| 1. |
- Palmgren, Michael, et al.
(författare)
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AS3MT-mediated tolerance to arsenic evolved by multiple independent horizontal gene transfers from bacteria to eukaryotes
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Organisms have evolved the ability to tolerate toxic substances in their environments, often by producing metabolic enzymes that efficiently detoxify the toxicant. Inorganic arsenic is one of the most toxic and carcinogenic substances in the environment, but many organisms, including humans, metabolise inorganic arsenic to less toxic metabolites. This multistep process produces mono-, di-, and trimethylated arsenic metabolites, which the organism excretes. In humans, arsenite methyltransferase (AS3MT) appears to be the main metabolic enzyme that methylates arsenic. In this study, we examined the evolutionary origin of AS3MT and assessed the ability of different genotypes to produce methylated arsenic metabolites. Phylogenetic analysis suggests that multiple, independent horizontal gene transfers between different bacteria, and from bacteria to eukaryotes, increased tolerance to environmental arsenic during evolution. These findings are supported by the observation that genetic variation in AS3MT correlates with the capacity to methylate arsenic. Adaptation to arsenic thus serves as a model for how organisms evolve to survive under toxic conditions.
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| 2. |
- Abdelhady, Dalia, et al.
(författare)
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The Nile and the Grand Ethiopian Renaissance Dam: Is There a Meeting Point between Nationalism and Hydrosolidarity?
- 2015
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Ingår i: Journal of Contemporary Water Research and Education. - 1936-704X. ; 155:1, s. 73-82
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Tidskriftsartikel (refereegranskat)abstract
- The soon-to-be completed Grand Ethiopian Renaissance Dam (GERD), which will be the largest hydroelectric power plant and among the largest reservoirs in Africa, has highlighted the need for expanding traditional integrated water resources management to better include the cultural, social, and political complexities of large water infrastructure in development projects. The GERD will store a maximum of 74 billion cubic meters of water corresponding to approximately the average annual outflow of the Nile from the Aswan high dam. Undoubtedly, the GERD will be vital for energy production and a key factor for food production, economic development, and poverty reduction in Ethiopia and the Nile Basin. However, the GERD is also a political statement that in one stroke has re-written the hydropolitical map of the Nile Basin. The GERD has become a symbol of Ethiopian nationalism or “renaissance” (hidase in Amharic). A contrasting concept to nationalism is hydrosolidarity. This concept has been put forward to better stress equitable use of water in international water management challenges that would lead to sustainable socioeconomic development. We use the opposing notions of nationalism and hydrosolidarity at three different scales, everyday politics, state policies, and interstate and global politics to analyse some aspects of the new hydropolitical map of the Nile Basin. We argue that nationalism and national interests are not necessarily negative standpoints but that there may instead be a meeting point where regional and national interests join with hydrosolidarity principles. We believe that this meeting point can maximize not only the common good, but also the good from a national interest point of view. For this, it is important not increase collaboration instead of being locked in to the historical narrative of nationalistic culture and historical discourse. This would benefit and improve future sustainability.
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| 3. |
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| 4. |
- Broberg Palmgren, Karin, et al.
(författare)
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Association between polymorphisms in RMI1, TOP3A, and BLM and risk of cancer, a case-control study.
- 2009
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 9:May 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mutations altering BLM function are associated with highly elevated cancer susceptibility (Bloom syndrome). Thus, genetic variants of BLM and proteins that form complexes with BLM, such as TOP3A and RMI1, might affect cancer risk as well. METHODS: In this study we have studied 26 tagged single nucleotide polymorphisms (tagSNPs) in RMI1, TOP3A, and BLM and their associations with cancer risk in acute myeloid leukemia/myelodysplatic syndromes (AML/MDS; N = 152), malignant melanoma (N = 170), and bladder cancer (N = 61). Two population-based control groups were used (N = 119 and N = 156). RESULTS: Based on consistency in effect estimates for the three cancer forms and similar allelic frequencies of the variant alleles in the control groups, two SNPs in TOP3A (rs1563634 and rs12945597) and two SNPs in BLM (rs401549 and rs2532105) were selected for analysis in breast cancer cases (N = 200) and a control group recruited from spouses of cancer patients (N = 131). The rs12945597 in TOP3A and rs2532105 in BLM showed increased risk for breast cancer. We then combined all cases (N = 584) and controls (N = 406) respectively and found significantly increased risk for variant carriers of rs1563634 A/G (AG carriers OR = 1.7 [95%CI 1.1-2.6], AA carriers OR = 1.8 [1.2-2.8]), rs12945597 G/A (GA carriers OR = 1.5 [1.1-1.9], AA carriers OR = 1.6 [1.0-2.5]), and rs2532105 C/T (CT+TT carriers OR = 1.8 [1.4-2.5]). Gene-gene interaction analysis suggested an additive effect of carrying more than one risk allele. For the variants of TOP3A, the risk increment was more pronounced for older carriers. CONCLUSION: These results further support a role of low-penetrance genes involved in BLM-associated homologous recombination for cancer risk.
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| 5. |
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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. |
- Broberg Palmgren, Karin, et al.
(författare)
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The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate.
- 2010
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 20:2, s. 104-111
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Toluene di-isocyanate (TDI) is widely used in the production of polyurethane foams and paints. As TDI causes respiratory disease in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. Polymorphisms in TDI metabolising genes may affect elimination kinetics, resulting in differences in body retention, and in its turn differences in adverse effects. OBJECTIVES: To analyze how genotype modifies the associations between (i) TDI in air (2,4-TDI and 2,6-TDI) and its metabolites toluene diamine (TDA; 2,4-TDA and 2,6-TDA) in hydrolyzed urine; and (ii) 2,4-TDA and 2,6-TDA in hydrolyzed plasma and 2,4-TDA and 2,6-TDA in urine. METHODS: Workers exposed to TDI were analyzed for 2,4-TDI and 2,6-TDI in air (N=70), 2,4-TDA and 2,6-TDA in hydrolyzed urine (N=124) and in plasma (N=128), and genotype: CYP1A1*2A, CYP1A1*2B, GSTA1-52, GSTM1O, GSTM3B, GSTP1 I105V, GSTP1 A114V, GSTT1O, MPO-463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, and SULT1A1 R213H. RESULTS: GSTP1 105 strongly modified the relationship between 2,4-TDA in plasma and in urine: ValVal carriers had about twice as steep regression slope than IleIle carriers. A similar pattern was found for 2,6-TDA. CYP1A1*2A, GSTM1, GSTP1, GSTT1, and MPO possibly influenced the relationship between TDA in plasma and urine. CONCLUSION: Our results show, for the first time, genetic modification on the human TDI metabolism. The findings suggest that GSTP1 genotype should be considered when evaluating biomarkers of TDI exposure in urine and plasma. Moreover, the results support earlier findings of GSTP1 105 Val as protective against TDI-related asthma.
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| 8. |
- 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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| 9. |
- Engström, Karin, et al.
(författare)
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Chronic exposure to cadmium and arsenic strongly influences concentrations of 8-oxo-7,8-dihydro-2'-deoxyguanosine in urine.
- 2010
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 48:9, s. 1211-1217
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to arsenic (As), cadmium (Cd) and lead (Pb) may generate oxidative stress, which can be assessed by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine, a sensitive marker of oxidatively damaged DNA. We have evaluated oxidative stress induced by mixed chronic exposure to As, Cd, Pb, as well as the influence of As metabolism and nutritional status, i.e. ferritin (Ft), selenium (Se), zinc (Zn), manganese (Mn) and body weight. 8-oxodG was measured in urine from 212 women in early pregnancy from Matlab, rural Bangladesh, using LC-MS/MS. Cd and Pb were analyzed in urine and erythrocytes, while Se, Mn and Zn were analyzed in erythrocytes, all by ICPMS. As and As metabolites were analyzed in urine by HPLC-ICPMS. Ferritin was analyzed in plasma by radioimmunoassay. Median concentration of 8-oxodG was 8.3 nmol/L (adjusted for specific gravity), range 1.2-43, corresponding to a median of 4.7 mug/g creatinine, range 1.8-32. 8-oxodG was positively associated with urinary Cd (ss=0.32, p<0.001), urinary As (ss=0.0007, p=0.001), fraction of the monomethylated arsenic metabolite (MMA) in urine (ss=0.0026, p=0.004) and plasma Ft (ss = 0.20, p<0.001). A joint effect was seen for U-Cd and U-As, but whether this effect was additive or multiplicative was difficult to discern.
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| 10. |
- Engström, Karin, et al.
(författare)
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Efficient Arsenic Metabolism - The AS3MT Haplotype Is Associated with DNA Methylation and Expression of Multiple Genes Around AS3MT.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- 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 predicted DNA methylation and gene expression of AS3MT as well as several genes in 10q24. This raises the possibility that several genes in this region are important for arsenic metabolism.
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