tissues. This hypothesis is supported by theoretical arguments and strong preliminary data. We proposed six Specific Aims focused on testing and developing this arsenic phytoremediation strategy. During the first 18 months of the grant we made significant progress on five Specific Aims and began work on the sixth as summarized below. Specific Aim 1: Enhance plant arsenic resistance and greatly expand sinks for arsenite by expressing elevated levels of thiol-rich, arsenic-binding peptides. Hyperaccumulation of arsenic depends upon making plants that are both highly tolerant to arsenic and that have the capacity to store large amounts of arsenic aboveground

  1. Use of Green Fluorescent Protein To Assess Urease Gene Expression by Uropathogenic Proteus mirabilis during Experimental Ascending Urinary Tract Infection

    PubMed Central

    Zhao, Hui; Thompson, Richard B.; Lockatell, Virginia; Johnson, David E.; Mobley, Harry L. T.

    1998-01-01

    Proteus mirabilis, a cause of complicated urinary tract infection, expresses urease when exposed to urea. While it is recognized that the positive transcriptional activator UreR induces gene expression, the levels of expression of the enzyme during experimental infection are not known. To investigate in vivo expression of P. mirabilis urease, the gene encoding green fluorescent protein (GFP) was used to construct reporter fusions. Translational fusions of urease accessory gene ureD, which is preceded by a urea-inducible promoter, were made with gfp (modified to express S65T/V68L/S72A [B. P. Cormack et al. Gene 173:33–38, 1996]). Constructs were confirmed by sequencing of the fusion junctions. UreD-GFP fusion protein was induced by urea in both Escherichia coli DH5α and P. mirabilis HI4320. By using Western blotting with antiserum raised against GFP, expression level was shown to correlate with urea concentration (tested from 0 to 500 mM), with highest induction at 200 to 500 mM urea. Fluorescent E. coli and P. mirabilis bacteria were observed by fluorescence microscopy following urea induction, and the fluorescence intensity of GFP in cell lysates was measured by spectrophotofluorimetry. P. mirabilis HI4320 carrying the UreD-GFP fusion plasmid was transurethrally inoculated into the bladders of CBA mice. One week postchallenge, fluorescent bacteria were detected in thin sections of both bladder and kidney samples; the fluorescence intensity of bacteria in bladder tissue was higher than that in the kidney. Kidneys were primarily infected with single-cell-form fluorescent bacteria, while aggregated bacterial clusters were observed in the bladder. Elongated swarmer cells were only rarely observed. These observations demonstrate that urease is expressed in vivo and that using GFP as a reporter protein is a viable approach to investigate in vivo expression of P. mirabilis virulence genes in experimental urinary tract infection. PMID:9423875

  2. A STUDY OF THE INTERCONVERSION OF METHYLATED ARSENIC OXIDES TO METHYLATED ARSENIC SULFIDES IN SOLUTIONS CONTAINING FREE SULFIDE

    EPA Science Inventory

    Evidence suggests that thiolated arsenicals are urinary metabolites in both humans and rats. These thiolated species may be formed in the digestive system or as metabolites within the body. The role they may play in the overall toxicity of arsenic is an active area of research....

  3. A STUDY OF THE INTERCONVERSION OF METHYLATED ARSENIC OXIDES TO METHYLATED ARSENIC SULFIDES IN SOLUTIONS CONTAINING FREE SULFIDE

    EPA Science Inventory

    Evidence suggests that thiolated arsenicals are urinary metabolites in both humans and rats. These thiolated species may be formed in the digestive system or as metabolites within the body. The role they may play in the overall toxicity of arsenic is an active area of research....

  4. Linking Microbial Activity with Arsenic Fate during Cow Dung Disposal of Arsenic-Bearing Wastes

    NASA Astrophysics Data System (ADS)

    Clancy, T. M.; Reddy, R.; Tan, J.; Hayes, K. F.; Raskin, L.

    2014-12-01

    To address widespread arsenic contamination of drinking water sources numerous technologies have been developed to remove arsenic. All technologies result in the production of an arsenic-bearing waste that must be evaluated and disposed in a manner to limit the potential for environmental release and human exposure. One disposal option that is commonly recommended for areas without access to landfills is the mixing of arsenic-bearing wastes with cow dung. These recommendations are made based on the ability of microorganisms to create volatile arsenic species (including mono-, di-, and tri-methylarsine gases) to be diluted in the atmosphere. However, most studies of environmental microbial communities have found only a small fraction (<0.1 %) of the total arsenic present in soils or rice paddies is released via volatilization. Additionally, past studies often have not monitored arsenic release in the aqueous phase. Two main pathways for microbial arsenic volatilization are known and include methylation of arsenic during methanogenesis and methylation by arsenite S-adenosylmethionine methyltransferase. In this study, we compare the roles of these two pathways in arsenic volatilization and aqueous mobilization through mesocosm experiments with cow dung and arsenic-bearing wastes produced during drinking water treatment in West Bengal, India. Arsenic in gaseous, aqueous, and solid phases was measured. Consistent with previous reports, less than 0.02% of the total arsenic present was volatilized. A much higher amount (~5%) of the total arsenic was mobilized into the liquid phase. Through the application of molecular tools, including 16S rRNA sequencing and quantification of gene transcripts involved in methanogenesis, this study links microbial community activity with arsenic fate in potential disposal environments. These results illustrate that disposal of arsenic-bearing wastes by mixing with cow dung does not achieve its end goal of promoting arsenic volatilization

  5. [Relationship between aryl hydrocarbon receptor G1661A gene polymorphism and level of urinary 1-hydroxypyrene of coke oven workers].

    PubMed

    Zhang, Hong-mei; Xue, Cui-e; Zhao, Jie; Nie, Ji-sheng; Zeng, Ping; Sun, Jian-ya; Niu, Qiao

    2008-01-01

    To study the relationship between polymorphism of aryl hydrocarbon receptor (AhR) gene in G1661A and the level of urinary 1-hydroxypyrene among coke oven workers. 295 male subjects were studied, including 214 workers working in coke oven plant and 81 controls working in raw material plant who were not generally exposed to polycyclic aromatic hydrocarbons occupationally. General in-formation of subjects were collected in a specific questionnaire including age, smoking and drinking habits, the history of occupation and so on. The AhR genotypes were detected by allele specific amplification (ASA), and the levels of urinary 1-hydroxypyrene were measured by high performance liquid chromatography with a fluorescence detector. The frequencies of G/G, G/A and A/A genotype were 52.8% (113/214), 27.6% (59/214) and 19.6% (42/214) in exposed group and 67.9% (55/81), 19.8% (16/81) and 12.3% (10/81) in control group, respectively. No significant difference was found in three genotypes between the exposed and control group. Allele frequencies of G and A were 66.6% (285/428) and 33.4% (143/428) in exposed group and 77.8% (126/162) and 22.2% (36/162) in control group, and no statistical differences were found in allele frequency between exposed and control group. After the length of service and external exposure orders in general linear model were adjusted, results of covariance analysis showed that logarithmic transformed urinary 1-hydroxypyrene levels were (3.62 +/- 0.12), (3.43 +/- 0.12) and (3.44 +/- 0.08) micromol/mol Cr in individuals with A/A, G/A and G/G, respectively. The logarithmic transformed urinary 1-hydroxypyrene levels were (3.24 +/- 0.09) and (3.43 +/- 0.10) micromol/mol Cr in individuals with allele of G and A. No statistical differences were found in level of 1-hydroxypyrene among A/A, G/A and G/G genotype individuals, and between allele G and allele A after external exposure orders and length of service were adjusted. The polymorphism of aryl hydrocarbon

  6. Biomarkers of exposure: a case study with inorganic arsenic.

    PubMed

    Hughes, Michael F

    2006-11-01

    The environmental contaminant inorganic arsenic (iAs) is a human toxicant and carcinogen. Most mammals metabolize iAs by reducing it to trivalency, followed by oxidative methylation to pentavalency. iAs and its methylated metabolites are primarily excreted in urine within 4-5 days by most species and have a relatively low rate of bioaccumulation. Intra- and interindividual differences in the methylation of iAs may affect the adverse health effects of arsenic. Both inorganic and organic trivalent arsenicals are more potent toxicants than pentavalent forms. Several mechanisms of action have been proposed for arsenic-induced toxicity, but a scientific consensus has not been achieved. Biomarkers of exposure may be used to quantify exposure to iAs. The most common biomarker of exposure for iAs is the measurement of total urinary arsenic. However, consumption of seafood containing high concentrations of organic arsenic can confound estimation of iAs exposure. Because these organic species are thought to be relatively nontoxic, their presence in urine may not represent increased risk. Speciation of urinary arsenic into inorganic and organic forms, and even oxidation state, gives a more definitive indication of the exposure to iAs. Questions still remain, however, as to how reliably the measurement of urinary arsenic, either total or speciated, may predict arsenic concentrations at target tissues as well as how this measurement could be used to assess chronic exposures to iAs.

  7. The NRF2-KEAP1 Pathway Is an Early Responsive Gene Network in Arsenic Exposed Lymphoblastoid Cells

    PubMed Central

    Córdova, Emilio J.; Martínez-Hernández, Angélica; Uribe-Figueroa, Laura; Centeno, Federico; Morales-Marín, Mirna; Koneru, Harsha; Coleman, Matthew A.; Orozco, Lorena

    2014-01-01

    Inorganic arsenic (iAs), a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 µM), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs. PMID:24516582

  8. Methylation of Inorganic Arsenic by Murine Fetal Tissue Explants

    PubMed Central

    Broka, Derrick; Ditzel, Eric; Quach, Stephanie; Camenisch, Todd D.

    2016-01-01

    Although it is generally believed that the developing fetus is principally exposed to inorganic arsenic and the methylated metabolites from the maternal metabolism of arsenic, little is known about whether the developing embryo can autonomously metabolize arsenic. This study investigates inorganic arsenic methylation by murine embryonic organ cultures of the heart, lung, and liver. mRNA for AS3mt, the gene responsible for methylation of arsenic, was detected in all of embryonic tissue types studied. In addition, methylated arsenic metabolites were generated by all three tissue types. The fetal liver explants yielded the most methylated arsenic metabolites (~7% of total arsenic/ 48 hr incubation) while the heart, and lung preparations produced slightly greater than 2% methylated metabolites. With all tissues the methylation proceeded mostly to the dimethylated arsenic species. This has profound implications for understanding ar