| 41. |
- Karasik, D., et al.
(författare)
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Disentangling the genetics of lean mass
- 2019
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 109:2, s. 276-287
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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| 42. |
- Klint, Helén, et al.
(författare)
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Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue
- 2017
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 122:1, s. 20-27
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Epidemiological studies report associations between exposure to the high-volume chemical and endocrine disruptor bisphenol A (BPA) and cardiovascular disorders, but there is a lack of experimental studies addressing the mechanisms of action of BPA on the cardiovascular system. In the present study, effects on markers for cardiovascular function of exposure to BPA and fructose in vivo in rat cardiac tissues, and of BPA exposure in human cardiomyocytes in vitro, were investigated.MATERIALS: Juvenile female Fischer 344 rats were exposed to 5, 50, and 500 μg BPA/kg bodyweight/day in their drinking water from 5 to 15 weeks of age, in combination with 5% fructose. Further, cultured human cardiomyocytes were exposed to 10 nM BPA to 1 × 10(4) nM BPA for six hours. Expression of markers for cardiovascular function and BPA target receptors was investigated using qRT-PCR.RESULTS: Exposure to 5 μg BPA/kg bodyweight/day plus fructose increased mRNA expression of Vegf, Vegfr2, eNos, and Ace1 in rat heart. Exposure of human cardiomyocytes to 1 × 10(4) nM BPA increased mRNA expression of eNOS and ACE1, as well as IL-8 and NFκβ known to regulate inflammatory response.CONCLUSIONS: . Low-dose exposure of juvenile rats to BPA and fructose induced up-regulation of expression of genes controlling angiogenesis and vascular tone in cardiac tissues. The observed effects of BPA in rat heart were in line with our present and previous studies of BPA in human endothelial cells and cardiomyocytes. These findings may aid in understanding the mechanisms of the association between BPA exposure and cardiovascular disorders reported in epidemiological studies.
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| 43. |
- La Merrill, Michele A., et al.
(författare)
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The association between p,p'-DDE levels and left ventricular mass is mainly mediated by obesity
- 2018
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Ingår i: Environmental Research. - : Academic Press. - 0013-9351 .- 1096-0953. ; 160, s. 541-546
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: The pesticide metabolite p,p'-DDE has been associated with left ventricular (LV) mass and known risk factors for LV hypertrophy in humans and in experimental models. We hypothesized that the associations of p,p'-DDE with LV hypertrophy risk factors, namely elevated glucose, adiposity and hypertension, mediate the association of p,p'-DDE with LV mass.METHODS: p,p'-DDE was measured in plasma from 70-year-old subjects (n = 988) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). When these subjects were 70-, 75- and 80- years old, LV characteristics were measured by echocardiography, while fasting glucose, body mass index (BMI) and blood pressure were assessed with standard clinical techniques.RESULTS: We found that p,p'-DDE levels were associated with increased fasting glucose, BMI, hypertension and LV mass in separate models adjusted for sex. Structural equation modeling revealed that the association between p,p'-DDE and LV mass was almost entirely mediated by BMI (70%), and also by hypertension (19%).CONCLUSION: The obesogenic effect of p,p'-DDE is a major determinant responsible for the association of p,p'-DDE with LV mass.
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| 44. |
- Lee, Duk-Hee, et al.
(författare)
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Association between background exposure to organochlorine pesticides and the risk of cognitive impairment : A prospective study that accounts for weight change
- 2016
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Ingår i: Environment International. - Oxford, United Kingdom : Elsevier. - 0160-4120 .- 1873-6750. ; 89-90, s. 179-184
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Tidskriftsartikel (refereegranskat)abstract
- Background: Background exposure to organochlorine (OC) pesticides was recently linked to cognitive impairment and dementia in cross-sectional and case-control studies. This prospective study was performed to evaluate if OC pesticides at baseline are associated with the future risk of cognitive impairment in elderly, with particular focus on weight change.Methods: Plasma concentrations of 3 OC pesticides (p,p'-DDE, trans-nonachlor, and hexachlorobenzene) were measured among 989 men and women aged 70years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Cognitive impairment was validated by reviewing medical records. During the ten year follow-up, cognitive impairment was developed in 75 subjects. When weight change from age 70 to 75 was considered in analyses, elderly with incident cases before age 75 were excluded to keep the prospective perspective, leaving 795 study subjects and 44 incident cases.Results: The summary measure of 3 OC pesticides predicted the development of cognitive impairment after adjusting for covariates, including weight change. Compared to subjects with OC pesticides <25th percentile, adjusted hazard ratios (HRs) in those with 25th-<75th and ≥75th percentiles were 3.5 (95% confidence interval: 1.5-8.5) and 3.2 (1.1-7.6), respectively (Ptrend=0.04). Among 506 subjects who maintained or gained body weight, adjusted HRs were 6.9 and 11.6 (1.4-92.6) among the elderly in the 25th-<75th and ≥75th percentiles compared to <25th percentile (Ptrend<0.01).Conclusions: This prospective study demonstrates that background exposure to OC pesticides are linked to the risk of developing cognitive impairment in elderly. The role of the chronic exposure to low dose OC pesticides in the development of dementia should be further evaluated in other populations.
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| 45. |
- 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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| 46. |
- Lejonklou, Margareta Halin, 1966-, et al.
(författare)
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Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring.
- 2017
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Ingår i: Journal of Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 125:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive.OBJECTIVES: The aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring.METHODS: Pregnant F344 rats were exposed to BPA via their drinking water, corresponding to (BPA0.5; ) or (BPA50; ), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring.RESULTS: Males and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels ( compared with , females BPA50 ; compared with , males BPA0.5 ) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls ( number of adipocytes/HPF compared with number of adipocytes/HPF; ) and by 123% in BPA0.5 females compared with BPA50 animals ( number of adipocytes/high power field (HPF) compared with number of adipocytes/HPF; ). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals ( number of adipocytes/HPF compared with number of adipocytes/HPF; ). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex.CONCLUSIONS: Developmental exposure to of BPA, which is 8-10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at were compared with the offspring of unexposed controls.
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| 47. |
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| 48. |
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| 49. |
- Lind, Lars, et al.
(författare)
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Endothelium-dependent vasodilation is related to the occurrence of cortical brain infarcts at MR imaging : The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study
- 2017
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Ingår i: Clinical Physiology and Functional Imaging. - : Wiley. - 1475-0961 .- 1475-097X. ; 37:2, s. 194-197
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Infarcts in the brain can be divided into larger cortical and smaller deep lacunar infarcts. The pathogenesis differs between these two types of infarctions.OBJECTIVE: This study aims to investigate the relationship between measures of endothelium-dependent vasodilation (EDV) and occurrence of cortical and lacunar infarcts in a population-based sample.METHODS: In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, 1016 subjects aged 70 were evaluated by the invasive forearm technique with acetylcholine (EDV) and brachial artery ultrasound to assess flow-mediated vasodilation (FMD). Six to seven years later MRI of the brain was performed, and the prevalence of cortical and lacunar infarcts was visually assessed in 407 randomly selected subjects.RESULTS: Lacunar infarcts were found in 22% and cortical infarcts in 5·9% of the subjects. EDV and FMD were both significantly related to the occurrence of cortical, but not lacunar infarcts. In a model adjusting for gender, waist circumference, body mass index, fasting blood glucose, systolic and diastolic blood pressure, HDL and LDL cholesterol, serum triglycerides, smoking, antihypertensive treatment and statin use, both EDV and FMD were independent predictors of cortical infarcts (P = 0·035 and P = 0·008, respectively).CONCLUSIONS: Endothelium-dependent vasodilation in both forearm resistance vessels and the brachial artery was related to the occurrence of cortical, but not lacunar, infarcts at MRI in a population-based sample independently of traditional risk factors.
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| 50. |
- Lind, Lars, et al.
(författare)
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Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p '-dde levels in a population-based sample
- 2017
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Ingår i: Environment International. - Oxford, United Kingdom : Elsevier. - 0160-4120 .- 1873-6750. ; 98, s. 212-218
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p'-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p, p'-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.Results: Evidence for genome-wide significant association with p,p'-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472 ng/g lipid, while the corresponding level for those being homozygote for the T allelewas 192 ng/g lipid (p= 1.5x10(-31)). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19: 41520351; p= 2.2 x 10(-8)). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p= 6.2 x 10(-9)) located 7 kb downstreamthe CYP2B6 gene (cg27089200, position chr19: 41531976). This CpG-sitewas also related to the lead SNP (p = 3.8 x 10(-35)), but mediated only 4% of the effect of the lead SNP on p, p'-DDE levels.Conclusion: Circulating levels of p, p'-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p, p'-DDE levels.
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