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Sökning: WFRF:(Broberg Karin)

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1.
  • Engström, Karin, et al. (författare)
  • Polymorphisms in ATP-binding cassette transporters associated with maternal methylmercury disposition and infant neurodevelopment in mother-infant pairs in the Seychelles Child Development Study
  • 2016
  • Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 94, s. 224-229
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: ATP-binding cassette (ABC) transporters have been associated with methylmercury (MeHg) toxicity in experimental animal models. Aims: To evaluate the association of single nucleotide polymorphisms (SNPs) in maternal ABC transporter genes with 1) maternal hair MeHg concentrations during pregnancy and 2) child neurodevelopmental outcomes. Materials and methods: Nutrition Cohort 2 (NC2) is an observational mother-child cohort recruited in the Republic of Seychelles from 2008-2011. Total mercury (Hg) was measured in maternal hair growing during pregnancy as a biomarker for prenatal MeHg exposure (N = 1313) (mean 3.9 ppm). Infants completed developmental assessments by Bayley Scales of Infant Development II (BSID-II) at 20 months of age (N = 1331). Genotyping for fifteen SNPs in ABCC1, ABCC2 and ABCB1 was performed for the mothers. Results: Seven of fifteen ABC SNPs (ABCC1 rs11075290, rs212093, and rs215088; ABCC2 rs717620; ABCB1 rs10276499, rs1202169, and rs2032582) were associated with concentrations of maternal hair Hg (p < 0.001 to 0.013). One SNP (ABCC1 rs11075290) was also significantly associated with neurodevelopment; children born to mothers with rs11075290 CC genotype (mean hair Hg 3.6 ppm) scored on average 2 points lower on the Mental Development Index (MDI) and 3 points lower on the Psychomotor Development Index (PDI) than children born to mothers with TT genotype (mean hair Hg 4.7 ppm) while children with the CT genotype (mean hair Hg 4.0 ppm) had intermediate BSID scores. Discussion: Genetic variation in ABC transporter genes was associated with maternal hair Hg concentrations. The implications for MeHg dose in the developing child and neurodevelopmental outcomes need to be further investigated.
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2.
  • Palmgren, Michael, et al. (författare)
  • AS3MT-mediated tolerance to arsenic evolved by multiple independent horizontal gene transfers from bacteria to eukaryotes
  • 2017
  • Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:4
  • 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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3.
  • Wahlberg, Karin, et al. (författare)
  • Maternal polymorphisms in glutathione-related genes are associated with maternal mercury concentrations and early child neurodevelopment in a population with a fish-rich diet
  • 2018
  • Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 115, s. 142-149
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Glutathione (GSH) pathways play a key role the metabolism and elimination of the neurotoxicant methylmercury (MeHg). We hypothesized that maternal genetic variation linked to GSH pathways could influence MeHg concentrations in pregnant mothers and children and thereby also affect early life development. Methods: The GCLM (rs41303970, C/T), GCLC (rs761142, T/G) and GSTP1 (rs1695, A/G) polymorphisms were genotyped in 1449 mothers in a prospective study of the Seychellois population with a diet rich in fish. Genotypes were analyzed in association with maternal hair and blood Hg, fetal blood Hg (cord blood Hg), as well as children's mental (MDI) and motor development (PDI; MDI and PDI assessed by Bayley Scales of Infant Development at 20 months). We also examined whether genotypes modified the association between Hg exposure and developmental outcomes. Results: GCLC rs761142 TT homozygotes showed statistically higher mean maternal hair Hg (4.12 ppm) than G carriers (AG 3.73 and GG 3.52 ppm) (p = 0.037). For the combination of GCLC rs761142 and GCLM rs41303970, double homozygotes TT + CC showed higher hair Hg (4.40 ppm) than G + T carriers (3.44 ppm; p = 0.018). No associations were observed between GSTP1 rs1695 and maternal hair Hg or between any genotypes and maternal blood Hg or cord blood Hg. The maternal GSTP1 rs1695 rare allele (G) was associated with a lower MDI among children (β = −1.48, p = 0.048). We also observed some interactions: increasing Hg in maternal and cord blood was associated with lower PDI among GCLC rs761142 TT carriers; and increasing Hg in hair was associated with lower MDI among GSTP1 rs1695 GG carriers. Conclusions: Maternal genetic variation in genes involved in GSH synthesis is statistically associated with Hg concentrations in maternal hair, but not in maternal or fetal blood. We observed interactions that suggest maternal GSH genetics may modify associations between MeHg exposure and neurodevelopmental outcomes.
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  • Yeates, Alison J, et al. (författare)
  • Genetic variation in FADS genes is associated with maternal long-chain PUFA status but not with cognitive development of infants in a high fish-eating observational study.
  • 2015
  • Ingår i: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 0952-3278 .- 1532-2823. ; 102-103, s. 13-20
  • Forskningsöversikt (refereegranskat)abstract
    • Long-chain n-6 and n-3 PUFA (LC-PUFA), arachidonic acid (AA) (20:4n-6) and DHA (22:6n-3), are critical for optimal brain development. These fatty acids can be consumed directly from the diet, or synthesized endogenously from precursor PUFA by Δ-5 (encoded by FADS1) and Δ-6 desaturases (encoded by FADS2). The aim of this study was to determine the potential importance of maternal genetic variability in FADS1 and FADS2 genes to maternal LC-PUFA status and infant neurodevelopment in populations with high fish intakes. The Nutrition Cohorts 1 (NC1) and 2 (NC2) are longitudinal observational mother-child cohorts in the Republic of Seychelles. Maternal serum LC-PUFA was measured at 28 weeks gestation and genotyping for rs174537 (FADS1), rs174561 (FADS1), rs3834458 (FADS1-FADS2) and rs174575 (FADS2) was performed in both cohorts. The children completed the Bayley Scales of Infant Development II (BSID-II) at 30 months in NC1 and at 20 months in NC2. Complete data were available for 221 and 1310 mothers from NC1 and NC2 respectively. With increasing number of rs3834458 minor alleles, maternal concentrations of AA were significantly decreased (NC1 p=0.004; NC2 p<0.001) and precursor:product ratios for linoleic acid (LA) (18:2n-6)-to-AA (NC1 p<0.001; NC2 p<0.001) and α-linolenic acid (ALA) (18:3n-3)-to-DHA were increased (NC2 p=0.028). There were no significant associations between maternal FADS genotype and BSID-II scores in either cohort. A trend for improved PDI was found among infants born to mothers with the minor rs3834458 allele.In these high fish-eating cohorts, genetic variability in FADS genes was associated with maternal AA status measured in serum and a subtle association of the FADS genotype was found with neurodevelopment.
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5.
  • Yeates, Alison Jayne, et al. (författare)
  • Maternal Long-Chain Polyunsaturated Fatty Acid Status, Methylmercury Exposure, and Birth Outcomes in a High-Fish-Eating Mother-Child Cohort
  • 2020
  • Ingår i: The Journal of nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 150:7, s. 1749-1756
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Maternal status of long-chain PUFAs (LC-PUFAs) may be related to fetal growth. Maternal fish consumption exposes the mother to the neurotoxicant methylmercury (MeHg), which, in contrast, may restrict fetal growth. OBJECTIVE: Our aim was to examine relations between maternal LC-PUFA status at 28 wk and birth outcomes (birth weight, length, and head circumference), controlling for MeHg exposure throughout pregnancy, in the Seychelles Child Development Study Nutrition Cohort 2. Our secondary aim was to examine the influence of maternal variation in genes regulating the desaturation of LC-PUFAs [fatty acid desaturase (FADS)] on birth outcomes. METHODS: From nonfasting blood samples collected at 28 wk of gestation, we measured serum total LC-PUFA concentrations and FADS1 (rs174537, rs174561), FADS1-FADS2rs3834458, and FADS2rs174575 genotypes, with hair total mercury concentrations assessed at delivery. Data were available for n = 1236 mother-child pairs. Associations of maternal LC-PUFAs, MeHg, and FADS genotype with birth outcomes were assessed by multiple linear regression models, adjusting for child sex, gestational age, maternal age, BMI, alcohol use, socioeconomic status, and parity. RESULTS: In our cohort of healthy mothers, neither maternal LC-PUFA status nor MeHg exposure were significant determinants of birth outcomes. However, when compared with major allele homozygotes, mothers who were heterozygous for the minor allele of FADS1 (rs174537 and rs174561, GT compared with TT, β = 0.205, P = 0.03; TC compared with CC, β = 0.203, P = 0.04) and FADS1-FADS2 (rs3834458, Tdel compared with DelDel, β = 0.197, P = 0.04) had infants with a greater head circumference (all P < 0.05). Homozygosity for the minor allele of FADS2 (rs174575) was associated with a greater birth weight (GG compared with CC, β = 0.109, P = 0.04). CONCLUSIONS: In our mother-child cohort, neither maternal LC-PUFA status nor MeHg exposure was associated with birth outcomes. The observed associations of variation in maternal FADS genotype with birth outcomes should be confirmed in other populations.
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6.
  • Abdelhady, Dalia, et al. (författare)
  • The Nile and the Grand Ethiopian Renaissance Dam: Is There a Meeting Point between Nationalism and Hydrosolidarity?
  • 2015
  • Ingår i: Journal of Contemporary Water Research and Education. - 1936-704X. ; 155:1, s. 73-82
  • 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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  • Ameer, Shegufta, et al. (författare)
  • Exposure to Inorganic Arsenic Is Associated with Increased Mitochondrial DNA Copy Number and Longer Telomere Length in Peripheral Blood
  • 2016
  • Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 4
  • 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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8.
  • Ameer, Syeda Shegufta, et al. (författare)
  • Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood
  • 2017
  • Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 321, s. 57-66
  • 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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10.
  • Azeem, Muhammad, et al. (författare)
  • Heterobasidion-growth inhibiting Bacillus subtilis A18 exhibits medium- and age-dependent production of lipopeptides
  • 2019
  • Ingår i: Microbiological Research. - : Elsevier. - 0944-5013 .- 1618-0623. ; 223-225, s. 129-136
  • Tidskriftsartikel (refereegranskat)abstract
    • Heterobasidion annosum s.s. and H. parviporum are severe pathogens of conifers causing butt rot and root rot thus reducing the economic value of timber. Here, the antifungal activity of Bacillus subtilis isolate A18 against these two Heterobasidion species was investigated. Five different culture media with different culture age were investigated to study the effect of substrate composition and culture age for metabolite production. Bacterial cultures and cell-free culture filtrates were tested for antifungal activity. Inhibition of fungal growth was analysed using the agar disc-diffusion method. MALDI-TOF and LC-HRMS analyses were used to identify the antifungal metabolites. Substrate composition and age of culture were found to be active variables with direct effect on the antifungal activity of bacterial culture extracts. High anti-fungal activity was observed when B. subtilis was cultured in PDB, SGB and LB media for four days. Mass-spectrometry analysis showed the presence of lipopeptides in culture filtrates identified as members of the surfactins, polymixins, kurstakins and fengycins. A culture filtrate containing fengycin-type lipopeptides showed the highest bioactivity against Heterobasidion species. Bacterial cultures had higher bioactivity compared to their respective cell free culture filtrates. The results of the present study suggest that B. subtilis A18 is a powerful biocontrol agent against Heterobasidion infections of tree wounds and stumps.
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11.
  • Barman, Malin, 1983, et al. (författare)
  • Nutritional impact on Immunological maturation during Childhood in relation to the Environment (NICE): a prospective birth cohort in northern Sweden
  • 2018
  • Ingår i: BMJ Open. - : BMJ. - 2044-6055 .- 2044-6055. ; 8:10
  • Tidskriftsartikel (refereegranskat)abstract
    • © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. INTRODUCTION: Prenatal and neonatal environmental factors, such as nutrition, microbes and toxicants, may affect health throughout life. Many diseases, such as allergy and impaired child development, may be programmed already in utero or during early infancy. Birth cohorts are important tools to study associations between early life exposure and disease risk. Here, we describe the study protocol of the prospective birth cohort, 'Nutritional impact on Immunological maturation during Childhood in relation to the Environment' (NICE). The primary aim of the NICE cohort is to clarify the effect of key environmental exposures-diet, microbes and environmental toxicants-during pregnancy and early childhood, on the maturation of the infant's immune system, including initiation of sensitisation and allergy as well as some secondary outcomes: infant growth, obesity, neurological development and oral health.METHODS AND ANALYSIS: The NICE cohort will recruit about 650 families during mid-pregnancy. The principal inclusion criterion will be planned birth at the Sunderby Hospital in the north of Sweden, during 2015-2018. Questionnaires data and biological samples will be collected at 10 time-points, from pregnancy until the children reach 4 years of age. Samples will be collected primarily from mothers and children, and from fathers. Biological samples include blood, urine, placenta, breast milk, meconium, faeces, saliva and hair. Information regarding allergic heredity, diet, socioeconomic status, lifestyle including smoking, siblings, pet ownership, etc will be collected using questionnaires. Sensitisation to common allergens will be assessed by skin prick testing and allergic disease will be diagnosed by a paediatrician at 1 and 4 years of age. At 4 years of age, the children will also be examined regarding growth, neurobehavioural and neurophysiological status and oral health.ETHICS AND DISSEMINATION: The NICE cohort has been approved by the Regional Ethical Review Board in Umeå, Sweden (2013/18-31M). Results will be disseminated through peer-reviewed journals and communicated on scientific conferences.
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16.
  • Broberg, Karin, et al. (författare)
  • Evaluation of 92 cardiovascular proteins in dried blood spots collected under field-conditions : Off-the-shelf affinity-based multiplexed assays work well, allowing for simplified sample collection
  • 2021
  • Ingår i: BioEssays. - : Wiley. - 0265-9247 .- 1521-1878. ; 43:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Workplace-collected blood spots deposited on filter paper were analysed with multiplexed affinity-based protein assays and found to be suitable for proteomics analysis. The protein extension assay (PEA) was used to characterize 92 proteins using 1.2 mm punches in repeated samples collected from 20 workers. Overall, 97.8% of the samples and 91.3% of the analysed proteins passed quality control. Both within and between spot correlations using six replicates from the same individual were above 0.99, suggesting that comparable levels are obtained from multiple punches from the same spot and from consecutive spots. Protein levels from dried blood and wet serum from the same individuals were compared and the majority of the analysed proteins were found to be significantly correlated. These results open up for simplified sample collection of blood in field conditions for proteomic analysis, but also highlight that not all proteins can be robustly measured from dried whole blood.
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17.
  • Broberg, Karin, et al. (författare)
  • Gene-Environment Interactions for Metals
  • 2014. - 4th
  • Ingår i: Handbook on the Toxicology of Metals. - 9780444594532 - 9780123973399 ; 1, s. 239-264
  • Bokkapitel (refereegranskat)abstract
    • It has become increasingly clear that the individual genetic background influences susceptibility to metal toxicity. Genetic variation in genes that regulate metal toxicokinetics and toxicodynamics influence the degree of metal accumulation and retention in the body, as well as toxic effects. Moreover, factors that regulate gene expression, so-called epigenetic factors, have been identified as targets for metal toxicity. This chapter addresses what is currently known about such gene-environment interactions. The picture that emerges for most metals is that the genetic influence is probably not attributed to a single gene for each metal; rather it is polygenic, with some genes having a stronger effect than others. The presence of variants of the human leukocyte antigen system and the risk of beryllium-related pulmonary disease was one of the first and maybe the strongest example of a gene-environment interaction. There are also clear gene-environment interactions for arsenic and lead. Evidence is rapidly growing for epigenetic effects of metals, e.g. for arsenic, cadmium, and lead, which may explain the association between metal exposure early in life and toxic effects later in life, as well as metal carcinogenicity.
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18.
  • Broberg, Karin, et al. (författare)
  • Manganese transporter genetics and sex modify the association between environmental manganese exposure and neurobehavioral outcomes in children
  • 2019
  • Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 130
  • Tidskriftsartikel (refereegranskat)abstract
    • There is increasing evidence that environmental manganese (Mn) exposure early in life can have negative effects on children's neurodevelopment and increase the risk of behavioral problems, including attention deficit hyperactivity disorder (ADHD). Factors that may contribute to differences in sensitivity to Mn exposure are sex and genetic variation of proteins involved in the regulation of Mn concentrations. Here we investigate if sex and polymorphisms in Mn transporter genes SLC30A10 and SLC39A8 influence the association between Mn exposure and ADHD-related behavioral problems in children. The SNPs rs1776029 and rs12064812 in SLC30A10, and rs13107325 in SLC39A8 were genotyped by TaqMan PCR or pyrosequencing in a population of Italian children (aged 11–14 years; n = 645) with a wide range of environmental Mn exposure. Mn in surface soil was measured in situ using XRF technology or modeled by geospatial analysis. Linear regression models or generalized additive models (GAM) were used for analyzing associations between soil Mn and neurobehavioral problems assessed by the Conners' behavior rating scales (self-, and parent-reported). Gene-environment interactions (Mn transporter genotype x soil Mn) were evaluated using a genetic score in which genotypes for the three SNPs were combined based on their association with blood Mn, as an indication of their influence on Mn regulation. We observed differences in associations between soil Mn and neurobehavior between sexes. For several self-reported Conners' scales, girls showed U-shaped relationships with higher (worse) Conners' scoring at higher soil Mn levels, and several parent-reported scales showed positive linear relationships between increasing soil Mn and higher Conner's scores. For boys, we observed a positive linear relationship with soil Mn for one Conner's outcome only (hyperactivity, parent-reported). We also observed some interactions between soil Mn and the genetic score on Conner's scales in girls and girls with genotypes linked to high blood Mn showed particularly strong positive associations between soil Mn and parent-reported Conners' scales. Our results indicate that sex and polymorphisms in Mn transporter genes contribute to differences in sensitivity to Mn exposure from the environment and that girls that are genetically less efficient at regulating Mn, may be a particularly vulnerable group.
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  • Broberg Palmgren, Karin, et al. (författare)
  • Association between polymorphisms in RMI1, TOP3A, and BLM and risk of cancer, a case-control study.
  • 2009
  • Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 9:May 11
  • 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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  • Broberg Palmgren, Karin, et al. (författare)
  • Lithium in Drinking Water and Thyroid Function
  • 2011
  • Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 119:6, s. 827-830
  • 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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  • Broberg Palmgren, Karin, et al. (författare)
  • The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate.
  • 2010
  • Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 20:2, s. 104-111
  • 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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24.
  • Conway, Marie C, et al. (författare)
  • Maternal and child FADS genotype as determinants of cord blood long chain polyunsaturated fatty acid (LCPUFA) concentrations in the Seychelles Child Development Study
  • 2021
  • Ingår i: British Journal of Nutrition. - 1475-2662. ; 126:11, s. 1687-1697
  • Tidskriftsartikel (refereegranskat)abstract
    • Optimal maternal long chain polyunsaturated fatty acid (LCPUFA) status is essential for the developing foetus. The fatty acid desaturase (FADS) genes are involved in the endogenous synthesis of LCPUFA. The minor allele of various FADS single nucleotide polymorphisms (SNPs) have been associated with increased maternal concentrations of the precursors linoleic acid (LA) and α-linolenic acid (ALA), and lower concentrations of arachidonic acid (AA) and docosahexaenoic acid (DHA). There is limited research on the influence of FADS genotype on cord PUFA status. The current study investigated the influence of maternal and child genetic variation in FADS genotype on cord blood PUFA status in a high fish-eating cohort. Cord blood samples (n=1088) collected from the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2) were analysed for total serum PUFA. Of those with cord PUFA data available, maternal (n=1062) and child (n=916), FADS1 (rs174537, rs174561), FADS2 (rs174575), and FADS1-FADS2 (rs3834458) were determined. Regression analysis determined that maternal minor allele homozygosity was associated with lower cord blood concentrations of docosahexaenoic acid (DHA) and the sum of EPA+DHA. Lower cord blood AA concentrations were observed in children who were minor allele homozygous for rs3834458 (β=0.075; p=0.037). Children who were minor allele carriers for rs174537, rs174561, rs174575 and rs3834458 had a lower cord blood AA:LA ratio (p<0.05 for all). Both maternal and child FADS genotype were associated with cord LCPUFA concentrations, and therefore, the influence of FADS genotype was observed despite the high intake of preformed dietary LCPUFA from fish in this population.
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25.
  • Conway, Marie C, et al. (författare)
  • The influence of fish consumption on serum n-3 polyunsaturated fatty acid (PUFA) concentrations in women of childbearing age : a randomised controlled trial (the iFish Study)
  • 2021
  • Ingår i: European Journal of Nutrition. - : Springer Science and Business Media LLC. - 1436-6215 .- 1436-6207. ; 60:3, s. 1415-1427
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Long-chain polyunsaturated fatty acids (LCPUFA) can be synthesised endogenously from linoleic acid (LA) and α-linolenic acid (ALA) in a pathway involving the fatty acid desaturase (FADS) genes. Endogenous synthesis is inefficient; therefore, dietary intake of preformed LCPUFA from their richest source of fish is preferred. This study investigated the effect of fish consumption on PUFA concentrations in women of childbearing age while stratifying by FADS genotype. The influence of fish consumption on lipid profile, and markers of inflammation and oxidative stress was also examined.METHODS: Healthy women (n = 49) provided a buccal swab which was analysed for FADS2 genotype (rs3834458; T/deletion). Participants were stratified according to genotype and randomised to an intervention group to receive either no fish (n = 18), 1 portion (n = 14) or 2 portions (n = 17) (140 g per portion) of fish per week for a period of 8 weeks. Serum PUFA was analysed at baseline and post-intervention. Lipid profile, and markers of inflammation and oxidative stress were also analysed.RESULTS: Participants consuming 2 portions of fish per week had significantly higher concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and total n-3 PUFA, and a lower n-6:n-3 ratio compared to those in the no fish or 1 portion per week group (all p < 0.05). Fish consumption did not have a significant effect on biomarkers of oxidative stress, inflammation and lipid profile in the current study.CONCLUSION: Consumption of 2 portions of fish per week has beneficial effects on biological n-3 PUFA concentrations in women of childbearing age; however, no effects on oxidative stress, inflammation or lipid profile were observed. This trial was registered at www.clinicaltrials.gov (NCT03765580), registered December 2018.
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26.
  • Demanelis, Kathryn, et al. (författare)
  • Association of Arsenic Exposure with Whole Blood DNA Methylation : An Epigenome-Wide Study of Bangladeshi Adults
  • 2019
  • Ingår i: Environmental Health Perspectives. - 1552-9924. ; 127:5
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Arsenic exposure affects [Formula: see text] people worldwide, including [Formula: see text] in Bangladesh. Arsenic exposure increases the risk of cancer and other chronic diseases, and one potential mechanism of arsenic toxicity is epigenetic dysregulation. OBJECTIVE: We assessed associations between arsenic exposure and genome-wide DNA methylation measured at baseline among 396 Bangladeshi adults participating in the Health Effects of Arsenic Longitudinal Study (HEALS) who were exposed by drinking naturally contaminated well water. METHODS: Methylation in whole blood DNA was measured at [Formula: see text] using the Illumina InfiniumMethylationEPIC (EPIC) array. To assess associations between arsenic exposure and CpG methylation, we used linear regression models adjusted for covariates and surrogate variables (SVs) (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent dataset of [Formula: see text] from 400 Bangladeshi individuals with arsenical skin lesions. RESULTS: We identified 34 CpGs associated with [Formula: see text] creatinine-adjusted urinary arsenic [[Formula: see text]]. Sixteen of these CpGs annotated to the [Formula: see text] array, and 10 associations were replicated ([Formula: see text]). The top two CpGs annotated upstream of the ABR gene (cg01912040, cg10003262 ). All urinary arsenic-associated CpGs were also associated with arsenic concentration measured in drinking water ([Formula: see text]). Meta-analysis ([Formula: see text] samples) identified 221 urinary arsenic-associated CpGs ([Formula: see text]). The arsenic-associated CpGs from the meta-analysis were enriched in non-CpG islands and shores ([Formula: see text]) and depleted in promoter regions ([Formula: see text]). Among the arsenic-associated CpGs ([Formula: see text]), we observed significant enrichment of genes annotating to the reactive oxygen species pathway, inflammatory response, and tumor necrosis factor [Formula: see text] ([Formula: see text]) signaling via nuclear factor kappa-B ([Formula: see text]) hallmarks ([Formula: see text]). CONCLUSIONS: The novel and replicable associations between arsenic exposure and DNA methylation at specific CpGs observed in this work suggest that epigenetic alterations should be further investigated as potential mediators in arsenic toxicity and as biomarkers of exposure and effect in exposed populations. https://doi.org/10.1289/EHP3849.
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27.
  • Engström, Karin, et al. (författare)
  • Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions.
  • 2009
  • Ingår i: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. - : Elsevier BV. - 1879-2871 .- 0027-5107. ; 667, s. 4-14
  • 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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28.
  • Engström, Karin, et al. (författare)
  • Chronic exposure to cadmium and arsenic strongly influences concentrations of 8-oxo-7,8-dihydro-2'-deoxyguanosine in urine.
  • 2010
  • Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 48:9, s. 1211-1217
  • 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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29.
  • Engström, Karin, et al. (författare)
  • Efficient Arsenic Metabolism - The AS3MT Haplotype Is Associated with DNA Methylation and Expression of Multiple Genes Around AS3MT.
  • 2013
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
  • 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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30.
  • Engström, Karin, et al. (författare)
  • Evaluation of the impact of genetic polymorphisms in glutathione-related genes on the association between methylmercury or n-3 polyunsaturated long chain fatty acids and risk of myocardial infarction : a case-control study
  • 2011
  • Ingår i: Environmental Health. - : BioMed Central (BMC). - 1476-069X. ; 10:33
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, which are present in fish, are protective against myocardial infarction. However, fish also contains methylmercury, which influences the risk of myocardial infarction, possibly by generating oxidative stress. Methylmercury is metabolized by conjugation to glutathione, which facilitates elimination. Glutathione is also an antioxidant. Individuals with certain polymorphisms in glutathione-related genes may tolerate higher exposures to methylmercury, due to faster metabolism and elimination and/or better glutathione-associated antioxidative capacity. They would thus benefit more from the protective agents in fish, such as eicosapentaenoic+docosahexaenoic acid and selenium. The objective for this study was to elucidate whether genetic polymorphisms in glutathione-related genes modify the association between eicosapentaenoic+docosahexaenoic acid or methylmercury and risk of first ever myocardial infarction. Methods: Polymorphisms in glutathione-synthesizing (glutamyl-cysteine ligase catalytic subunit, GCLC and glutamyl-cysteine ligase modifier subunit, GCLM) or glutathione-conjugating (glutathione S-transferase P, GSTP1) genes were genotyped in 1027 individuals from northern Sweden (458 cases of first-ever myocardial infarction and 569 matched controls). The impact of these polymorphisms on the association between erythrocyte-mercury (proxy for methylmercury) and risk of myocardial infarction, as well as between plasma eicosapentaenoic+docosahexaenoic acid and risk of myocardial infarction, was evaluated by conditional logistic regression. The effect of erythrocyte-selenium on risk of myocardial infarction was also taken into consideration. Results: There were no strong genetic modifying effects on the association between plasma eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury and risk of myocardial infarction risk. When eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury were divided into tertiles, individuals with GCLM-588 TT genotype displayed a lower risk relative to the CC genotype in all but one tertile; in most tertiles the odds ratio was around 0.5 for TT. However, there were few TT carriers and the results were not statistically significant. The results were similar when taking plasma eicosapentaenoic+docosahexaenoic acid, erythrocyte-selenium and erythrocyte-mercury into account simultaneously. Conclusions: No statistically significant genetic modifying effects were seen for the association between plasma eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury and risk of myocardial infarction. Still, our results indicate that the relatively rare GCLM-588 TT genotype may have an impact, but a larger study is necessary for confirmation.
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31.
  • Engström, Karin, et al. (författare)
  • Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina.
  • 2007
  • Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 115:4, s. 599-605
  • 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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32.
  • Engström, Karin, et al. (författare)
  • Genetic variation in arsenic (+3 oxidation state) methyltransferase (AS3MT), arsenic metabolism and risk of basal cell carcinoma in a European population.
  • 2015
  • Ingår i: Environmental and Molecular Mutagenesis. - : Wiley. - 1098-2280 .- 0893-6692. ; 56:1, s. 60-69
  • Tidskriftsartikel (refereegranskat)abstract
    • Exposure to inorganic arsenic increases the risk of basal cell carcinoma (BCC). Arsenic metabolism is a susceptibility factor for arsenic toxicity, and specific haplotypes in arsenic (+3 oxidation state) methyltransferase (AS3MT) have been associated with increased urinary fractions of the most toxic arsenic metabolite, methylarsonic acid (MMA). The aim of this study is to elucidate the association of AS3MT haplotypes with arsenic metabolism and the risk of BCC. Four AS3MT polymorphisms were genotyped in BCC cases (N = 529) and controls (N = 533) from Eastern Europe with low to moderate arsenic exposure (lifetime average drinking water concentration: 1.3 µg/L, range 0.01-167 µg/L). Urinary metabolites [inorganic arsenic (iAs), MMA, dimethylarsinic acid (DMA)] were analyzed by HPLC-ICPMS. Five AS3MT haplotypes (based on rs3740400 A/C, rs3740393 G/C, rs11191439 T/C and rs1046778 T/C) had frequencies >5%. Individuals with the CCTC haplotype had lower %iAs (P = 0.032) and %MMA (P = 0.020) in urine, and higher %DMA (P = 0.033); individuals with the CGCT haplotype had higher %MMA (P < 0.001) and lower %DMA (P < 0.001). All haplotypes showed increased risk of BCC with increasing arsenic exposure through drinking water (ORs 1.1-1.4, P values from <0.001 to 0.082), except for the CCTC haplotype (OR 1.0, CI 0.9-1.2, P value 0.85). The results suggest that carriage of AS3MT haplotypes associated with less-efficient arsenic methylation, or lack of AS3MT haplotypes associated with a more-efficient arsenic methylation, results in higher risk of arsenic-related BCC. The fact that AS3MT haplotype status modified arsenic metabolism, and in turn the arsenic-related BCC risk, supports a causal relationship between low-level arsenic exposure and BCC. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc.
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33.
  • Engström, Karin, et al. (författare)
  • Genetic variation in glutathione-related genes and body burden of methylmercury
  • 2008
  • Ingår i: Journal of Environmental Health Perspectives. - Research Triangle Park, N.C. : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 116:6, s. 734-739
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Exposure to toxic methylmercury (MeHg) through fish consumption is a large problem worldwide, and it has led to governmental recommendations of reduced fish consumption and blacklisting of mercury-contaminated fish. The elimination kinetics of MeHg varies greatly among individuals. Knowledge about the reasons for such variation is of importance for improving the risk assessment for MeHg. One possible explanation is hereditary differences in MeHg metabolism. MeHg is eliminated from the body as a glutathione (GSH) conjugate. OBJECTIVES: We conducted this study to assess the influence of polymorphisms in GSH-synthesizing [glutamyl-cysteine ligase modifier subunit (GCLM-588) and glutamyl-cysteine ligase catalytic subunit (GCLC-129)] or GSH-conjugating [glutathione S-transferase pi 1 (GSTP1-105 and GSTP1-114)] genes on MeHg retention. METHODS: Based on information obtained from questionnaires, 292 subjects from northern Sweden had a high consumption of fish (lean/fat fish two to three times per week or more). We measured total Hg in erythrocytes (Ery-Hg) and long-chain n-3 polyunsaturated fatty acids in plasma (P-PUFA; an exposure marker for fish intake). RESULTS: The GSTP1 genotype modified Ery-Hg; effects were seen for GSTP1-105 and -114 separately, and combining them resulted in stronger effects. We found evidence of effect modification: individuals with zero or one variant allele demonstrated a steeper regression slope for Ery-Hg (p = 0.038) compared with individuals with two or more variant alleles. The GCLM-588 genotype also influenced Ery-Hg (p = 0.035): Individuals with the GCLM-588 TT genotype demonstrated the highest Ery-Hg, but we saw no evidence of effect modification with increasing P-PUFA. CONCLUSIONS: These results suggest a role of GSH-related polymorphisms in MeHg metabolism.
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34.
  • Engström, Karin, et al. (författare)
  • 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
  • Ingår i: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. - : Elsevier BV. - 1879-2871 .- 0027-5107. ; 683:1-2, s. 98-105
  • 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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35.
  • Engström, Karin, et al. (författare)
  • Polymorphisms in Arsenic(+III)methyltransferase (AS3MT) Predict Gene Expression of AS3MT as well as Arsenic Metabolism.
  • 2011
  • Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 119, s. 182-188
  • 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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36.
  • Engström, Karin, et al. (författare)
  • Polymorphisms in Genes Encoding Potential Mercury Transporters and Urine Mercury Concentrations in Populations Exposed to Mercury Vapor from Gold Mining.
  • 2013
  • Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 121:1, s. 85-91
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Elemental mercury (Hg0) is widely used in small-scale gold mining. Individuals working or living in mining areas have high urinary concentrations of Hg (U-Hg). Differences in genes encoding potential Hg-transporters may affect uptake and elimination of Hg. Objective: To identify single nucleotide polymorphisms (SNPs) in Hg-transporter genes that modify U-Hg. Methods: 1,017 men and women from Indonesia, the Philippines, Tanzania, and Zimbabwe were classified either as controls (no Hg exposure from gold mining) or as having low (living in a gold-mining area) or high exposure (working as gold miners). U-Hg was analyzed by cold-vapor atomic absorption spectrometry. Eighteen SNPs in eight Hg-transporter genes were analyzed. Results: U-Hg concentrations were higher among ABCC2/MRP2 rs1885301 A-allele carriers than among GG homozygotes in all populations, though differences were not statistically significant in most cases. MRP2 SNPs showed particularly strong associations with U-Hg in the subgroup with highest exposure (miners in Zimbabwe) where rs1885301 A-allele carriers had higher U-Hg than GG homozygotes (geometric mean (GM): 36.4 µg/g creatinine vs. 21.9; p=0.027), rs2273697 GG homozygotes had higher U-Hg than A-allele carriers (GM: 37.4 vs. 16.7; p=0.001), and rs717620 A-allele carriers had higher U-Hg than GG homozygotes (GM: 83 vs. 28; p=0.084). The SLC7A5/LAT1 rs33916661 GG genotype was associated with higher U-Hg in all populations (statistically significant for all Tanzanians combined). SNPs in SLC22A6/OAT1 (rs4149170) and SLC22A8/OAT3 (rs4149182) were associated with U-Hg mainly in the Tanzanian study groups. Conclusions: SNPs in putative Hg-transporter genes may influence U-Hg concentrations.
  •  
37.
  • Engström, Karin, et al. (författare)
  • Prenatal lead exposure is associated with decreased cord blood DNA methylation of the glycoprotein VI gene involved in platelet activation and thrombus formation
  • 2015
  • Ingår i: Environmental epigenetics. - : Oxford University Press (OUP). - 2058-5888. ; 1:1, s. 1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Early-life lead exposure impairs neurodevelopment and later exposure affects the cardiovascular system. Lead has been associated with reduced global 5-methylcytosine DNA methylation, suggesting that lead toxicity acts through epigenetic mechanisms. The objective of this study is to clarify how early-life lead exposure alters DNA methylation of specific genes, using an epigenomic approach. We measured lead concentrations in urine [gestational week (GW), 8] and erythrocytes (GW 14), using inductively coupled plasma mass spectrometry, for 127 pregnant mothers recruited in the MINIMat food and supplementation cohort in rural Bangladesh. Cord blood DNA methylation was analyzed with the Infinium HumanMethylation450K BeadChip, and top sites were validated by methylation-sensitive high-resolution melt curve analysis. Maternal urinary lead concentrations (divided into quartiles) showed significant (after adjustment for false discovery rate) inverse associations with methylation at nine CpGs. Three of these sites were in the 5'-end, including the promoter, of glycoprotein IV (GP6); cg18355337 (q = 0.029, β = -0.30), cg25818583 (q = 0.041, β = -0.18), and cg23796967 (q = 0.047, β = -0.17). The methylation in another CpG site in GP6 was close to significant (cg05374025, q = 0.057, β = - 0.23). The erythrocyte lead concentrations (divided into quartiles) were also inversely associated with CpG methylation in GP6, although this was not statistically significant after false discovery rate adjustments. Eight CpG sites in GP6 constituted a differentially methylated region in relation to urinary lead (P = 0.005, q = 0.48) and erythrocyte lead (P = 0.007, q = 0.46). In conclusion, we found that moderate prenatal lead exposure appears to epigenetically affect GP6, a key component of platelet aggregation and thrombus formation, suggesting a novel link between early lead exposure and cardiovascular disease later in life.
  •  
38.
  • Engström, Karin, et al. (författare)
  • Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women
  • 2017
  • Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:5, s. 2067-2078
  • Tidskriftsartikel (refereegranskat)abstract
    • Arsenic, a carcinogen with immunotoxic effects, is a common contaminant of drinking water and certain food worldwide. We hypothesized that chronic arsenic exposure alters gene expression, potentially by altering DNA methylation of genes encoding central components of the immune system. We therefore analyzed the transcriptomes (by RNA sequencing) and methylomes (by target-enrichment next-generation sequencing) of primary CD4-positive T cells from matched groups of four women each in the Argentinean Andes, with fivefold differences in urinary arsenic concentrations (median concentrations of urinary arsenic in the lower- and high-arsenic groups: 65 and 276 mu g/l, respectively). Arsenic exposure was associated with genome-wide alterations of gene expression; principal component analysis indicated that the exposure explained 53% of the variance in gene expression among the top variable genes and 19% of 28,351 genes were differentially expressed (false discovery rate < 0.05) between the exposure groups. Key genes regulating the immune system, such as tumor necrosis factor alpha and interferon gamma, as well as genes related to the NF-kappa-beta complex, were significantly downregulated in the high-arsenic group. Arsenic exposure was associated with genome-wide DNA methylation; the high-arsenic group had 3% points higher genome-wide full methylation (> 80% methylation) than the lower-arsenic group. Differentially methylated regions that were hyper-methylated in the high-arsenic group showed enrichment for immune-related gene ontologies that constitute the basic functions of CD4-positive T cells, such as isotype switching and lymphocyte activation and differentiation. In conclusion, chronic arsenic exposure from drinking water was related to changes in the transcriptome and methylome of CD4-positive T cells, both genome wide and in specific genes, supporting the hypothesis that arsenic causes immunotoxicity by interfering with gene expression and regulation.
  •  
39.
  • Enroth, Stefan, 1976-, et al. (författare)
  • High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer
  • 2019
  • Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations. The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85 and specificity = 0.93 for detection of ovarian cancer stages I-IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.
  •  
40.
  • Gardner, Renee M, et al. (författare)
  • Pregnancy and the methyltransferase genotype independently influence the arsenic methylation phenotype.
  • 2012
  • Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 22:7, s. 508-516
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: The methyltransferase genotype and pregnancy both influence the arsenic metabolism phenotype, but it is unknown whether these factors interact, explaining the drastic changes in the efficiency of arsenic metabolism observed among pregnant women. The aim of this study was to evaluate the relative contribution of the methyltransferase genotype and pregnancy to the arsenic metabolism phenotype. METHODS: We studied longitudinally the arsenic metabolite pattern in urine (at approximately gestational weeks 8, 14, and 30) of 303 women exposed to arsenic through drinking water and food in rural Bangladesh. Urinary arsenic metabolites were measured by high-performance liquid chromatography-inductively coupled plasma mass spectrometry. Data were available on genotypes for 16 polymorphisms, combined as haplotypes, in three methyltransferases: arsenic(+III)methyltransferase (AS3MT) and DNA-methyltransferases 1a and 3b (DNMT1a and DNMT3b). Changes in the arsenic metabolite pattern over time were evaluated by haplotype using logistic quantile regression. RESULTS: All four AS3MT haplotypes and all three DNMT1a haplotypes significantly influenced the metabolite pattern in the pregnant women, with consistent effects of genotype over the entire course of pregnancy. No interaction was found between the haplotypes and pregnancy-related changes in the arsenic metabolism phenotype. DNMT3b haplotypes did not significantly influence the metabolite pattern. We observed a pregnancy-attributable decrease of 5.7% in the most risk-associated monomethylated metabolite, methylarsonic acid, whereas changes between 1.6 and 5.3% of methylarsonic acid could be attributed to haplotypes of AS3MT and DNMT1a. CONCLUSION: Independent of the genotype, the efficiency of arsenic methylation increased markedly over the course of pregnancy. The effect of pregnancy on the metabolite pattern during the observational period was greater than the effect of genotype.
  •  
41.
  • Gliga, Anda R., et al. (författare)
  • Exposure to Mild Steel Welding and Changes in Serum Proteins With Putative Neurological Function—A Longitudinal Study
  • 2020
  • Ingår i: Frontiers in Public Health. - : Frontiers Media SA. - 2296-2565. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Welders are exposed to high levels of metal particles, consisting mainly of iron and manganese (Mn) oxide. Metal particles, especially those containing Mn can be neurotoxic. In this exploratory study, we evaluated associations between welding and expression of 87 putative neurology-related proteins in serum in a longitudinal approach. The study cohort from southern Sweden included welders working with mild steel (n = 56) and controls (n = 67), all male and non-smoking, which were sampled at two timepoints (T1, T2) 6-year apart. Observed associations in the longitudinal analysis (linear mixed models) were further evaluated (linear regression models) in another cross-sectional sample which included welders (n = 102) and controls (n = 89) who were sampled only once (T1 or T2). The median respirable dust levels for welders after adjusting for respiratory protection was at T1 0.6 (5–95 percentile: 0.2–4.2) and at T2 0.5 (0.1–1.8) mg/m3. The adjusted median respirable Mn concentration was at T2 0.049 mg/m3 (0.003–0.314) with a Spearman correlation between adjusted respirable dust and respirable Mn of rS = 0.88. We identified five neurology-related proteins that were differentially expressed in welders vs. controls in the longitudinal sample, of which one (nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1; NMNAT1) was also differentially expressed in the cross-sectional sample. NMNAT1, an axon-protective protein linked to Alzheimers disease, was upregulated in welders compared with controls but no associations were discerned with degree of exposure (welders only: years welding, respirable dust, cumulative exposure). However, we identified five additional proteins that were associated with years welding (GCSF, EFNA4, CTSS, CLM6, VWC2; welders only) both in the longitudinal and in the cross-sectional samples. We also observed several neurology-related proteins that were associated with age and BMI. Our study indicates that low-to-moderate exposure to welding fumes is associated with changes in circulating levels of neurology-related proteins.
  •  
42.
  • Gliga, Anda R., et al. (författare)
  • Maternal exposure to cadmium during pregnancy is associated with changes in DNA methylation that are persistent at 9 years of age
  • 2022
  • Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 163
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cadmium (Cd) exposure during gestation has been associated with altered DNA methylation at birth, but it is not known if the changes in methylation persist into childhood. Objectives: To evaluate whether gestational Cd-related changes of DNA methylation persist from birth to 9 years of age. Methods: We studied mother–child dyads in a longitudinal cohort in rural Bangladesh. Cadmium concentrations in maternal blood (erythrocyte fraction; Ery-Cd) at gestational week 14 and in child urine (U-Cd, long-term exposure marker) at 9 years were measured using inductively coupled plasma mass spectrometry. The epigenome-wide DNA methylation was measured in mononuclear cells (PBMCs) prepared from cord blood and peripheral blood at 9 years in 71 children (hereafter referred to as the explorative group) by Infinium HumanMethylation450K BeadChip. Replication of one differentially methylated region (DMR; 9 CpG sites) was performed in PBMCs of 160 9-year-old children (validation group) by EpiTyper MALDI-TOF mass spectrometry. Results: The median maternal Ery-Cd concentration was 1.24 µg/kg (range 0.35, 4.55) in the explorative group and 0.83 µg/kg (0.08, 2.97) in the validation group. The median U-Cd concentration in the 9-year-old children was 0.26 µg/L (0.09, 1.06) in the explorative group and 0.32 µg/L (0.07, 1.33) in the validation group. In the explorative group, we identified ten DMRs, both in cord blood and in PBMCs at 9 years, that were associated with maternal Ery-Cd. Eight out of the ten DMRs were hypomethylated and three of the hypomethylated DMRs were located in the HLA region on chromosome 6. One of the DMRs (hypomethylated) in the HLA region (upstream of the zinc finger protein 57 homolog, ZFP57 gene) was replicated in the validation group, and we found that it was hypomethylated in relation to maternal Ery-Cd, but not child U-Cd. Conclusion: Gestational exposure to Cd appears to be associated with regional changes, especially hypomethylated, in DNA methylation that linger from birth up to prepubertal age.
  •  
43.
  • Gliga, Anda R, et al. (författare)
  • Prenatal arsenic exposure is associated with increased plasma IGFBP3 concentrations in 9-year-old children partly via changes in DNA methylation
  • 2018
  • Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 92:8, s. 2487-2500
  • Tidskriftsartikel (refereegranskat)abstract
    • Exposure to inorganic arsenic (As), a carcinogen and epigenetic toxicant, has been associated with lower circulating levels of insulin-like growth factor 1 (IGF1) and impaired growth in children of pre-school age. The aim of this study was to assess the potential impact of exposure to As on IGF1 and insulin-like growth factor-binding protein 3 (IGFBP3) as well as DNA methylation changes in 9-year-old children. To this end, we studied 9-year-old children from a longitudinal mother-child cohort in rural Bangladesh (n = 551). Prenatal and concurrent exposure to As was assessed via concentrations in maternal urine at gestational week 8 and in child urine at 9 years, measured by HPLC-HG-ICPMS. Plasma IGF1 and IGFBP3 concentrations were quantified with immunoassays. DNA methylation was measured in blood mononuclear cells at 9 years in a sub-sample (n = 113) using the Infinium HumanMethylation450K BeadChip. In multivariable-adjusted linear regression models, prenatal As (natural log-transformed), but not children's concurrent urinary As, was positively associated with IGFBP3 concentrations (β = 76, 95% CI 19, 133). As concentrations were not associated with IGF1. DNA methylation analysis revealed CpGs associated with both prenatal As and IGFBP3. Mediation analysis suggested that methylation of 12 CpG sites for all children was mediator of effect for the association between prenatal As and IGFBP3. We also found differentially methylated regions, generally hypermethylated, that were associated with both prenatal As and IGFBP3. In all, our study revealed that prenatal exposure to As was positively associated with IGFBP3 concentrations in children at 9 years, independent of IGF1, and this association may, at least in part, be epigenetically mediated.
  •  
44.
  • Gliga, Anda R., et al. (författare)
  • Short and long-term associations between serum proteins linked to cardiovascular disease and particle exposure among constructions workers
  • 2023
  • Ingår i: Scandinavian Journal of Work, Environment and Health. - : Scandinavian Journal of Work, Environment and Health. - 0355-3140 .- 1795-990X. ; 49:2, s. 145-154
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives Construction workers are exposed to respirable dust, including respirable crystalline silica (RCS), which is a potential risk factor for cardiovascular disease (CVD). The aim of this study was to evaluate whether exposure to particles among construction workers is associated with short-and long-term alterations in CVD-related serum proteins. Methods Using proximity extension assay, we measured 92 serum proteins linked to CVD among active male construction workers (N=65, non-smokers) sampled on two occasions: during work and after vacation. First, we used linear models to identify short-term changes in proteins associated with particle exposure (assessed as respirable dust and RCS) during work. Secondly, we used linear mixed models to evaluate whether these associations were long-term, ie, persistent after vacation. Results The median exposure to respirable dust and RCS during work were 0.25 mg/m3 and 0.01 mg/m3, respec-tively. Respirable dust was associated with short-term changes in six proteins (tissue factor, growth hormone, heme oxygenase-1, dickkopf-related protein-1, platelet-derived growth factor-B, stem cell factor); long-term associations were observed for the former three proteins. RCS was associated with short-term changes in five proteins (carcinoembryonic antigen-related cell adhesion molecule-8, hydroxyacid oxidase-1, tissue factor, car-bonic anhydrase-5A, lectin-like oxidized LDL receptor-1); long-term associations were observed for the former four proteins. Conclusions Moderate exposure to particles in the construction industry is associated with both short-and long-term changes in circulating CVD-related proteins. Further studies are needed to evaluate if these changes are predictors of occupationally induced clinical CVD.
  •  
45.
  • Grahn, Karin, et al. (författare)
  • Occupational exposure to particles and biomarkers of cardiovascular disease – during work and after vacation
  • 2022
  • Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 0340-0131 .- 1432-1246. ; 95, s. 1537-1548
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Ambient particle matter is a risk factor for cardiovascular disease (CVD). However, little is known about associations between particles in occupational settings and risk of CVD. We investigated associations between occupational dust exposure and biomarkers of CVD, and potential recovery effects after vacation.Methods Personal dust exposure measurements (respirable silica, respirable dust < 4 mu m, and particles of 0.1-10 mu m (PM 0.1-10) were conducted once, and biological sampling were performed twice on non-smoking, male construction workers in Stockholm county, Sweden; during work and immediately after summer vacation. Linear regressions with adjustments for confounders and covariates were performed evaluating associations between occupational dust exposure and biomarkers. Paired t tests were performed evaluating changes before and after vacation.Results Sixty-five workers participated. Homocysteine concentrations were significantly higher with increasing concentrations (mg/m(3)) of respirable silica, respirable dust, and PM 0.1-10, and pulse rate with higher levels of respirable dust and dust of PM 0.1-10. Homocysteine levels were also positively correlated to number of years of dust exposure, as were low-density lipoprotein (LDL) levels. A clear recovery effect was present for LDL after vacation, but not for homocysteine.Conclusions Occupational dust exposure was associated with some CVD risk markers, even at mean exposure concentrations below the Swedish occupational exposure limits for respirable silica and respirable dust, respectively. Vacation resulted in recovery for some risk markers. However, the change of the homocysteine and LDL levels suggest a long-term effect. Reduction of occupational exposure to dust may decrease the risk of CVD among exposed workers.
  •  
46.
  • Grahn, Karin, et al. (författare)
  • Occupational noise exposure and acute effects on pulse rate and blood pressure
  • 2022
  • Ingår i: Proceedings of the International Congress on Acoustics.
  • Konferensbidrag (refereegranskat)abstract
    • Environmental exposure to noise and particle matter (PM) are risk factors for cardiovascular disease (CVD). Although there are often higher levels in occupational settings, little is known about noise and particle exposures at work and CVD risks. We investigated occupational noise and particle exposures and acute effects on pulse rate and blood pressure. 46 active, non-smoking, male construction workers were included in the study. Continuously logged personal exposure measurements of noise (LAmax, LCpeak) and dust of PM 0.1-10, continuously logged pulse rate and blood pressure measurements were performed for one working day on each participant. Significant associations were seen between these three exposures and acute changes in pulse rate. The effects were seen below the Swedish occupational exposure limits for LAmax and LCpeak, indicating that these limits may not protect from adverse cardiovascular effects. Also, an additive effect on pulse rate was seen if simultaneously exposed to noise and dust. No association were found between these exposures and blood pressure.
  •  
47.
  • Harari, Florencia, et al. (författare)
  • N-6-Adenine-Specific DNA Methyltransferase 1 (N6AMT1) Polymorphisms and Arsenic Methylation in Andean Women
  • 2013
  • Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 121:7, s. 797-803
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: In humans, inorganic arsenic is metabolized to methylated metabolites mainly by arsenic (+3 oxidation state) methyltransferase (AS3MT). AS3MT polymorphisms are associated with arsenic metabolism efficiency. Recently, a putative N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) was found to methylate arsenic in vitro. OBJECTIVE: We evaluated the role of N6AMT1 polymorphisms in arsenic methylation efficiency in humans. METHODS: We assessed arsenic methylation efficiency in 188 women exposed to arsenic via drinking water (similar to 200 mu g/L) in the Argentinean Andes by measuring the relative concentrations of arsenic metabolites in urine [inorganic arsenic, methylarsonic acid (MMA), and dimethylarsinic acid] by high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. We performed genotyping for N6AMT1 and AS3MT polymorphisms by Taqman assays, and gene expression (in blood; n = 63) with Illumina HumanHT-12 v4.0. RESULTS: Five N6AMT1 single nucleotide polymorphisms (SNPs; rs1997605, rs2205449, rs2705671, rs16983411, and rs1048546) and two N6AMT1 haplotypes were significantly associated with the percentage of MMA (%MMA) in urine, even after adjusting for AS3MT haplotype. %MMA increased monotonically according to the number of alleles for each SNP (e. g., for rs1048546, mean %MMA was 7.5% for GG, 8.8% for GT, and 9.7% for TT carriers). Three SNPs were in linkage disequilibrium (R-2 > 0.8). Estimated associations for joint effects of N6AMT1 (haplotype 1) and AS3MT (haplotype 2) were generally consistent with expectations for additive effects of each haplotype on %MMA. Carriers of N6AMT1 genotypes associated with lower %MMA showed the lowest N6AMT1 expression, but associations were monotonic according to copy number for only one genotype and one haplotype. CONCLUSIONS: N6AMT1 polymorphisms were associated with arsenic methylation in Andean women, independent of AS3MT. N6AMT1 polymorphisms may be susceptibility markers for arsenic-related toxic effects.
  •  
48.
  • Harari, Raul, et al. (författare)
  • Exposure and Toxic Effects of Elemental Mercury in Gold Mining Activities
  • 2009
  • Ingår i: Epidemiology. - : Ovid Technologies (Wolters Kluwer Health). - 1044-3983. ; 20:6, s. 264-265
  • Tidskriftsartikel (refereegranskat)abstract
    • Elemental mercury (Hg0) is widely used in gold-mining activities in South America, Africa and Asia. Miners use Hg0 to extract gold, and are exposed by inhalation when burning the gold amalgam to get rid of the Hg0. Burning is usually performed only once per 1–3 weeks. Gold buyers again burn the gold to be sure that they only buy gold. Hg0 affects the central nervous system (CNS), but the exposure-response relationship for discrete but important effects is not well known. As indicators of exposure, Hg levels in blood, plasma and urine are useful. It is usually assumed that there is a simple relationship between exposure and these biomarkers. However, recent data indicate that genetic traits may modify the retention of Hg. Also, there is a possibility that such factors may influence the exposure-response curves.
  •  
49.
  •  
50.
  • Jönsson, Lena S, et al. (författare)
  • Gene expression in nasal lavage from hairdressers exposed to persulphate.
  • 2009
  • Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 82, s. 1261-1266
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Many hairdressers experience work-related symptoms from the airways caused by bleaching powder. This contains persulphates, which could be irritating to the mucous membrane and also may evoke an allergic reaction. However, specific IgE antibodies are difficult to detect. We found earlier that hairdressers with work-related bleaching powder-associated nasal symptoms reacted to persulphate, but that atopics also did and that the mechanism appeared to be similar in the two groups. In this study, we analysed gene expression of cytokines in the nose in order to further investigate the mechanism for work-related bleaching powder-associated nasal symptoms. METHODS: The study subjects belonged to either hairdressers with work-related bleaching powder-associated nasal symptoms (S; n = 6), hairdressers without work-related bleaching powder-associated symptoms (WS; n = 7) or atopics (A; n = 6). Nasal lavage was performed before and during (up to 4 h after the last challenge) provocation with potassium persulphate. Expression of two genes involved in allergic inflammation [interleukin 5 (IL5) and IL13] and one involved in cell-mediated immunity (interferon-gamma; IFNG) were analysed in nasal lavage with quantitative PCR. RESULTS: The change of IL5 in the S group differed when compared to the WS group (P = 0.0051), in the A group when compared to the WS group (P = 0.014), but not in the S group when compared to the A group (P = 0.82). The change of IL13 in the A group differed when compared to the S (P = 0.041) and WS (P = 0.014) groups, but no difference was noticed between the S and WS groups (P = 0.30). The relative level of IFNG increased from before challenge to during challenge in the S group (P = 0.031). CONCLUSIONS: Symptomatic hairdressers showed increased expression of IL5 and IFNG, but not IL13, during challenge. Hairdressers without work-related bleaching powder-associated nasal symptoms showed no markedly changed reaction. Atopics showed increased expression of IL5 and IL13. Thus, this may indicate a difference in the mechanism of symptoms between symptomatic hairdressers and atopics. However, due to the low number of participants, further studies are needed to elucidate the mechanism for persulphate-associated nasal symptoms.
  •  
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