| 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. |
- 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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| 3. |
- 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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| 4. |
- Engström, Karin, et al.
(författare)
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Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina.
- 2007
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 115:4, s. 599-605
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Tidskriftsartikel (refereegranskat)abstract
- The susceptibility to arsenic-induced diseases differs greatly between individuals, possibly due to interindividual variations in As metabolism that affect retention and distribution of toxic metabolites. To elucidate the role of genetic factors in As metabolism, we studied how polymorphisms in six genes affected the urinary metabolite pattern in a group of indigenous women (n = 147) in northern Argentina who were exposed to approximately 200 mu g/L As in drinking water. These women had low urinary percentages of monomethylated As (MMA) and high percentages of dimethylated As (DMA). MMA has been associated with adverse health effects, and DMA has the lowest body retention of the metabolites. The genes studied were arsenic(+ 111) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferases mu I (GSTM1) and theta I (GSTT1). We found three intronic polymorphisms in AS3MT (G12390C, C14215T, and G35991A) associated with a lower percentage of MMA (%MMA) and a higher percentage of DMA (%DMA) in urine. The variant homozygotes showed approximately half the %MMA compared with wild-type homozygotes. These polymorphisms were in strong linkage, with high allelic frequencies (72-76%) compared with other populations. We also saw minor effects of other polymorphisms in the multivariate regression analysis with effect modification for the deletion genotypes for GSTM1 (affecting %MMA) and GSTT1 (affecting %MMA and %DMA). For pregnant women, effect modification was seen for the folate-metabolizing genes MTR and MTHFA In conclusion, these findings indicate that polymorphisms in AS3MT-and possibly GSTM1, GSTT1, MTR, and MTHFR-are responsible for a large part of the interindividual variation in As metabolism and susceptibility.
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| 5. |
- Engström, Karin, et al.
(författare)
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Low 8-oxo-7,8-dihydro-2'-deoxyguanosine levels and influence of genetic background in an Andean population exposed to high levels of arsenic.
- 2010
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Ingår i: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. - : Elsevier BV. - 1879-2871 .- 0027-5107. ; 683:1-2, s. 98-105
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Arsenic (As) causes oxidative stress through generation of reactive oxygen species. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a sensitive marker of oxidative DNA damage, has been associated with As exposure in some studies, but not in others, possibly due to population-specific genetic factors. OBJECTIVES: To evaluate the association between As and 8-oxodG in urine in a population with a low urinary monomethylated As (%MMA) and high dimethylated As (%DMA), as well as the genetic impact on (a) 8-oxodG concentrations and (b) the association between As and 8-oxodG. MATERIALS AND METHODS: Women (N=108) in the Argentinean Andes were interviewed and urine was analyzed for arsenic metabolites (ICPMS) and 8-oxodG (LC-MS/MS). Twenty-seven polymorphisms in genes related to oxidative stress and one in As(+III)methyltransferase (AS3MT) were studied. RESULTS: Median concentration of 8-oxodG was 4.7nmol/L (adjusted for specific weight; range 1.6-13, corresponding to 1.7mug/g creatinine, range 0.57-4.8) and of total urinary As metabolites (U-As) 290mug/L (range 94-720; 380mug/g creatinine, range 140-1100). Concentrations of 8-oxodG were positively associated with %MMA (strongest association, p=0.013), and weakly associated with U-As (positively) and %DMA (negatively). These associations were strengthened when taking ethnicity into account, possibly reflecting genetic differences in As metabolism and genes regulating oxidative stress and DNA maintenance. A genetic influence on 8-oxodG concentrations was seen for polymorphisms in apurinic/apyrimidinic endonuclease 1 (APEX1), DNA-methyltransferases 1 and 3b (DNMT1, DNMT3B), thioredoxin reductase 1 (TXNRD1) and 2 (TXNRD2) and glutaredoxin (GLRX). CONCLUSION: Despite high As exposure, the concentrations of 8-oxodG in this population were low compared with other As-exposed populations studied. The strongest association was found for %MMA, stressing that some inconsistencies between As and 8-oxodG partly depend on population variations in As metabolism. We found evidence of genetic impact on 8-oxodG concentrations.
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| 6. |
- Engström, Karin, et al.
(författare)
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Polymorphisms in Arsenic(+III)methyltransferase (AS3MT) Predict Gene Expression of AS3MT as well as Arsenic Metabolism.
- 2011
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 119, s. 182-188
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Tidskriftsartikel (refereegranskat)abstract
- Background: Arsenic is mono- (MMA) and dimethylated (DMA) in humans and the methylation pattern demonstrates large inter-individual differences. The fraction of urinary MMA is a marker for susceptibility to arsenic-related diseases. Objectives: The impact of polymorphisms in five methyltransferase genes on arsenic metabolism was evaluated in two populations, one in South America, one in southeast Asia. The methyltransferase genes were arsenic(+III)methyltransferase (AS3MT), DNAmethyltransferase 1a and 3b (DNMT1a, DNMT3b), phosphatidylethanolamine Nmethyltransferase (PEMT) and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women, exposed to arsenic in drinking water in the Argentinean Andes (N=172; median urinary arsenic 200 μg/L) and in rural Bangladesh (N=361; 100 μg/L, all in early pregnancy). Urinary arsenic metabolites were measured by HPLC-ICPMS. Polymorphisms (N=22) were genotyped with Sequenom™. AS3MT expression was measured with qPCR using TaqMan® expression assays. Results: Six AS3MT polymorphisms were significantly associated with arsenic metabolite patterns in both populations (p-values ≤0.01). The most frequent AS3MT haplotype in Bangladesh was associated with higher %MMA, and the most frequent in Argentina with lower %MMA and higher %DMA. Four polymorphisms in the DNMTs were associated with metabolite patterns in Bangladesh. Non-coding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altering levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.
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| 7. |
- Gardner, Renee M., et al.
(författare)
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Arsenic methylation efficiency increases during the first trimester of pregnancy independent of folate status
- 2011
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 31:2, s. 210-218
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to inorganic arsenic during pregnancy may negatively influence the offspring, though efficient metabolism of arsenic to dimethylarsinic acid (DMA) likely reduces the health risks. This study aimed to evaluate methylation of arsenic over the entire pregnancy and the influence of nutritional status. We studied longitudinally the arsenic metabolite pattern in the urine of 324 pregnant women exposed to arsenic via drinking water and food in rural Bangladesh. Metabolism of arsenic to DMA increased markedly over the course of pregnancy, with the greatest improvement occurring in the first trimester, along with a marked decrease in the most risk-associated monomethylated metabolite. This improvement in methylation was not associated with nutritional status, including vitamin B(12) and folate. Efficient methylation to DMA was associated with improved urinary excretion of arsenic, relative to blood arsenic concentrations, indicating that micronutrient-independent up-regulation of arsenic metabolism already in early pregnancy may provide protection for the fetus.
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| 8. |
- Kippler, Maria, et al.
(författare)
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Biomonitorering av kadmium i urin hos svenska kvinnor
- 2024
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Exponering för låga halter av kadmium via kosten kan ge upphov till benskörhet, ökad risk för frakturer samt hjärtkärlsjukdom. Kvinnor utgör en riskgrupp. Syftet med studien vara var att jämföra halter av kadmium i urin hos svenska icke-rökande kvinnor i åldern 50–59 år boende i olika delar av landet samt att relatera kadmiumhalterna i urin till kända exponeringskällor. Medianhalten av kadmium i urin bland de undersökta kvinnorna (N=130) var 0,21 μg/g kreatinin respektive 0,20 μg/L (justerat för densitet). Åtta procent av kvinnorna hade en kadmiumhalt som överskred 0,5 μg/g kreatinin och 3 % av kvinnorna hade en halt som överskred 1 μg/g kreatinin och som visat skadlig påverkan på skelettet respektive njurarna. Kvinnor bosatta i Västerbotten och Norrbotten hade lägre kadmiumhalter i urin än kvinnor i Skåne, Stockholm och Västra Götaland. Kvinnor som var födda i ett land utanför Europa hade högre kadmiumhalter i urin än kvinnor födda i Europa. Med avseende på olika typer av livsmedel så hade kvinnor som sällan åt kött och bröd högre kadmiumhalter i urin. Likaså hade kvinnor med högre intag av baljväxter högre kadmiumhalter än kvinnor som rapporterade att de aldrig åt baljväxter. Vi fann inga signifikanta samband med andra typer av livsmedel, kosttillskott, eller källor till dricksvatten. Vi fann geografiska, etniska och kost-relaterade skillnader i kadmiumhalter i urin hos icke-rökande medelålders kvinnor i Sverige. Åtta procent av kvinnorna överskred den kadmiumhalt i urin som har kopplats till skador på skelettet. Vid jämförelse med kadmiumhalterna i urin från den föregående undersökningen 2018–2019 bland icke-rökande kvinnor i åldern 50–59 år så fanns det ingen indikation på att exponeringen har minskat över tid. Därför rekommenderas en fortsatt biomonitorering av kadmiumhalterna i känsliga grupper och insatser för att minska kadmiumexponering i befolkningen är nödvändiga.
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| 9. |
- Kippler, Maria, et al.
(författare)
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Environmental exposure to arsenic and cadmium during pregnancy and fetal size : a longitudinal study in rural Bangladesh
- 2012
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 34:4, s. 504-511
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Tidskriftsartikel (refereegranskat)abstract
- Prenatal exposures to arsenic (As) and cadmium (Cd) have been associated with decreased size at birth. We here studied associations of prenatal As and Cd exposures with multiple fetal size parameters measured by ultrasound in gestational week (GW) 14 and 30 in a population-based mother-child cohort in rural Bangladesh. We measured As (n=1929) and Cd (n=1616) in urine during pregnancy. In the longitudinal evaluation of combined exposure, urinary Cd (UCd) showed an inverted U-shaped association (turning-point 1.5μg Cd/L) with all fetal size parameters, while UAs showed no significant association. Cross-sectional analyses indicated that associations with UCd were somewhat stronger in early gestation. Stratification indicated stronger associations between UCd and fetal size in girls than in boys, and in poorer than in richer families, while UAs was weakly associated with fetal size in boys. In conclusion, particularly Cd, but also As, appeared to influence fetal development in a sex-dependent manner.
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| 10. |
- Kuehnelt, Doris, et al.
(författare)
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Selenium metabolism to the trimethylselenonium ion (TMSe) varies markedly because of polymorphisms in the indolethylamine N-methyltransferase gene
- 2015
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 102:6, s. 1406-1415
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Tidskriftsartikel (refereegranskat)abstract
- Background: Selenium is an essential element, but its metabolism in humans is not well characterized. A few small studies indicate that the trimethylselenonium ion (TMSe) is a common selenium metabolite in humans. Objective: This study aimed to elucidate the human metabolism of selenium to TMSe. Design: Study individuals constituted subsamples of 2 cohorts: 1) pregnant women (n = 228) and their 5-y-old children (n = 205) in rural Bangladesh with poor selenium status [median urinary selenium (U-Se): 6.4 mu g/L in mothers, 14 mu g/L in children] and 2) women in the Argentinian Andes (n = 83) with adequate selenium status (median U-Se: 24 mu g/L). Total U-Se and blood selenium were measured by inductively coupled plasma mass spectrometry (ICPMS), and urinary concentrations of TMSe were measured by high-performance liquid chromatography/vapor generation/ICPMS. A genomewide association study (GWAS) was performed for 1,629,299 (after filtration) single nucleotide polymorphisms (SNPs) in the Bangladeshi women (n = 72) by using Illumina Omni5M, and results were validated by using real-time polymerase chain reaction. Results: TMSe "producers" were prevalent (approximately one-third) among the Bangladeshi women and their children, in whom TMSe constituted similar to 10-70% of U-Se, whereas "nonproducers" had, on average, 0.59% TMSe. The TMSe-producing women had, on average, 2-mu g U-Se/L higher concentrations than did the nonproducers. In contrast, only 3 of the 83 Andean women were TMSe producers (6-15% TMSe in the urine); the average percentage among the nonproducers was 0.35%. Comparison of the percentage of urinary TMSe in mothers and children indicated a strong genetic influence. The GWAS identified 3 SNPs in the indolethylamine N-methyltransferase gene (INMT) that were strongly associated with percentage of TMSe (P < 0.001, false-discovery rate corrected) in both cohorts. Conclusions: There are remarkable population and individual variations in the formation of TMSe, which could largely be explained by SNPs in INMT. The TMSe-producing women had higher U-Se concentrations than did nonproducers, but further elucidation of the metabolic pathways of selenium is essential for the understanding of its role in human health.
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