| 11. |
- Lee, Duk-Hee, et al.
(författare)
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Neurotoxic chemicals in adipose tissue : A role in puzzling findings on obesity and dementia
- 2018
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 90:4, s. 176-182
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Tidskriftsartikel (refereegranskat)abstract
- Midlife obesity is associated with increased risk of dementia, whereas late-life obesity is commonly associated with a lower risk of dementia. Although methodologic issues are often discussed in this apparent risk reversal, chronic exposure to low-dose organochlorine pesticides (OCPs), an emerging risk factor for dementia in general populations, may contribute to a direct explanation for these differences. OCPs are strong lipophilic chemicals with very long half-lives (several years), primarily stored in adipose tissue and very slowly released and metabolized over years. As serum concentrations of neurotoxic OCPs strongly correlate with brain OCPs (r = 0.95), any condition enhancing the release of OCPs from the adipose tissue into circulation would increase the risk of dementia. Increased release of OCPs from adipose tissue typically occurs in (1) dysfunctional adipocytes accompanied by uncontrolled lipolysis and (2) weight loss. Weight gain may help sequester circulating OCPs in adipose tissue. As obesity is the most common reason that adipocytes become dysfunctional, midlife obesity can increase dementia risk through the chronic release of OCPs into circulation. However, late-life obesity potentially decreases dementia risk because weight loss after midlife will increase the release of OCPs while weight gain may actually decrease the release. These countervailing forces may underlie paradoxical associations with dementia of obesity in midlife vs late life which is influenced by weight change after midlife. This hypothesis should be tested in future experimental and human studies on obesity and dementia.
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| 12. |
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| 13. |
- Lind, P. Monica, 1957-, et al.
(författare)
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Changes in plasma levels of perfluoroalkyl substances (PFASs) are related to increase in carotid intima-media thickness over 10 years - a longitudinal study
- 2018
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Ingår i: Environmental Health. - : BMC. - 1476-069X. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: It has previously been reported that the environmental contaminants perfluoroalkyl substances (PFASs) are linked to atherosclerosis in cross-sectional studies. Since cross-sectional studies could be subject to reverse causation, the purpose of this study was to analyze if the longitudinal changes in PFASs during a 10-year follow-up were related to the change in carotid artery intima-media thickness (IMT, ultrasound) during the same period.Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 1016 individuals were investigated at age 70; 826 of them were reinvestigated at age 75 and 602 at age 80 years. Eight different PFASs were measured in plasma by ultra-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and IMT was measured at all three time points. Random-effects mixed regression models were used to examine the associations over time.Results: IMT increased 0.058 mm during the 10-year period (p <0.0001). Following adjustment for baseline values of PFASs (age 70) and sex, the changes in plasma levels of 6 of the 8 measured PFASs were significantly related to the change in IMT over the 10-year follow-up period in a positive fashion (p <0.0062 using Bonferroni correction for 8 tests). Further adjustment for traditional cardiovascular (CV) risk factors (HDL and LDL cholesterol, smoking, systolic blood pressure, statin use, fasting glucose and serum triglycerides) affected these relationships only marginally.Conclusion: The change in plasma levels of several PFASs during 10 years was positively related to increase in IMT seen during the same period, giving prospective evidence that PFASs might interfere with the atherosclerotic process.
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| 14. |
- Lind, P. Monica, 1957-, et al.
(författare)
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Endocrine-disrupting chemicals and risk of diabetes : an evidence-based review
- 2018
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 61:7, s. 1495-1502
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Forskningsöversikt (refereegranskat)abstract
- The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. We found > 40 cross-sectional and seven prospective studies regarding EDCs and risk of diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene (p,p'-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p'-DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus, evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p'-DDE. For other chemicals, both prospective studies and supporting animal data are still lacking.
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| 15. |
- Lind, P. Monica, 1957-, et al.
(författare)
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High plasma organochlorine pesticide levels are related to increased biological age as calculated by DNA methylation analysis
- 2018
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 113, s. 109-113
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Organochlorine pesticides (OCPs) have been shown in the experimental setting to alter DNA methylation. Since DNA methylation changes during the life-span, formulas have been presented to calculate "DNA methylation age" as a measure of biological age.OBJECTIVES: We aimed to investigate if circulating levels of three OCPs were related to increased DNA methylation age METHODS: 71CpG DNA methylation age (Hannum formula) was calculated based on data from the Illumina 450 k Bead Methylation chip in 1000 subjects in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between DNA methylation age and chronological age was calculated (DiffAge). 2,2-bis (4-chlorophenyl)-1,1-dichloroethene (p,p'-DDE), hexachlorobenzene (HCB), and transnonachlor (TNC) levels were measured in plasma by high-resolution gas chromatography coupled mass spectrometry (HRGC-HRMS).RESULTS: Increased p,p'-DDE and TNC, but not HCB, levels were related to increased DiffAge both in sex and BMI-adjusted models, as well as in multiple adjusted models (sex, education level, exercise habits, smoking, energy and alcohol consumption and BMI) (p = 0.0051 and p = 0.011, respectively). No significant interactions between the OCPs and sex or BMI regarding DiffAge were found.CONCLUSION: In this cross-sectional study, increased levels of two out of three OCPs were related to increased DNA methylation age, further suggesting negative health effects in humans of these widespread environmental contaminants.
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| 16. |
- Mobacke, Ingrid, et al.
(författare)
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Circulating levels of perfluoroalkyl substances and left ventricular geometry of the heart in the elderly.
- 2018
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 115, s. 295-300
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Some persistent organic pollutants (POPs) such as hexachlorobenzene (HCB) and some polychlorinated biphenyls (PCBs) have been shown to interfere with myocardial function and geometry. We therefore investigated if also another group of POPs: per- and polyfluoroalkyl substances (PFASs) were associated with alterations in left ventricular geometry.METHODS: 801 subjects aged 70 years were investigated in a cross-sectional study within the scope of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFASs were detected in >75% of participants´ plasma by ultra-performance liquid chromatograph/tandem mass spectrometry. Left ventricular geometry was determined by echocardiography. Multivariable linear regression was used to investigate the associations between PFASs and left ventricular geometry of the heart after exclusion of subjects with previous myocardial infarction (n = 72).RESULTS: When adjusting for multiple comparisons, none of the eight PFASs evaluated were significantly related to left ventricular mass. However, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were related to relative wall thickness (RWT) in a negative fashion (p < 0.0021). Besides being inversely related to RWT, PFNA was also positively related to left ventricular end-diastolic volume (LVEDD) (p < 0.0021). These analyses were adjusted for traditional cardiovascular risk factors.CONCLUSION: In this cross-sectional study, several of the PFASs evaluated, especially PFNA, were related to myocardial geometry: a reduction in relative wall thickness and an increase in left ventricular diameter following adjustment for traditional cardiovascular risk factors, suggesting a role for PFASs in cardiac remodeling.
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| 17. |
- Oscarsson, Jan, et al.
(författare)
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Effects of free omega-3 carboxylic acids and fenofibrate on liver fat content in patients with hypertriglyceridemia and non-alcoholic fatty liver disease : A double-blind, randomized, placebo-controlled study
- 2018
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Ingår i: Journal of Clinical Lipidology. - : Elsevier BV. - 1933-2874 .- 1876-4789. ; 12:6, s. 1390-1403
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Treatment with omega-3 fatty acids and fenofibrates reduces serum triglyceride levels, but few studies have compared the effect of these agents on liver fat. OBJECTIVE: The aim of the EFFECT I trial (NCT02354976) was to determine the effects of free omega-3 carboxylic acids (OM-3CA) and fenofibrate on liver fat in overweight or obese individuals with non-alcoholic fatty liver disease and hypertriglyceridemia. METHODS: Seventy-eight patients were randomized to receive oral doses of 4 g OM-3CA (n = 25), 200 mg fenofibrate (n = 27), or placebo (n = 26) for 12 weeks in a double-blind, parallel-group study. Liver proton density fat fraction (PDFF) and volume, pancreas volume, and adipose tissue volumes were assessed by magnetic resonance imaging. RESULTS: Changes in liver PDFF at 12 weeks were not significantly different across treatment groups (relative changes from baseline: placebo, +4%; OM-3CA, -2%; and fenofibrate, +17%). The common PNPLA3 genetic polymorphism (I148M) did not significantly influence the effects of OM-3CA or fenofibrate on liver PDFF. Fenofibrate treatment significantly increased liver and pancreas volumes vs placebo treatment, and the changes in liver and pancreas volumes were positively correlated (rho 0.45, P = .02). Total liver fat volume increased significantly in patients using fenofibrate vs OM-3CA (+23% vs 3%, P = .04). Compared with OM-3CA, fenofibrate increased total liver fat and liver volume. Serum triglycerides decreased with OM-3CA (-26%, P = .02) and fenofibrate (-38%, P < .001) vs placebo. In contrast to OM-3CA, fenofibrate reduced plasma docosahexaenoic acid levels and increased plasma acetylcarnitine and butyrylcarnitine levels, estimated delta-9 desaturase activity and the concentration of urine F2-isoprostanes. CONCLUSIONS: OM-3CA and fenofibrate reduced serum triglycerides but did not reduce liver fat. Fenofibrate increased total liver volume and total liver fat volume vs OM-3CA, indicating a complex effect of fenofibrate on human hepatic lipid metabolism.
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| 18. |
- Salihovic, Samira, 1985-, et al.
(författare)
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Changes in markers of liver function in relation to changes in perfluoroalkyl substances : A longitudinal study
- 2018
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 117, s. 196-203
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Tidskriftsartikel (refereegranskat)abstract
- Background: While it is known that perfluoroalkyl substances (PFASs) induce liver toxicity in experimental studies, the evidence of an association in humans is inconsistent.Objective: The main aim of the present study was to examine the association of PFAS concentrations and markers of liver function using panel data.Methods: We investigated 1002 individuals from Sweden (50% women) at ages 70, 75 and 80 in 2001-2014. Eight PFASs were measured in plasma using isotope dilution ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). Bilirubin and hepatic enzymes alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT) were determined in serum using an immunoassay methodology. Mixed-effects linear regression models were used to examine the relationship between the changes in markers of liver function and changes in PFAS levels.Results: The changes in majority of PFAS concentrations were positively associated with the changes in activity of ALT, ALP, and GGT and inversely associated with the changes in circulating bilirubin after adjustment for gender and the time-updated covariates LDL- and HDL-cholesterol, serum triglycerides, BMI, statin use, smoking, fasting glucose levels and correction for multiple testing. For example, changes in perfluorononanoic acid (PFNA) were associated with the changes liver function markers beta(BILIRUBIN) = -1.56, 95% confidence interval (CI) -1.93 to -1.19, beta(ALT)= 0.04, 95% CI 0.03-0.06, and beta(ALP)= 0.11, 95% CI 0.06-0.15.Conclusion: Our longitudinal assessment established associations between changes in markers of liver function and changes in plasma PFAS concentrations. These findings suggest a relationship between low-dose background PFAS exposure and altered liver function in the general population.
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| 19. |
- Stubleski, Jordan, 1990-, et al.
(författare)
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A method for analysis of marker persistent organic pollutants in low-volume plasma and serum samples using 96-well plate solid phase extraction
- 2018
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Ingår i: Journal of Chromatography A. - : Elsevier. - 0021-9673 .- 1873-3778. ; 1546, s. 18-27
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to develop and validate a 96-well plate solid phase extraction method for analysis of 23 lipophilic persistent organic pollutants (POPs) in low-volume plasma and serum samples which is applicable for biomonitoring and epidemiological studies. The analysis of selected markers for internal exposure: 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and polybrominated diphenylether 47 (BDE 47) was evaluated by comparing two SPE sorbents and GC-HRMS or GC-MS/MS detection. The final method extracted 23 POPs from 150 μL of serum and plasma using a 96-well extraction plate containing 60 mg Oasis HLB sorbent per well prior to GC-HRMS magnetic sector analysis. The extraction method was applied to 40 plasma samples collected for an epidemiological study. The recovery of selected POPs ranged from 31% to 63% (n = 48), and detection limits ranged from 2.2 to 45 pg/mL for PCBs, 4.2 to 167 pg/mL for OCPs, 7.8 pg/mL for OCDD and 6.1 pg/mL for BDE 47. This method showed good precision with relative standard deviations of selected POP concentrations in quality control samples (n = 48) ranging from 11% to 25%. The trueness was determined with standard reference material serum (n = 48) and the deviation from certified values ranged from 1 to 27%. Of the 23 POPs analyzed, 18 were detected in 43% to 100% of plasma samples collected for the epidemiological study. The method showed good robustness with low inter-well plate variation (11-31%) determined by twelve 96-well plate extractions, and can extract 96 samples, including quality controls and procedural blanks in 2-3 days. Comparison with GC-MS/MS analysis showed that similar concentrations (within 0.5% to 30%) of most POPs could be obtained with GC-APCI-MS/MS. Larger deviations were observed for PCB 194 (60%) and trans-nonachlor (43%). The developed method produces accurate concentrations of low-level marker POPs in plasma and serum, providing a suitable high-throughput sample preparation procedure for biomonitoring and epidemiological studies involving large sample size and limited sample volume. GC-HRMS was chosen over GC-MS/MS, however the latter showed promising results, and could be used as an alternative to GC-HRMS analysis for most POPs.
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| 20. |
- Stubleski, Jordan, 1990-, et al.
(författare)
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Longitudinal changes in persistent organic pollutants (POPs) from 2001 to 2009 in a sample of elderly Swedish men and women
- 2018
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Ingår i: Environmental Research. - : Academic Press. - 0013-9351 .- 1096-0953. ; 165, s. 193-200
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prospective cohort studies evaluating the temporal trends of background-level persistent organic pollutants (POPs) and their potential negative health effects in humans are needed.OBJECTIVE: The objectives of this study are to examine the five year longitudinal trend in chlorinated and brominated (Cl/Br) POP concentrations in a sample of elderly individuals and to investigate the relationship between gender, changes in body weight, plasma lipid levels and POP concentrations.METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, plasma samples were collected from the same individuals over a 5 year period. Originally 992 subjects (all aged 70) were sampled between 2001 and 2004 and 814 returning subjects (all aged 75) were sampled again from 2006 to 2009. Plasma concentrations of 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and one polybrominated diphenylether (BDE 47) were determined using high-throughput 96-well plate solid phase extraction and gas chromatography-high resolution mass spectrometry (GC-HRMS).RESULTS: During the 5-year follow-up, plasma concentrations of all POPs significantly decreased (p < 0.00001). Median reductions ranged from 4% (PCB105) to 45% (PCB 99), with most reductions being in the 30-40% range. For most POPs, a larger decline was seen in men than in women. The relationship between the weight change and change in POP concentrations was generally negative, but a positive relationship between lipid levels and POP concentrations when expressed as wet-weight was observed. In general, similar changes in POP concentrations and their relationships to body weight were observed regardless of using either wet-weight (pg/mL) or lipid-normalized (ng/g lipid) concentrations.CONCLUSION: In this longitudinal cohort study, gender and minor, but varying changes in body weight and lipid levels greatly influenced the individual-based changes in POP concentrations. In general, our findings suggest that men and women with larger decreases in body weight and greater increases in lipid levels have the slowest decline in body burden of POPs. Based on the results from this study, either wet-weight or lipid normalized concentrations can be used to determine the percent change in POP concentrations and their relationships to physiological changes and differences.
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