| 1. |
- Ameer, Shegufta, et al.
(författare)
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Exposure to Inorganic Arsenic Is Associated with Increased Mitochondrial DNA Copy Number and Longer Telomere Length in Peripheral Blood
- 2016
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Exposure to inorganic arsenic (iAs) through drinking water causes cancer. Alterations in mitochondrial DNA copy number (mtDNAcn) and telomere length in blood have been associated with cancer risk. We elucidated if arsenic exposure alters mtDNAcn and telomere length in individuals with different arsenic metabolizing capacity.METHODS: We studied two groups in the Salta province, Argentina, one in the Puna area of the Andes (N = 264, 89% females) and one in Chaco (N = 169, 75% females). We assessed arsenic exposure as the sum of arsenic metabolites [iAs, methylarsonic acid (MMA), dimethylarsinic acid (DMA)] in urine (U-As) using high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. Efficiency of arsenic metabolism was expressed as percentage of urinary metabolites. MtDNAcn and telomere length were determined in blood by real-time PCR.RESULTS: Median U-As was 196 (5-95 percentile: 21-537) μg/L in Andes and 80 (5-95 percentile: 15-1637) μg/L in Chaco. The latter study group had less-efficient metabolism, with higher %iAs and %MMA in urine compared with the Andean group. U-As was significantly associated with increased mtDNAcn (log2 transformed to improve linearity) in Chaco (β = 0.027 per 100 μg/L, p = 0.0085; adjusted for age and sex), but not in Andes (β = 0.025, p = 0.24). U-As was also associated with longer telomere length in Chaco (β = 0.016, p = 0.0066) and Andes (β = 0.0075, p = 0.029). In both populations, individuals with above median %iAs showed significantly higher mtDNAcn and telomere length compared with individuals with below median %iAs.CONCLUSIONS: Arsenic was associated with increased mtDNAcn and telomere length, particularly in individuals with less-efficient arsenic metabolism, a group who may have increased risk for arsenic-related cancer.
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| 2. |
- Ameer, Syeda Shegufta, et al.
(författare)
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Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood
- 2017
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 321, s. 57-66
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Tidskriftsartikel (refereegranskat)abstract
- Background 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. Objectives To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. Methods 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. Results U-As concentrations, ranging 10–1251 μg/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 1000 CpGs 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. Conclusions Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap.
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| 3. |
- Ameer, S. S., et al.
(författare)
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Exposure to inorganic arsenic and mitochondrial DNA copy number and telomere length in peripheral blood
- 2016
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Ingår i: Arsenic Research and Global Sustainability - Proceedings of the 6th International Congress on Arsenic in the Environment, AS 2016. - 9781138029415 ; , s. 450-452
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Konferensbidrag (refereegranskat)abstract
- Exposure to inorganic arsenic (iAs) is a risk factor for cancer. Alterations in mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) have been associated with cancer risk. Two Argentinean groups were studied: A) Puna area of Andes and B) Chaco. Arsenic exposure was assessed as the sum of arsenic metabolites (iAs, MMA, and DMA) in urine (U-As) using HPLC-HG-ICPMS. MtDNAcn, TL, and genotype of the arsenic-methylating gene AS3MT were determined in blood by real-timePCR. The Chaco participants had less-efficient metabolism, with higher%iAs and%MMA in urine, and lower frequency of the efficient-metabolizing AS3MT haplotype. U-As was associated with increased mtDNAcn in Chaco but not in Andes. U-As was associated with longer TL in Chaco, but less so in Andes. Individuals with%iAs>median showed significantly higher mtDNAcn and TL in both groups. Arsenic was associated with increased mtDNAcn and TL, particularly in individuals with less-efficient arsenic metabolism, who might have increased risk for arsenic-related cancer.
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| 4. |
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| 5. |
- Broberg, K., et al.
(författare)
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Exposure to inorganic arsenic and gene expression in peripheral blood
- 2016
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Ingår i: Arsenic Research and Global Sustainability - Proceedings of the 6th International Congress on Arsenic in the Environment, AS 2016. - 9781138029415 ; , s. 448-449
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Konferensbidrag (refereegranskat)abstract
- Arsenic is an established carcinogen and a risk factor for several non-malignant diseases. Mechanisms of arsenic toxicity may include interference with gene expression. The impact of arsenic exposure on gene expression was evaluated in women (n = 80) living in the Puna of the northern Argentinian Andes with varying concentrations (10–1251 μg/L) of arsenic in drinking water. DirectHyb HumanHT-12 v4.0 was used for genome wide gene expression analysis. Robust linear regression model was used to each array to evaluate the relations between arsenic exposure, gene expression and with the influence of arsenic metabolism efficiency. Also, Ingenuity Pathway Analysis (IPA) was performed to look for relevant pathways, diseases, networks etc. associated with the genes. In the association between arsenic and gene expression, most of the genes were downregu-lated. Pathway analyses revealed different expression pattern associated with arsenic exposure between women with high and low urinary %MMA, indicating variation in arsenic susceptibility by arsenic-methylation.
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| 6. |
- Broberg Palmgren, Karin, et al.
(författare)
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Lithium in Drinking Water and Thyroid Function
- 2011
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 119:6, s. 827-830
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High concentrations of lithium in drinking water were previously discovered in the Argentinean Andes Mountains. Lithium is used worldwide for treatment of bipolar disorder and treatment-resistant depression. One known side effect is altered thyroid function. OBJECTIVES: We assessed associations between exposure to lithium from drinking water and other environmental sources and thyroid function. METHODS: Women (n = 202) were recruited in four Andean villages in northern Argentina. Lithium exposure was assessed based on concentrations in spot urine samples, measured by inductively coupled plasma mass spectrometry. Thyroid function was evaluated by plasma free thyroxine (T-4) and pituitary gland thyroid-stimulating hormone (TSH), analyzed by routine immuno metric methods. RESULTS: The median urinary lithium concentration was 3,910 mu g/L (5th, 95th percentiles, 270 mu g/L, 10,400 mu g/L). Median plasma concentrations (5th, 95th percentiles) of T-4 and TSH were 17 pmol/L (13 pmol/L, 21 pmol/L) and 1.9 mIU/L, (0.68 mIU/L, 4.9 mIU/L), respectively. Urine lithium was inversely associated with T-4 [beta for a 1,000-mu g/L increase = -0.19; 95% confidence interval (CI), -0.31 to -0.068; p = 0.002] and positively associated with TSH (beta = 0.096; 95% CI, 0.033 to 0.16; p = 0.003). Both associations persisted after adjustment (for T-4, beta = -0.17; 95% CI, -0.32 to -0.015; p = 0.032; for TSH: beta = 0.089; 95% CI, 0.024 to 0.15; p = 0.007). Urine selenium was positively associated with T-4 (adjusted T-4 for a 1 mu g/L increase: beta = 0.041; 95% CI, 0.012 to 0.071; p = 0.006). CONCLUSIONS: Exposure to lithium via drinking water and other environmental sources may affect thyroid function, consistent with known side effects of medical treatment with lithium. This stresses the need to screen for lithium in all drinking water sources.
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| 7. |
- Concha, Gabriela, et al.
(författare)
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High-Level Exposure to Lithium, Boron, Cesium, and Arsenic via Drinking Water in the Andes of Northern Argentina.
- 2010
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Ingår i: Environmental Science & Technology. - : American Chemical Society (ACS). - 1520-5851 .- 0013-936X. ; 44:17, s. 6875-6880
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Tidskriftsartikel (refereegranskat)abstract
- Elevated concentrations of arsenic in drinking water are common worldwide, however, little is known about the presence of other potentially toxic elements. We analyzed 31 different elements in drinking water collected in San Antonio de los Cobres and five surrounding Andean villages in Argentina, and in urine of the inhabitants, using ICP-MS. Besides confirmation of elevated arsenic concentrations in the drinking water (up to 210 mug/L), we found remarkably high concentrations of lithium (highest 1000 mug/L), cesium (320 mug/L), rubidium (47 mug/L), and boron (5950 mug/L). Similarly elevated concentrations of arsenic, lithium, cesium, and boron were found in urine of the studied women (N = 198): village median values ranged from 26 to 266 mug/L of arsenic, 340 to 4550 mug/L of lithium, 34 to 531 mug/L of cesium, and 2980 to 16 560 mug/L of boron. There is an apparent risk of toxic effects of long-term exposure to several of the elements, and studies on associations with adverse human health effects are warranted, particularly considering the combined, life-long exposure. Because of the observed wide range of concentrations, all water sources used for drinking water should be screened for a large number of elements; obviously, this applies to all drinking water sources globally.
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| 8. |
- Concha, Gabriela
(författare)
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Metabolism of inorganic arsenic and biomarkers of exposure
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Humans as well as most mammals metabolize inorganic arsenic (Inorg As), a recognized human carcinogen, by methylation. The end-metabolites methylarsonic acid (MMA) and dimethylarsinic acid (DMA) are less toxic and more readily excreted in the urine than Inorg As. Generally, people exposed to arsenic have 10-30% Inorg As, 10- 20% MMA and 60-80% DMA in urine, with considerable interindividual variation. Little is known about factors influencing the metabolism in humans. The aim of the present study was to investigate such factors e.g. age, ethnicity, and pregnancy in people chronically exposed to arsenic via drinking water in two villages in northern Argentina. Also, transfer of arsenic to the fetus and human milk was studied. For assessment of arsenic exposure, total arsenic concentrations in drinking water, food, breast milk and blood (B- As) were determined using hydride generation atomic absorption spectrophotometry (HGAAS), after dry ashing. Concentrations of arsenic metabolites in urine (U-Asmet, i.e. Inorg As+MMA+DMA; direct HG-AAS) and B- As were used as biomarkers of exposure to Inorg As. In order to assess methylation capacity, arsenic metabolites in urine and plasma were speciated. using ionexchange chromatography and HG-AAS. Fetal exposure was investigated by determination of arsenic concentrations in cord blood, placenta, matemal blood and urine. The concentration of arsenic in drinking water in the villages was about 200 µg As/L, which is considerably higher than the drinking water guideline of 10 µg As/L recommended by the WHO. The staple food soup and maize porridge had the highest concentrations of arsenic (300-400 µg As/kg). The high arsenic exposure caused clearly elevated B-As and U-Asmet, in the investigated children (n=57, age 3-15 yrs) and women (n=39, age 18-66 yrs). The B-As (10 µg As/L) was 10 times higher and the U-Asmet (300-440 µg AsAL) was 30 times higher than in the control area, where the water contained <1 µg As/L. There was a unique pattern of arsenic metabolites in the urine, characterized by the low urinary excretion of MMA (about 3%), compared to more than 10% (often 10-20%) in other population groups studied. The data indicate the existence of genetic polymorphism in the methylation of arsenic. Interestingly, the individuals with low % MMA were of native Andean origin and they seemed to retain less arsenic than people with more MMA in urine. Studies of intra- and inter-individual variation in the metabolism of Inorg As showed a remarkably stable methylation from day-to-day, but a slight diurnal variation. A pronounced inter-individual variation in methylation (%DMA 51-8 1 %) was observed. Thus, the genetic influence seemed to be more important than the environmental. Another important finding was that children had significantly lower % DMA (50%) and higher urinary % inorganic arsenic (about 47%) compared to the women, but similar low %MMA. Thus, the results indicate lower arsenic methylating capacity in children, and that children retain more arsenic than adults. The concentration of arsenic in cord blood was almost as high as, and significantly correlated to, that in matemal blood in late gestation (9 and 11 µg As/L, respectively; r = 0.79). Thus, arsenic was readily transferred to the human fetus. Essentially all arsenic in maternal plasma and urine, cord plasma and infant urine was in the form of DMA, indicating an increase in the arsenic methylation in late gestation and that the fetus was mostly exposed to DMA prior to birth. This is important from a toxicological point of view, as experimental studies have indicated that DMA is less toxic to the embryo and fetus than Inorg As. In spite of the high concentrations of arsenic in maternal blood and urine, the concentrations of arsenic in breast milk were low, on average 3 µg As/L. Breast feeding led to a decrease in the arsenic concentrations in the urine of the infants during the nursing period.
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| 9. |
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| 10. |
- Engström, Karin, et al.
(författare)
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Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions.
- 2009
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Ingår i: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. - : Elsevier BV. - 1879-2871 .- 0027-5107. ; 667, s. 4-14
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The susceptibility to arsenic (As)-induced diseases differs greatly between individuals, probably to a large extent due to genetic differences in arsenic metabolism. The aim for this study was to identify genetic variants affecting arsenic metabolism. METHODS: We evaluated the association between urinary metabolite pattern and polymorphisms in three gene-groups related to arsenic metabolism: (1) methyltransferases, (2) other genes involved in one-carbon metabolism and (3) genes involved in reduction reactions. Forty-nine polymorphisms were successfully genotyped in indigenous women (N=104) from northern Argentina, exposed to approximately 200mug/L of arsenic in drinking water, with a unique metabolism with low percent monomethylated arsenic (%MMA) and high percent dimethylated As (%DMA). RESULTS: Genetic factors affecting arsenic metabolite pattern included two polymorphisms in arsenic (+III) methyltransferase (AS3MT) (rs3740400, rs7085104), where carriers had lower %MMA and higher %DMA. These single nucleotide polymorphisms (SNPs) were in strong linkage disequilibrium (LD) with three intronic AS3MT SNPs, previously reported to be associated with arsenic metabolism, indicating the existence of a strongly methylating, population-specific haplotype. The CYP17A1 rs743572, 27kilobasepairs (kbs) upstream of AS3MT, was in strong LD with the AS3MT SNPs and thus had similar effects on the metabolite profile. Smaller effects were also seen for one-carbon metabolism genes choline dehydrogenase (CHDH) (rs9001, rs7626693) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) (rs1801394) and genes involved in reduction reactions, glutaredoxin (GLRX) (rs3822751) and peroxiredoxin 2 (PRDX2) (rs10427027, rs12151144). Genotypes associated with more beneficial arsenic metabolite profile (low %MMA and/or high %DMA in urine) were more common in this population, which has been exposed to arsenic in drinking water for thousands of years. CONCLUSIONS: Polymorphisms in AS3MT and in genes involved in one-carbon metabolism and reduction reactions affects arsenic metabolism.
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