| 1. |
- Palmgren, Michael, et al.
(författare)
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AS3MT-mediated tolerance to arsenic evolved by multiple independent horizontal gene transfers from bacteria to eukaryotes
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Organisms have evolved the ability to tolerate toxic substances in their environments, often by producing metabolic enzymes that efficiently detoxify the toxicant. Inorganic arsenic is one of the most toxic and carcinogenic substances in the environment, but many organisms, including humans, metabolise inorganic arsenic to less toxic metabolites. This multistep process produces mono-, di-, and trimethylated arsenic metabolites, which the organism excretes. In humans, arsenite methyltransferase (AS3MT) appears to be the main metabolic enzyme that methylates arsenic. In this study, we examined the evolutionary origin of AS3MT and assessed the ability of different genotypes to produce methylated arsenic metabolites. Phylogenetic analysis suggests that multiple, independent horizontal gene transfers between different bacteria, and from bacteria to eukaryotes, increased tolerance to environmental arsenic during evolution. These findings are supported by the observation that genetic variation in AS3MT correlates with the capacity to methylate arsenic. Adaptation to arsenic thus serves as a model for how organisms evolve to survive under toxic conditions.
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| 2. |
- Ameer, Syeda Shegufta, et al.
(författare)
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Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood
- 2017
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 321, s. 57-66
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Tidskriftsartikel (refereegranskat)abstract
- Background Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. Objectives To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. Methods The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N = 80 women) and DNA methylation (N = 93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. Results U-As concentrations, ranging 10–1251 μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000 CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. Conclusions Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap.
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| 3. |
- Engström, Karin, et al.
(författare)
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Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women
- 2017
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:5, s. 2067-2078
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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.
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| 4. |
- Llop, Sabrina, et al.
(författare)
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CYP3A genes and the association between prenatal methylmercury exposure and neurodevelopment
- 2017
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 105, s. 34-42
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Tidskriftsartikel (refereegranskat)abstract
- Background Results on the association between prenatal exposure to methylmercury (MeHg) and child neuropsychological development are heterogeneous. Underlying genetic differences across study populations could contribute to this varied response to MeHg. Studies in Drosophila have identified the cytochrome p450 3A (CYP3A) family as candidate MeHg susceptibility genes. Objectives We evaluated whether genetic variation in CYP3A genes influences the association between prenatal exposure to MeHg and child neuropsychological development. Methods The study population included 2639 children from three birth cohort studies: two subcohorts in Seychelles (SCDS) (n = 1160, 20 and 30 months of age, studied during the years 2001–2012), two subcohorts from Spain (INMA) (n = 625, 14 months of age, 2003–2009), and two subcohorts from Italy and Greece (PHIME) (n = 854, 18 months of age, 2006–2011). Total mercury, as a surrogate of MeHg, was analyzed in maternal hair and/or cord blood samples. Neuropsychological development was evaluated using Bayley Scales of Infant Development (BSID). Three functional polymorphisms in the CYP3A family were analyzed: rs2257401 (CYP3A7), rs776746 (CYP3A5), and rs2740574 (CYP3A4). Results There was no association between CYP3A polymorphisms and cord mercury concentrations. The scores for the BSID mental scale improved with increasing cord blood mercury concentrations for carriers of the most active alleles (β[95% CI]: = 2.9[1.53,4.27] for CYP3A7 rs2257401 GG + GC, 2.51[1.04,3.98] for CYP3A5 rs776746 AA + AG and 2.31[0.12,4.50] for CYP3A4 rs2740574 GG + AG). This association was near the null for CYP3A7 CC, CYP3A5 GG and CYP3A4 AA genotypes. The interaction between the CYP3A genes and total mercury was significant (p < 0.05) in European cohorts only. Conclusions Our results suggest that the polymorphisms in CYP3A genes may modify the response to dietary MeHg exposure during early life development.
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| 5. |
- Alhamdow, Ayman, et al.
(författare)
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Chimney sweeps in Sweden : a questionnaire-based assessment of long-term changes in work conditions, and current eye and airway symptoms
- 2017
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 0340-0131 .- 1432-1246. ; 90:2, s. 207-216
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To explore chimney sweeping work tasks, chimney sweeps’ use of protective equipment, and type of fuel used by clients, over time. Further, to assess work-relatedness of current eye and airway symptoms. Methods: In a cross-sectional study in 2011, male Swedish chimney sweeps (n = 483; age 21–69 years) answered a questionnaire about their occupational history and eye and airway symptoms. Results: Between 1960 and 2010, black-soot-sweeping in private homes was the major task, although it decreased during the time period, for chimney sweeps. Between 1975 and 2010, the use of petroleum oil decreased, whereas the use of pellets and wood increased. Also, the use of gloves and masks increased significantly. Black-soot-sweeping in industry was associated with work-related eye symptoms (prevalence odds ratio POR = 3.76, 95% CI: 1.72–8.24, for every 10% increment of working time, adjusted for age and tobacco smoking). Chimney sweeps also had slightly higher prevalence of cough with increasing black-soot-sweeping (POR = 1.06, 95% CI: 0.99–1.13 for every 10% increment, further adjusted for the use of mask), and the association was more pronounced, although nonsignificant, for black-soot-sweeping in industry (adjusted POR = 1.26, 95% CI: 0.98–1.61). Conclusions: Chimney sweeping tasks and use of protective equipment as well as type of fuel used by the clients changed significantly over the last 35 years, which may have changed chimney sweeps’ exposure to soot. Still, chimney sweeps in Sweden have black-soot-sweeping-related eye and airway symptoms.
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| 6. |
- Alhamdow, Ayman, et al.
(författare)
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Early markers of cardiovascular disease are associated with occupational exposure to polycyclic aromatic hydrocarbons
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Occupational exposure to soot, rich in polycyclic aromatic hydrocarbons (PAH), has been associated with increased risk of cardiovascular disease (CVD). However, our knowledge about PAH exposure and early markers of CVD remains limited. In this cross-sectional study of 151 chimney sweeps and 152 controls, we investigated occupational exposure to PAH and early markers of CVD. Blood pressure (BP) (chimney sweeps only), urinary PAH metabolites and serum biomarkers were measured (C-reactive protein, homocysteine, gamma-glutamyltransferase, cholesterol, HDL, LDL, and triglycerides). Chimney sweeps had up to 7 times higher concentrations of PAH metabolites in urine than controls (P < 0.001): Median concentrations (adjusted for specific gravity) for 1-hydroxypyrene, 2-hydroxyphenanthrene, 3-hydroxybenzo[a]pyrene, and 3-hydroxybenzo[a]anthracene were 0.56 μg/L, 0.78 μg/L, 4.75 ng/L, and 6.28 ng/L, respectively. Compared with controls, chimney sweeps had increased homocysteine, cholesterol, and HDL (β = 3.4 μmol/L, 0.43 mmol/L, and 0.13 mmol/L, respectively, P ≤ 0.003, adjusted for age, BMI, and smoking). In chimney sweeps, PAH metabolites correlated positively with the percentage of soot sweeping (P < 0.001). 2-hydroxyphenanthrene, 3-hydroxybenzo[a]pyrene, and 3-hydroxybenzo[a]anthracene were positively associated with diastolic BP (P < 0.044, adjusted for age, BMI, and smoking). PAH exposure among chimney sweeps resulted in elevated levels of markers for CVD risk. These findings stress the need to reduce occupational exposure to PAH.
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| 7. |
- Collin, Sven-Olof Yrjö, et al.
(författare)
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The auditor as consigliere in family firm
- 2017
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Ingår i: Journal of Family Business Management. - : Emerald Group Publishing Limited. - 2043-6238 .- 2043-6246. ; 7:1, s. 2-20
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThe purpose of this paper is to develop and test a concept of auditor as consigliere in family firms, that captures additional functions to monitoring, those of advice, mediating, and conveying.Design/methodology/approachThe concept is tested through a survey conducted on 309 Swedish auditors.FindingsThe data indicate that the consigliere role is generally not emphasized, indicating that auditors primarily perform the monitoring role of the audit. However, the authors do find indications of the auditor performing the consigliere role, through performing the advisory and mediating functions and, to a smaller degree, the conveying function.Research limitations/implicationsThe survey is limited in response rate and in separating governance situations from consigliere functions.Practical implicationsWith reservation for professional independence, the auditor as consigliere could be part of the governance of the family firm, but should be trained for this activity.Social implicationsRegulators should pay attention to the consigliere role when, for example, stipulating compulsory rotation of auditors.Originality/valueThe paper shows that the auditor is more than a monitor in family firms. The consigliere role, even if not at all dominating, has to be considered, at least in family firms.
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| 8. |
- Hedmer, Maria, et al.
(författare)
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Diesel Exhaust Exposure Assessment Among Tunnel Construction Workers—Correlations Between Nitrogen Dioxide, Respirable Elemental Carbon, and Particle Number
- 2017
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Ingår i: Annals of Work Exposures and Health. - : Oxford University Press (OUP). - 2398-7308 .- 2398-7316. ; 61:5, s. 539-553
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Occupational exposure to diesel exhaust is common due the widespread use of dieselpowered combustion engines. Diesel exhaust is chemically complex and consists of thousands of compounds present as gases and particulate matter. Both nitrogen dioxide (NO2) and elemental carbon(EC) have been used as markers for diesel exhaust exposure. Currently EC is regarded as the best surrogate of diesel exhaust. The objective was to quantify the occupational exposure to diesel exhaust in underground tunnel construction work using a multi-metric approach, and to investigate the correlations between NO2, respirable EC, respirable organic carbon (OC), respirable total carbon(TC), respirable dust (RD), and particle number. Also, the use of NO2 as a proxy for diesel exhaust was evaluated, how much of the variability in the diesel exhaust exposure was attributed to within and between individual factors and if there was a difference between expert and self-administered measurements of NO2. Methods: The personal exposure to diesel exhaust was assessed by expert supervised measurements of NO2, EC, OC, TC, RD and particle number in the breathing zones of underground tunnel workers. Stationary sampling of NO2, EC, OC, TC, RD, size-fractioned mass concentration, and particle number were conducted. The personal and stationary measurements were conducted on threeoccasions simultaneously. The workers measured their exposure by repeated self-administered measurements of NO2. The self-administered measurements were performed twice for each worker with at least one month lag between the samplings. Results: In the simultaneous sampling of diesel exhaust, the geometric mean (GM) concentration of NO2 and respirable EC were 72 μg m−3 (10th–90th percentile 34–140 μg m−3) and 2.6 μg m−3 (10th–90th percentile 1.6–7.3 μg m−3), respectively. The GM for OC and TC was 28 μg m−3 (10th–90th percentile 20–42 μg m−3) and 31 μg m−3 (10th–90th percentile 20–50 μg m−3), respectively. The GM for RD and particle number was 180 μg m−3 (10th–90th percentile 20–530 μg m−3) and 47 900 cm−3 (10th–90th percentile (27 500–94 100 cm−3), respectively. A significant correlation was found between NO2 and respirable EC [Spearman’s correlation r = 0.53 (P = 0.05)]. The within-worker variability of NO2 was 45.5% and the between-worker variability was 54.5%. The self-administered measured concentrations of NO2 (GM 70 μg m−3) did not statistically differ from the NO2 concentrations measured by an expert (P > 0.35).Conclusion: The diesel exhaust exposure in tunnel construction work was low. A significant correlation between NO2 and EC was observed. This indicates that NO2 could be used as a proxy for diesel exhaust in tunnel work if diesel exhaust is the only source of NO2 and if the ratio between EC and NO2 is known and constant. Passive sampling of NO2 is much easier and cheaper to perform compared with active sampling of EC. It is possible to utilize self-administered NO2 measurements in extreme and inaccessible work environments. This study adds support to continued use of NO2 as an exposure marker in combination with EC for diesel exhaust exposure. In tunnel construction work, the variability in the diesel exhaust exposure was high both between- and within-workers.
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| 9. |
- Mohlkert, Lilly -Ann, et al.
(författare)
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Preterm arteries in childhood : dimensions, intima-media thickness, and elasticity of the aorta, coronaries, and carotids in 6-y-old children born extremely preterm
- 2017
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Ingår i: Pediatric Research. - : NATURE PUBLISHING GROUP. - 0031-3998 .- 1530-0447. ; 81:2, s. 299-306
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Preterm birth increases risk for adult cardiovascular disease. We hypothesized that arteries in 6-y-old children born preterm are narrower, with thicker intima-media and stiffer than in peers born at term. METHODS: Children born extremely preterm (EXP, n = 176, birthweights: 348-1,161 g) and at term (CTRL, n = 174, birth weights: 2,430-4,315 g) were included. Using ultrasonography, we determined diameters of the coronaries (CA), common carotid arteries (CCA) and aorta, the carotid intima media thickness (CIMT), and the stiffness index of the CCA and aorta. RESULTS: Arteries were 5-10% narrower in EXP than in CTRL (P < 0.005) but after adjustment for body surface area, diameter differences diminished or disappeared. EXP-children born small for gestational age exhibited similar arterial dimensions as those born appropriate for date. The cIMT was 0.38 (SD = 0.04) mm and did not differ between groups. Carotid but not aortic stiffness was lower in EXP than in CTRL. CONCLUSION: In 6-y-old children born extremely preterm, conduit arteries are of similar or smaller size than in controls born at term, and they have no signs of accelerated intima media thickening or arterial stiffening. While these findings are reassuring for these children and their families, the causal pathways from preterm birth to adult cardiovascular disease remain unknown.
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| 10. |
- Sanchez, Hugo, et al.
(författare)
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High levels of circulating folate concentrations are associated with DNA methylation of tumor suppressor and repair genes p16, MLH1, and MGMT in elderly Chileans
- 2017
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Changes in DNA methylation, one of the most studied epigenetic mechanisms, are considered an initial marker for early cancer detection. We evaluated how availability of dietary factors (folates and vitamin B12) involved in one-carbon metabolism may contribute to DNA methylation changes of cancer-related genes in human subjects. Methods: We studied, by pyrosequencing, the methylation of tumor suppressor gene p16, DNA repair genes MLH1 and MGMT, and the repetitive element LINE-1 (as a surrogate for global DNA methylation), in blood of elderly individuals (n = 249) who had been exposed to folic acid (FA) through FA-fortified wheat flour during the last 12 years. Results: We found that serum folate and to a lesser extent, vitamin B12 concentrations, were significantly correlated with DNA methylation of p16, MLH1, and MGMT, but not with LINE-1. High serum folate concentrations (>45.3 nmol/L) were present in 31.1% of the participants. Although the methylated fraction of CpG sites in p16, MLH1, and MGMT was low (1.17-3.8%), high folate concentrations were significantly associated with methylation at the 3rd tertile of specific CpG sites in all genes with OR between 1.97 and 4.17. Conclusions: This study shows that a public policy, like food fortification with FA that increases circulating serum folate levels, could affect methylation levels of specific genes linked to cancer risk. Our present results deserve additional studies to clarify the real impact of high FA levels for risk of cancer in a whole population chronically exposed to a fortified food such as wheat flour. Trial registration: ISRCTN 48153354 and ISRCTN 02694183.
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