| 1. |
- Penell, Johanna, et al.
(författare)
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Persistent organic pollutants are related to the change in circulating lipid levels during a 5 year follow-up
- 2014
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Ingår i: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 134, s. 190-197
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Tidskriftsartikel (refereegranskat)abstract
- When reporting circulating levels of persistent organic pollutants (POPs), usually lipid-normalized values are given. However, animal experiments and some human data indicate that exposure to POPs may change lipid values. The aim of the present study is to investigate if POP levels can predict future changes in levels of circulating lipids. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, lipids were measured at age 70 and at age 75 in 598 subjects without lipid-lowering medication. Twenty-three different POPs, including 16 polychlorinated biphenyls (PCBs), five organochlorine pesticides, one dioxin (OCDD) and one flame retardant brominated compound (BDE47) were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) at age 70. Strong relationships were seen among the baseline levels of the non-dioxin-like PCBs 194, 206 and 209 and the degree of increase in total serum cholesterol and LDL-cholesterol during the 5 year follow-up. These relationships were generally stronger when lipidnormalized levels were used compared to wet-weight based levels. On the contrary, for two of the pesticides, hexachlorobenzene and trans-nonachlordane, levels were inversely related to the change in LDL-cholesterol, with strongest associations found using wet-weight based levels. PCBs 194, 206 and 209 were inversely related to the change in HDL-cholesterol, in particular for wet-weight based levels. However, these relationships were only significant for wet-weight PCB 194 following adjustment for multiple testing. None of the POPs was related to the change in serum triglycerides. When investigating the association between the change in total serum cholesterol and LDL-cholesterol across different categories of change in BMI, we noted robust results especially in the group with stable BMI, suggesting that the observed relationships were not due to fluctuations in BMI over time. In conclusion, POPs are related to the change in lipids over time, especially LDL-cholesterol. This may explain why POP exposure previously has been linked to atherosclerosis and cardiovascular disease.
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| 2. |
- Sjöberg Lind, Ylva, et al.
(författare)
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Circulating levels of persistent organic pollutants (POPs) are associated with left ventricular systolic and diastolic dysfunction in the elderly
- 2013
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 123, s. 39-45
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVE:Major risk factors for congestive heart failure (CHF) are myocardial infarction, hypertension, diabetes, atrial fibrillation, smoking, left ventricular hypertrophy (LVH) and obesity. However, since these risk factors only explain part of the risk of CHF, we investigated whether persistent organic pollutants (POPs) might also play a role.METHODS:In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, left ventricular ejection fraction, (EF), E/A-ratio and isovolumic relaxation time (IVRT), were determined by echocardiography and serum samples of 21 POPs were analyzed in serum measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 998 subjects all aged 70 years.RESULTS:In this cross-sectional analysis, high levels of several of the polychlorinated biphenyls (PCB congeners 99, 118, 105, 138, 153, and 180) and octachlorodibenzo-p-dioxin (OCDD) were significantly related to a decreased EF. Some POPs were also related to a decreased E/A-ratio (PCBs 206 and 209). All the results were adjusted for gender, hypertension, diabetes, smoking, LVH and BMI, and subjects with myocardial infarction or atrial fibrillation were excluded from the analysis.CONCLUSIONS:Circulating levels of POPs were related to impairments in both left ventricular systolic and diastolic function independently of major congestive heart failure risk factors, suggesting a possible role of POPs in heart failure.
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| 3. |
- Sjöberg Lind, Ylva, et al.
(författare)
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Persistent organic pollutants and abnormal geometry of the left ventricle in the elderly
- 2013
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Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 31:8, s. 1547-1553
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Tidskriftsartikel (refereegranskat)abstract
- Background:Established risk factors for left ventricular hypertrophy (LVH) are hypertension, diabetes, and obesity. However, as these risk factors explain only part of the variation in left ventricular mass, we investigated whether persistent organic pollutants (POPs) might also play a role in LVH, because exposure to polychlorinated biphenyl 126 induced cardiac growth in rats.Methods:In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), left ventricular mass index (LVMI), relative wall thickness (RWT), and geometric groups of LVH, were determined by echocardiography and 21 POPs were measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 1016 individuals aged 70 years. All individuals with a history of myocardial infarction were excluded from analysis (n=72).Results:Several of the POPs were related to abnormal left ventricular geometry before adjustment for established risk factors, but lost in significance following adjustment. However, the pesticide hexachlorobenzene (HCB) levels were significantly related to RWT, and concentric left ventricular remodeling, also following adjustment for sex, blood pressure, antihypertensive treatment, diabetes, and BMI (Pandlt;0.0001).Conclusion:In this cross-sectional study, circulating levels of HCB were related to increased wall thickness of the left ventricle and concentric left ventricular remodeling, independently of LVH risk factors, suggesting a role of this environmental contaminant in abnormal growth of the left ventricle.
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| 4. |
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| 5. |
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| 6. |
- Ax, Erika, et al.
(författare)
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Circulating levels of environmental contaminants are associated with dietary patterns in older adults
- 2015
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Ingår i: Environment International. - Oxford, United Kingdom : Elsevier. - 0160-4120 .- 1873-6750. ; 75, s. 93-102
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Tidskriftsartikel (refereegranskat)abstract
- Background: Food intake contributes substantially to our exposure to environmental contaminants. Still, little is known about our dietary habits' contribution to exposure variability.Objective: The aim of this study was to assess circulating levels of environmental contaminants in relation to predefined dietary patterns in an elderly Swedish population.Methods: Dietary data and serum concentrations of environmental contaminants were obtained from 844 70-year-old Swedish subjects (50% women) in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Dietary data from 7-day food records was used to assess adherence to a Mediterranean-like diet, a low carbohydrate-high protein diet and the WHO dietary recommendations. Circulating levels of 6 polychlorinated biphenyl markers, 3 organochlorine pesticides, 1 dioxin and 1 polybrominated diphenyl ether, the metals cadmium, lead, mercury and aluminum and serum levels of bisphenol A and 4 phthalate metabolites were investigated in relation to dietary patterns in multivariate linear regression models.Results: A Mediterranean-like diet was positively associated with levels of several polychlorinated biphenyls (118, 126, 153, and 209), trans-nonachlor and mercury. A low carbohydrate-high protein diet was positively associated with polychlorinated biphenyls 118 and 153, trans-nonachlor, hexachlorobenzene and p, p'-dichlorodiphenyldichloroethylene, mercury and lead. The WHO recommended diet was negatively related to levels of dioxin and lead, and borderline positively to polychlorinated biphenyl 118 and trans-nonachlor.Conclusion: Dietary patterns were associated in diverse manners with circulating levels of environmental contaminants in this elderly Swedish population. Following the WHO dietary recommendations seems to be associated with a lower burden of environmental contaminants.
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| 7. |
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| 8. |
- Brittebo, Eva, 1951-, et al.
(författare)
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Bioactivation and effects of environmental pollutants in human and rodent blood vessel endothelial cells
- 2012
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Ingår i: Organohalogen compound database (http://www.dioxin20xx.org/ohc_database_search.htm).
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Konferensbidrag (refereegranskat)abstract
- IntroductionRecent epidemiological studies reveal associations between exposure to environmental pollutants and cardiovascular disorders in humans. Elevated serum concentrations of polychlorinated biphenyls (PCBs) have for instance been associated with cardiovascular risk factors such as hypertension (1-3). Exposure to the carbonate plastic monomer bisphenol A (BPA) has been associated with an increased incidence of cardiovascular disease and atherogenic changes in the vascular wall (4-6). The contention that the human cardiovascular system is a sensitive target for toxic chemicals gain support from our earlier and recent experimental studies in rodents, birds and fish, as well as in cultured human primary endothelial cells. It is also compatible with earlier observations that certain polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens that may also contribute to atherosclerosis in mice and birds (7,8).In this presentation we will briefly discuss effects of Ah receptor (AhR) agonists (e.g. the coplanar PCB126 or BNF, ß-naphthoflavone) on the expression of cytochrome P450 (CYP)1 enzymes in various endothelia in rodents in vivo or ex vivo, as well as in cultured human umbilical vein endothelial cells (HUVEC). The CYP1-dependent bioactivation and irreversible binding of prototype polyaromatic hydrocarbons (PAH) and heterocyclic amines such as benzo(a)pyrene (BaP), 7,12-dimethyl- benz(a)anthracene (DMBA) and 3-amino-1,4-dimethyl-5H-pyrido- [4,3-b]indole (Trp-P1) in these endothelia will be reviewed. We will also report how PCB126 affects vasoactive factors in HUVEC, and how these effects are modulated by physiological 17ß-oestradiol concentrations. Some effects of PCB126, 1-nitropyrene (1-NP) and bisphenol A (BPA) on biomarkers for endothelial dysfunction, cell stress and DNA damage in HUVEC will finally be presented.Material and methodsHuman umbilical vein endothelial cells (HUVEC) were purchased from Science Cell Research laboratories, Carlsbad, CA. C57Bl mice and Wistar or Sprague Dawley rats were purchased from various suppliers. All animal experiments were approved by the Local Ethical Committee for Research on Animals in Uppsala and the studies followed the guidelines laid down by the Swedish and European Union legislation on animal experimentation. Rodents, tissue-slices and cultured cells were treated with model chemicals as previously described. Tape section and light microscopy autoradiographic imaging using 3H-labelled BaP, DMBA and Trp-P-1 and immunohistochemistry was performed as previously described (9-19). Precision-cut tissue slices for in vitro autoradiography were prepared as described in (14) and the slices were incubated with various 3H-labelled chemicals. HUVEC were exposed to various compounds and the detection of biomarkers of endothelial dysfunction, DNA damage were performed as described (20-22). Finally, female Fischer rats were exposed to BPA (0.025, 0.25 and 2.5 mg/l) and fructose (50 g/l) in the drinking water from 5 to 15 weeks of age to mimic human exposure (unpublished data).Results and discussionCo-localization of CYP1A1 expression and BaP, DMBA and Trp-P-1 adduct formation in endothelial linings As demonstrated by immunohistochemistry, a high CYP1A immunoreactivity occurred in capillaries of the heart, skeletal muscle, uterus and in blood-brain interfaces such as the leptomeninges and plexus choroideus, whereas no expression was observed for instance in cerebral capillary endothelial cells of mice treated with AhR agonists (9-11). No, or very low constitutive immunoreactivities were observed in these endothelia in vehicle-treated animals. No basal or induced CYP1B1 expression was observed in endothelial cells, while a weak CYP1B1 immunostaining was detected in the muscle layer of small arteries. It should be noted that in subcellular preparations of whole organs, e.g. heart and brain, the CYP1A1 in endothelial cells is diluted due to cells that do not express high levels of CYP1A1, for examples myocytes or neurons, in excess. A cell-specific metabolism in endothelial cells may therefore remain undetected due to the presence of metabolically inactive cells. In order to detect minor sites of bioactivation such as endothelial linings we employed light microscopic autoradiographic imaging to examine the bioactivation and subsequent irreversible binding of the radiolabelled prototype toxicants in tissues of animals pretreated with AhR-agonists. As determined by light microscopic autoradiography of AhR-agonist-treated mice exposed to 3H-labelled BaP, DMBA or Trp-P-1 and birds exposed to 3H-Trp-P-1 a significant accumulation of non-extractable radioactivity occurred in endothelial linings (9-18). The bound radioactivity occurred in the nuclei and the perinuclear cytoplasm, suggesting that the autoradiograms depict both DNA- and protein-bound adducts. Since the binding sites of 3H-labelled BaP, DMBA or Trp-P-1 corresponded with the sites of CYP1A1 induction, we concluded that rodents express a constitutively low but highly inducible and functional CYP1A1 in endothelial cells. The binding of reactive metabolites in endothelial cells exceeded the binding in all other cell types in AhR-agonist treated mice and was abolished by pretreatment with the CYP1A1 inhibitor ellipticine, supporting a CYP1A1-catalysed metabolic activation in situ to a reactive species (9, 10,12). These findings imply that there is a preferential CYP1A1-catalysed formation of reactive metabolites from all three carcinogens in endothelial cells expressing high CYP1A1 levels. Interestingly, however, carcinogenesis in endothelial cells is a relative rare finding, suggesting that degenerative lesions and cell death may be more prevalent responses to metabolism-activated carcinogens/mutagens in these cells. Experiments with 3H-DMBA and 3H-Trp-P-1 in HUVEC confirmed that AhR-agonists induced an increased bioactivation, suggesting that also human endothelial cells should be targets for toxicity of reactive intermediates formed from CYP1A1- activated carcinogens/mutagens (17-18). This conclusion is supported by immunohistochemical studies on the heavily vascularized human endometrium demonstrating an expression of CYP1A1 and CYP1B1 protein in and around human endometrial blood vessels, although a large interindividualvariation was observed (19). None of the endometrial biopsy samples displayed vascular expression of CYP2A6, CYP2B6, CYP2C8/2C9/2C19, CYP2D6, or CYP3A4/5 protein.Effects of PCB 126, 1-NP, and BPA on biomarkers of endothelial dysfunction and cell stress in endothelial cells In vitro studies demonstrated that PCB126 increased the levels of vasoconstriction factors and decreased the levels of vasodilating factors in cultured HUVEC in a fashion that is characteristic for endothelial dysfunction related to human hypertension. The study showed that the co-planar PCB126 induced expression of the endothelium-derived vasoconstriction factor COX-2 and stimulated formation of the vasoconstrictor prostaglandin PGF2 via the AhR in HUVEC (20). COX-2 is known to play a role in hypertension by catalysing the formation of vasoconstriction prostaglandins and by stimulating reactive oxygen species (ROS) production. Further studies demonstrated that PCB126 increased the production of the vasoconstriction prostaglandin PGF2 and ROS in HUVEC. The relationship between increased ROS production and human hypertension is well established, ROS promotes vasoconstriction by stimulating the production of vasoconstriction prostaglandins and by reducing bioavailability of the vasorelaxing factor NO. Indeed, exposure to PCB126 slightly reduced the production of NO in HUVEC. Furthermore, the PCB126-induced mRNA expressions of CYP1A1, CYP1B1 and COX-2 in HUVEC were enhanced in the presence of physiological levels of 17- estradiol. This suggests that increased levels of oestrogen stimulate AhR-dependent transcription of genes previously associated with endothelial dysfunction and hypertension.In another study we have examined the effects of a nitrated PAH, 1-nitropyrene, that is abundant in diesel exhausts (21). The results revealed that 1-NP induced DNA damage, increased levels of ROS and increased protein expression of the endoplasmic reticulum stress chaperone GRP78 in cultured HUVEC. Induction of CYP1A1 by PCB126 as well as inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction and not by CYP1-dependent bioactivation to reactive intermediates.Recent in vitro studies demonstrated that bisphenol A increased the mRNA expression of genes that regulate vasoconstriction and angiogenesis in HUVEC (eNOS, VEGF, VEGFR2, connexin 43 and ACE1) and in human cardiomyocytes (eNOS and ACE1) (22). The results also showed that BPA increased the expression of P-eNOS(ser1177) and the production of NO in HUVEC. NO is the main effector molecule in angiogenesis downstream of VEGF. Based on the findings that BPA increase the expression of proangiogenic factors we investigated whether BPA could stimulate in vitro angiogenesis in HUVEC using the endothelial tube formation assay. The results demonstrated that BPA increased HUVEC tube formation suggesting that BPA can act directly on the endothelium and stimulate angiogenesis. Long-term exposure in rats revealed that environmentally relevant levels of BPA, increased the cardiac mRNA expression of genes that regulate vasoconstriction and angiogenesis. Ten weeks exposure of rats from preadolescence to adulthood to BPA in the drinking water increased theexpression of eNOS, VEGF, VEGFR2 and ACE1 in the heart. Taken together, the genes that were upregulated in rat cardiac tissues in vivo were also upregulated in human endothelial cells and cardiomyocytes in vitro. The heart is a heavily vascularized t
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| 9. |
- Dunder, Linda, et al.
(författare)
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Associations between per- and polyfluoroalkyl substances (PFAS) and diabetes in two population-based cohort studies from Sweden
- 2023
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Ingår i: Journal of Exposure Science and Environmental Epidemiology. - : Nature Publishing Group. - 1559-0631 .- 1559-064X. ; 33:5, s. 748-756
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been suggested to contribute to the development of metabolic diseases such as obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). However, evidence from epidemiological studies remain divergent. The aim of the present study was to evaluate associations between PFAS exposure and prevalent diabetes in a cross-sectional analysis and fasting glucose in a longitudinal analysis.METHODS: In 2373 subjects aged 45-75 years from the EpiHealth study, three PFAS; perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) were analyzed in plasma together with information on prevalent diabetes. Participants in the PIVUS study (n = 1016 at baseline, all aged 70 years) were followed over 10 years regarding changes in plasma levels of six PFAS; PFHxS, PFOA, PFOS, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), and changes in plasma levels of fasting glucose.RESULTS: In the EpiHealth study, no overall associations could be observed between the levels of PFOA, PFOS or PFHxS and prevalent diabetes. However, there was a significant sex-interaction for PFOA (p = 0.02), and an inverse association could be seen between PFOA (on a SD-scale) and prevalent diabetes in women only (OR: 0.71, 95% CI: 0.52, 0.96, p-value: 0.02). This association showed a non-monotonic dose-response curve. In the PIVUS study, inverse relationships could be observed between the changes in levels (ln-transformed) of PFOA and PFUnDA vs the change in fasting glucose levels (ln-transformed) over 10 years (p = 0.04 and p = 0.02, respectively). As in EpiHealth, these inverse associations were significant only in women (PFOA: β: -0.03, p = 0.02, PFUnDA: β: -0.03, p = 0.03).IMPACT: Exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to unfavorable human health, including metabolic disorders such as obesity, diabetes and non-alcoholic fatty liver disease. However, results from in vivo, in vitro and epidemiological studies are incoherent. The aim of the present study was therefore to investigate associations between PFAS and diabetes in a cross-sectional study and glucose levels in a longitudinal study. Results show inverse associations in women only. Results also display non-monotonic dose response curves (i.e., that only low levels of PFOA are related to higher probability of prevalent diabetes). This suggests that sex differences and complex molecular mechanisms may underlie the observed findings. A better understanding of the factors and molecular mechanisms contributing to such differences is recognized as an important direction for future research.CONCLUSIONS: PFOA was found to be inversely related to both prevalent diabetes and changes in plasma glucose levels among women only. Thus, our findings suggest there are sex differences in the inverse relationship of PFOA and type 2 diabetes and glucose levels.
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| 10. |
- Dunder, Linda, et al.
(författare)
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Changes in plasma levels of per- and polyfluoroalkyl substances (PFAS) are associated with changes in plasma lipids : A longitudinal study over 10 years
- 2022
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 211
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Associations between per- and polyfluoroalkyl substances (PFAS), mainly PFOS and PFOA, and increased blood lipids have been reported primarily from cross-sectional studies. The aim of the present study was to investigate associations between multiple PFAS and blood lipids in a longitudinal fashion.METHODS: A total of 864 men and women aged 70 years and free from lipid medication were included from the PIVUS study, 614 and 404 of those were reinvestigated at age 75 and 80. At all three occasions, eight PFAS were measured in plasma using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were also measured in plasma at all three occasions. Mixed-effects linear regression models were used to examine the relationship between the changes in PFAS levels and changes in lipid levels.RESULTS: Changes in plasma levels of six out of the eight investigated PFAS were positively associated with changes in plasma lipids after adjustment for sex, change in body mass index (BMI), smoking, physical activity, statin use (age was the same in all subjects), and correction for multiple testing. For example, changes in perfluorodecanoic acid (PFDA) were positively associated with the changes in total cholesterol (β: 0.23, 95% confidence interval (CI): 0.14 to 0.32), triglycerides (β: 0.08, 95% CI: 0.04-0.12) and HDL-cholesterol (β: 0.08, 95% CI: 0.04-0.11).CONCLUSION: In this longitudinal study with three measurements over 10 years of both plasma PFAS and lipids, changes in six out of the eight investigated PFAS were positively associated with changes in plasma lipids, giving further support for a role of PFAS exposure in human lipid metabolism.
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| 11. |
- Dunder, Linda
(författare)
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Exposure to Bisphenol A (BPA) and Metabolic Disruption
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Metbolic disorders such as obesity, type 2 diabetes, liver lipid disorders and metabolic syndrome are increasing rapidly and have largely been attributed to genetic background and changes in diet, exercise and aging. However, there is now considerable evidence showing that other environmental factors, including environmental chemicals, may contribute to the rapid increase in the incidence of these metabolic diseases. Of particular growing concern is low-dose developmental exposure to endocrine disrupting chemicals (EDCs). The developing period is an extremely sensitive window of exposure to environmental stressors, including EDCs, and early life exposure has been linked to metabolic disorders later in life. Consistent with hormones, EDCs can act at very low serum concentrations and even small changes in the endocrine system may lead to extensive effects. The overall aim of this thesis has been to investigate potential metabolic disruption following exposure to Bisphenol A (BPA), which is a known EDC. The experimental animal study demonstrated that male and female rat offspring generally exhibited differential susceptibility to developmental exposure to BPA (0.5 µg/kg BW/day or 50 µg/kg BW/day). The main results showed that the lowest dose of BPA induced increased plasma triglyceride levels and increased adipocyte cell density in inguinal white adipose tissue in female offspring. Further, this low dose increased fatty acid indices and altered the fatty acid composition in male offspring and enhanced insulin secretion in pancreatic islets from male and female offspring and dams. Contrastingly, the higher BPA-dose decreased insulin secretion in pancreatic islets from male and female offspring and dams. The increased fatty acid indices, and the altered fatty acid composition together with enhanced insulin secretion may be early risk factors for insulin resistance. Furthermore, depending on the tissue, dose and sex, BPA altered the expression of genes involved in lipid and adipocyte homeostasis.The epidemiological study with a meta-analysis of data from the National Health and Nutrition Survey (NHANES) did not disclose any associations between urinary BPA and dyslipidemia. However, considering the cross-sectional nature of the present study, this should rather be investigated in carefully designed prospective cohort studies with repeated BPA measurements. Nonetheless, we hope that this paper can encourage researchers to evaluate NHANES data using meta-analyses instead of pooling of data.This thesis concludes that exposure to BPA, which is a known EDC, most likely is a contributor, along with genetic, social and behavioral factors, to the development of metabolic disorders.
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| 12. |
- Dunder, Linda, et al.
(författare)
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Low-dose developmental bisphenol A exposure alters fatty acid metabolism in Fischer 344 rat offspring
- 2018
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 166, s. 117-129
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Tidskriftsartikel (refereegranskat)abstract
- Background. Bisphenol A (BPA) is an endocrine disruptor and also a suggested obesogen and metabolism-disrupting chemical. Accumulating data indicates that the fatty acid (FA) profile and their ratios in plasma and other metabolic tissues are associated with metabolic disorders. Stearoyl-CoA desaturase 1 (SCD-1) is a key regulator of lipid metabolism and its activity can be estimated by dividing the FA product by its precursor measured in blood or other tissues. Objective: The primary aim of this study was to investigate the effect of low-dose developmental BPA exposure on tissue-specific FA composition including estimated SCD-1 activity, studied in 5- and 52-week (wk)-old Fischer 344 (F344) rat offspring. Methods: Pregnant F344 rats were exposed to BPA via their drinking water corresponding to 0: [CTRL], 0.5: [BPA0.5], or 50 mu g/kg BW/day: [BPA50], from gestational day 3.5 until postnatal day 22. Results: BPA0.5 increased SCD-16 (estimated as the 16:1n-7/16:0 ratio) and SCD-18 (estimated as the 18:1n-9/ 18:0 ratio) indices in inguinal white adipose tissue triglycerides (iWAT-TG) and in plasma cholesterol esters (PL-CE), respectively, in 5-wk-old male offspring. In addition, BPA0.5 altered the FA composition in male offspring, e.g. by decreasing levels of the essential polyunsaturated FA linoleic acid (18:2n-6) in iWAT-and liver-TG. No differences were observed regarding the studied FAs in 52-wk-old offspring, although a slightly increased BW was observed in 52-wk-old female offspring. Conclusions: Low-dose developmental BPA exposure increased SCD-16 in iWAT-TG and SCD-18 in PL-CE of male offspring, which may reflect higher SCD-1 activity in these tissues. Altered desaturation activity and signs of altered FA composition are novel findings that may indicate insulin resistance in the rat offspring. These aforementioned results, together with the observed increased BW, adds to previously published data demonstrating that BPA can act as a metabolism disrupting chemical.
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| 13. |
- Dunder, Linda, et al.
(författare)
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Plasma levels of per- and polyfluoroalkyl substances (PFAS) and cardiovascular disease - Results from two independent population-based cohorts and a meta-analysis
- 2023
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 181
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Tidskriftsartikel (refereegranskat)abstract
- Background: Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals that have been linked to increased cholesterol levels and thus may have a role in the development of cardiovascular disease (CVD).Objectives: To investigate associations between PFAS exposure and incident CVD (a combined CVD end-point consisting of myocardial infarction, ischemic stroke, or heart failure) in two independent population-based cohorts in Sweden. In addition, we performed a meta-analysis also including results from previous studies.Methods: In 2,278 subjects aged 45-75 years from the EpiHealth study, the risk of incident CVD in relation to relative plasma levels of perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) was investigated. Associations between plasma levels of six PFAS and incident CVD were also examined in the PIVUS-study (n = 1,016, all aged 70 years). In addition, a meta-analysis was performed including three previous prospective studies, together with the results from the present study.Results: There were no overall statistically significant associations between levels of the different PFAS and incident CVD, neither in EpiHealth nor in PIVUS. However, there was a significant sex interaction for PFOS in EpiHealth (p = 0.008), and an inverse association could be seen only in men (Men, HR: 0.68, 95 % CI: 0.52, 0.89) (Women, HR: 1.13, 95 % CI: 0.82, 1.55). A meta-analysis of five independent studies regarding PFOA and incident CVD showed a risk ratio (RR) of 0.80 (CI: 0.66, 0.94) when high levels were compared to low levels.Conclusions: This longitudinal study using data from two population-based cohort studies in Sweden did not indicate any increased risk of incident CVD for moderately elevated PFAS levels. A meta-analysis of five independent cohort studies rather indicated a modest inverse association between PFOA levels and incident CVD, further supporting that increasing PFAS levels are not linked to an increased risk of CVD.
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| 14. |
- Dunder, Linda, et al.
(författare)
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Plasma levels of per- and polyfluoroalkyl substances (PFAS) are associated with altered levels of proteins previously linked to inflammation, metabolism and cardiovascular disease
- 2023
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 177
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been linked to immunotoxic and cardiometabolic effects in both experimental and epidemiological studies, but with conflicting results.AIM: The aim of the present study was to investigate potential associations between plasma PFAS levels and plasma levels of preselected proteomic biomarkers previously linked to inflammation, metabolism and cardiovascular disease.METHODS: Three PFAS (perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexane sulfonic acid (PFHxS)) were measured by non-targeted metabolomics and 249 proteomic biomarkers were measured by the proximity extension assay (PEA) in plasma from 2,342 individuals within the Epidemiology for Health (EpiHealth) study from Sweden (45-75 years old, 50.6 % men).RESULTS: After adjustment for age and sex, 92% of the significant associations between PFOS concentrations and proteins were inverse (p < 0.0002, Bonferroni-adjusted). The results were not as clear for PFOA and PFHxS, but still with 80% and 64 % of the significant associations with proteins being inverse. After adjustment for age, sex, smoking, education, exercise habits and alcohol consumption, levels of epidermal growth factor receptor (EGFR), and paraoxonase type 3 (PON3) remained positively associated with all three PFAS, while resistin (RETN) and urokinase plasminogen activator surface receptor (uPAR) showed inverse associations with all three PFAS.CONCLUSIONS: Our findings imply that PFAS exposure is cross-sectionally linked to altered levels of proteins previously linked to inflammation, metabolism and cardiovascular disease in middle-aged humans.
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| 15. |
- Dunder, Linda, et al.
(författare)
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Urinary bisphenol A and serum lipids : a meta-analysis of six NHANES examination cycles (2003-2014)
- 2019
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ PUBLISHING GROUP. - 0143-005X .- 1470-2738. ; 73:11, s. 1012-1019
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mounting evidence from both experimental and epidemiological studies suggest that exposure to the endocrine disruptor bisphenol A (BPA) has a role in metabolic disorders. The aim of the present study was to assess whether urinary BPA concentrations were associated with dyslipidaemia in children (<= 17 years old) and adults (>= 18 years old) by performing a meta-analysis of data from six cycles (2003-2014) in the National Health and Nutrition Examination Survey (NHANES).Methods: We conducted a meta-analysis of data from 4604 children and 10 989 adult participants who were part of a substudy of urinary BPA measurements from six NHANES cycles from 2003 to 2014. Linear regression models conducted in each cycle were used to perform a meta-analysis to investigate associations between urinary BPA and serum levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG) and apolipoprotein B (ApoB).Results: The meta-analysis did not disclose any significant associations between urinary BPA concentrations and LDL-C, HDL-C, TC, TG and ApoB in children. In adults, the meta-analysis revealed negative regression coefficients for all five lipid variables. However, no associations were significant following Bonferroni correction for multiple tests.Conclusions: In the present meta-analysis of cross-sectional data from NHANES, no associations were found between urinary BPA and the five different lipid variables when investigated in both children and adults. However, considering the cross-sectional nature of the present study, results should be clarified in carefully designed longitudinal cohort studies with repeated BPA measurements.
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| 16. |
- Fox, Glen A, et al.
(författare)
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Health of herring gulls (Larus argentatus) in relation to breeding location in the early 1990s : III. Effects on the bone tissue
- 2008
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Ingår i: Journal of Toxicology and Environmental Health. - : Informa UK Limited. - 1528-7394 .- 1087-2620. ; 71:21, s. 1448-1456
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Tidskriftsartikel (refereegranskat)abstract
- Health effects associated with the Great Lakes environment were assessed in adult herring gulls (Larus argentatus) in the early 1990s, including the size and quality of their bones. Femurs were excised from 140 individuals from 10 colonies distributed throughout the Great Lakes and 2 reference colonies in Lake Winnipeg (freshwater) and the Bay of Fundy (marine). Femurs of gulls from the Great Lakes differed from the freshwater or marine reference for 9 of 12 variables of size, composition, and strength assessed using peripheral quantitative computed tomography (pQCT) and biomechanical testing. Femurs of Great Lakes gulls were significantly smaller in length (-2.9%), periosteal circumference (-2.4%), and cross-sectional area (-5.4%) than freshwater reference birds. Femurs of the Great Lakes gulls had a lower significant cortical bone mineral content (-8.1%) and density (-2%) than the marine reference. A significant increase in the amount the bone could bend before it broke (+34%) and the energy required to break it (+44%) and a significant decrease (-16.3%) in stiffness during three-point biomechanical bending test were also detected in Great Lakes versus the freshwater gulls. These differences are indicative of impaired mineralization. When divided into high and low 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity equivalent (TCDD-TEQ) colonies, the amount the bone could bend before it broke and the energy required to break it were significantly higher in the high TEQ colonies, but not high polychlorinated biphenyl (PCB) colonies. Breeding location and dietary choices of Great Lakes herring gulls in the early 1990s resulted in modulations of physiological processes that affected the size, mineralization, and biomechanical properties of bone.
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| 17. |
- Heindel, Jerrold J., et al.
(författare)
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Obesity II : Establishing causal links between chemical exposures and obesity
- 2022
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Ingår i: Biochemical Pharmacology. - : Elsevier. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 199
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Forskningsöversikt (refereegranskat)abstract
- Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.
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| 18. |
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| 19. |
- Hong, N-S, et al.
(författare)
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The association between obesity and mortality in the elderly differs by serum concentrations of persistent organic pollutants : a possible explanation for the obesity paradox
- 2011
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 36:9, s. 1170-1175
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Numerous studies have documented an obesity paradox in which the overweight and obese elderly have a better prognosis than those with ideal body weight. Good prognosis among the overweight or obese elderly may reflect the relative safety of storing the harmful lipophilic chemicals, known as persistent organic pollutants (POPs), in adipose tissue rather than in other critical organs. Therefore, we hypothesized lower mortality among the obese elderly with a higher body burden of POPs, but this pattern may not exist among the obese elderly with a lower body burden of POPs.PARTICIPANTS: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2004 study with a mean 4.2-year follow-up, we tested whether the association between fat mass and total mortality in 635 (652 for organochlorine pesticides) elderly participants aged >= 70 years differed depending on serum concentrations of 23 POPs.RESULTS: There were statistically significant interactions between fat mass and POPs in predicting total mortality. In those with low POP concentrations, there was no obesity paradox; mortality increased with fat mass (hazard ratios about 2-3 in the highest vs lowest quintile of fat mass). However, consistent with an obesity paradox, these patterns completely disappeared in those with high POP concentrations. Compared with the lowest quintile of fat mass, statistically significantly lower mortality was observed in the elderly in the third to fifth quintiles of fat mass. In the case of polychlorinated biphenyls, the mortality in the highest quintile of fat mass was only one-fifth of that in the lowest quintile.CONCLUSION: These findings are consistent with our hypothesis that adipose tissue provides relatively safe storage of toxic lipophilic chemicals, a phenomenon that could explain the obesity paradox. Although weight loss may be beneficial among the obese elderly with low POP concentrations, weight loss in the obese elderly with higher serum concentrations of POPs may carry some risk.
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| 20. |
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| 21. |
- Jayasinghe, Saroj, et al.
(författare)
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High serum levels of p,p'-DDE are associated with an accelerated decline in GFR during 10 years follow-up
- 2018
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Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 644, s. 371-374
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Tidskriftsartikel (refereegranskat)abstract
- Over the past 20 years, the global incidence of chronic kidney disease (CKD) has been increasing and organochlorine pesticides (such as DDT) is a suspected etiological factor. The present study examines the associations between low level background exposure to p,p'-DDE (1-dichloro-2,2-bis (p-chlorophenyl) ethylene), the main DDT metabolite, and kidney function during a 10-year follow-up. Data was analysed from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 1016, 50% women, all aged 70 years). Serum levels of p,p'-DDE was measured by gas chromatography coupled to high-resolution mass spectrometry (GC/HRMS) at baseline (i.e. age of 70 years). Glomerular filtration rate (GFR) was estimated using serum creatinine and cystatin C at 70, 75 and 80 years of age. A significant decline in GFR was seen during the 10-year follow-up (-24 ml/min/1.73 m2, p < 0.0001). A significant negative interaction was seen between baseline p,p'-DDE levels and change in GFR over time (p < 0.0001) following adjustment for sex, systolic blood pressure, diabetes, BMI, smoking and education level at age 70. Subjects with the lowest levels of p,p'-DDE levels at age 70 showed the lowest decline in GFR over 10 years, while subjects with the highest p,p'-DDE levels showed the greatest decline.Baseline levels of p,p'-DDE were related to an accelerated reduction in GFR over 10 years suggesting a nephrotoxic effect of DDT/p,p'-DDE. These findings support a potential role for DDT in the epidemic of CKD of unknown etiology (CKDu) in agricultural communities of Sri Lanka and Central America where DDT was previously used.
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| 22. |
- Jugan, Juliann, et al.
(författare)
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The associations between p,p'-DDE levels and plasma levels of lipoproteins and their subclasses in an elderly population determined by analysis of lipoprotein content
- 2020
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Ingår i: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lipoproteins at aberrant levels are known to play a role in cardiovascular disease. The metabolite of the insecticide dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), physically associates with lipids and accumulates in adipose tissue. Little is known about which lipoproteins associate with p,p'-DDE. An association between p,p'-DDE exposure and altered levels of circulating lipids was assessed in a large human cohort using a detailed analysis of lipoprotein content.METHODS: Plasma samples were collected from the subset of 75-year old Swedes in the Prospective Investigation of the Vasculature of Uppsala Seniors (PIVUS) cohort who were not prescribed lipid lowering medication (n = 571). p,p'-DDE concentrations in plasma were measured using high-throughput solid phase extraction and gas chromatography-high resolution mass spectrometry. Analysis of plasma lipoprotein content was performed with nuclear magnetic resonance spectroscopy.RESULTS: Detectable levels of p,p'-DDE were found in the plasma samples of all subjects. Elevated p,p'-DDE levels were associated with increased concentrations of lipoproteins of all diameters, with the exception of high density lipoprotein (HDL) of diameters between 14.3 nm-10.9 nm. Of the lipoprotein constituents, triglycerides were most uniformly associated with elevated p,p'-DDE across lipoproteins. p,p'-DDE was furthermore associated with apolipoprotein B, but not apolipoprotein A1.CONCLUSIONS: The positive associations observed between each lipoprotein class and elevated p,p'-DDE support previous data suggesting that p,p'-DDE interacts with lipoproteins within plasma. It is speculated that both physio-chemical and biological mechanisms may explain why p,p'-DDE does not uniformly associate with lipids across lipoproteins.
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| 23. |
- 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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| 24. |
- Kumar, Jitender, et al.
(författare)
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Influence of persistent organic pollutants on oxidative stress in population-based samples
- 2014
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 114, s. 303-309
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Tidskriftsartikel (refereegranskat)abstract
- Persistent organic pollutants (POPs) are a large group of chemicals widely used and produced in various industrial applications. Many cell culture/animal studies have shown that POPs can induce oxidative stress. Since such data is lacking in humans, we conducted a large population-based study to analyze associations between POPs and oxidative stress markers. We measured following POPs; 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin, and polybrominated diphenyl ether 47, and oxidative stress markers; homocysteine, reduced [GSH] and oxidized glutathione [GSSG], glutathione ratio [GSSG/GSH], total glutathione, oxidized low-density lipoprotein [ox-LDL], ox-LDL antibodies, conjugated dienes, baseline conjugated dienes of LDL, and total anti-oxidative capacity in plasma samples collected from 992 70-year old individuals (50% women) from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Linear regression analyses were performed to study the associations between oxidative stress markers and summary measures of POPs including the total toxic equivalence (TEQ), sums of PCBs and BC pesticides (main exposures) while adjusting for potential confounders. In multivariable-adjusted analyses, sum of PCBs showed strong associations with ox-LDL (beta = 0.94; P = 2.9 * 10(-6)). Further, sum of PCBs showed association with glutathione-related markers (GSSG: beta = 0.01; P = 6.0 *10(-7); GSSG/GSH: beta = 0.002; P = 9.7 * 10(-10)), although in reverse direction. Other summary measures did not show any significant association with these markers. In our study of elderly individuals from the general population, we show that plasma levels of POPs are associated with markers of increased oxidative stress thereby suggesting that even low dose background exposure to POPs may be involved in oxidative stress. (C) 2014 Elsevier Ltd. All rights reserved.
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| 25. |
- Kumar, Jitender, et al.
(författare)
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Influence of persistent organic pollutants on the complement system in a population-based human sample
- 2014
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 71, s. 94-100
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Tidskriftsartikel (refereegranskat)abstract
- Background: Persistent organic pollutants (POPS) are toxic compounds generated through various industrial activities and have adverse effects on human health. Studies performed in cell cultures and animals have revealed that POPs can alter immune-system functioning. The complement system is part of innate immune system that helps to clear pathogens from the body. We performed a large-scale population-based study to find out associations between summary measures of different POPs and different complement system markers.Methods: In this cross-sectional study, 16 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, octachloro-p-dibenzodioxin, and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) were analyzed for their association with levels of protein complement 3 (C3), 3a (C3a), 4 (C4) and C3a/C3 ratio. A total of 992 individuals (all aged 70 years, 50% females) were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. Regression analysis adjusting for a variety of confounders was performed to study the associations of different POP exposures (total toxic equivalency value or TEQ and sum of 16 PCBs) with protein complements.Results: The TEQ values were found to be positively associated with C3a (beta = 0.07, 95% CI = 0.017-0.131, p = 0.01) and C3a/C3 ratio (beta = 0.07, 95% Cl = 0.015-0.126, p = 0.01) taking possible confounders into account. The association observed was mainly driven by PCB-126.Conclusion: In this study involving 992 elderly individuals from the general population, we showed that POPs, mainly PCB-126, were associated with levels of complement system markers indicating that the association of these toxic compounds with downstream disease could be mediated by activation of immune system. (C) 2014 Elsevier Ltd. All rights reserved.
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