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  • 1.
    Andersson, Helén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Eva, Brittebo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Experimental studies of bisphenol A in cardiovascular cells and tissues: effects on genes that regulate angiogenesis and vascular tone2012In:  , 2012Conference paper (Refereed)
  • 2.
    Brittebo, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Helén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Bioactivation and effects of environmental pollutants in human and rodent blood vessel endothelial cells2012In: Organohalogen compound database (http://www.dioxin20xx.org/ohc_database_search.htm), 2012Conference paper (Refereed)
    Abstract [en]

    Introduction

    Recent 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 methods

    Human 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 discussion

    Co-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 interindividual

    variation 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 the

    expression 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 tissue that consists mainly of cardiac endothelial cells and cardiomyocytes and although cardiomyocytes dominate the volume of the myocardium the number of endothelial cells exceeds the number of cardiomyocytes by approximately three to one. Thus, the effects of BPA on eNOS VEGF, VEGFR2 and ACE1 mRNA expression in rat cardiac tissues are most likely to be related to an effect of BPA on endothelial cells but may also involve cardiomyocytes.

    We conclude that endothelial cells may be targets for bioactivation and toxicity of environmental pollutants. The immunohistochemical and autoradiographic data demonstrated a differential expression of CYP1 enzymes and metabolic activation of pollutants in various endothelial linings suggesting that some but not all endothelial linings may be targets for xenobiotics metabolised by AhR-regulated enzymes. Studies on the effects of PCB126, 1-nitropyrene and BPA in cultured human primary endothelial cells demonstrated up-regulation of various biomarkers for endothelial dysfunction and cell stress suggesting that the human endothelium may be a sensitive target for these pollutants. The bioactivation and effects of environmental pollutants in endothelial cells should be further studied in order to unravel the role of these chemicals in human cardiovascular disease.

  • 3.
    Klint, Helén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lejonklou, Margareta H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karimullina, Elina
    University of California, Irvine, Department of Developmental and Cell Biology, Irvine, CA 92697, USA.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    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 tissue2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 20-27Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bladin, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Pettersson, Vendela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Waldén, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring.2017In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 125, no 6, article id 067018Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bladin, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rönn, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala Univ, Publ Hlth & Caring Sci, Uppsala, Sweden.
    Lind, monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Waldén, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Adipose tissue and metabolic homeostasis in Fischer F344 rats, exposed to developmental low doses of bisphenol A, are affected in a gender specific and non-monotonic manner2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S253-S253Article in journal (Other academic)
  • 6.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karimullina, Elina
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Jacobson Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Blumberg, Bruce
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Does developmental exposure to bisphenol A induce bone and adipose tissue disturbances?2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S243-S243Article in journal (Other academic)
  • 7.
    Lind, Monica
    et al.
    Institute of Environmental Medicine, Karolinska Institutet.
    Johansson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Subclinical Hypervitaminosis A in Rat: Measurements of bone mineral density (BMD) do not reveal adverse skeletal changes2006In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 159, no 1, p. 73-80Article in journal (Refereed)
    Abstract [en]

    We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet containing 12IU Vitamin A per g pellet (control, C), or a standard diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") Vitamin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevated 4- and 20-fold. Although neither average food intake nor final body weights were significantly different between groups, a dose-dependent reduction in serum levels of Vitamin D and E, but not Vitamin K, was found. In the 50xC-group the length of the humerus was the same as in controls, but the diameter was reduced (-4.1%, p<0.05). Peripheral quantitative computed tomography (pQCT) at the diaphysis showed that bone mineral density (BMD) was unchanged and that periosteal circumference had decreased significantly (-3.7%, p<0.05). Ash weight of the humerus was not affected, but since bone volume decreased, volumetric BMD, as measured by the bone ash method, even increased (+2.5%, p<0.05). In conclusion, interference with other fat-soluble Vitamins is a possible indirect mechanism of Vitamin A action. Moreover, BMD measurements do not reveal early adverse skeletal changes induced by moderate excesses of Vitamin A in rats. Since the WHO criterium for osteoporosis is based on BMD, further studies are warranted to examine whether this is also true in humans.

  • 8.
    Ljunggren, S. A.
    et al.
    Linkoping Univ, Occupat & Environm Med Ctr, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Iggland, M.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karlsson, H.
    Linkoping Univ, Occupat & Environm Med Ctr, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A2016In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 347-349, p. 6-16Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25 mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome.

  • 9.
    Roos, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, P Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Circulating Levels of Persistent Organic Pollutants in Relation to Visceral and Subcutaneous Adipose Tissue by Abdominal MRI2013In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, no 2, p. 413-418Article in journal (Refereed)
    Abstract [en]

    We and others have shown relationships between circulating levels of persistent organic pollutants (POPs) and different measures of obesity in both cross-sectional and prospective studies. Since viscerally located fat seems to be the most harmful type, we investigated whether plasma POP levels were more closely related to visceral adipose tissue (VAT) than to subcutaneous adipose tissue (SAT). Thousand hundred and sixteen subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study; 23 POPs were analyzed using high-resolution gas chromatography/high-resolution mass spectrometry. Abdominal magnetic resonance imaging, measuring VAT and SAT, respectively, was performed in a representative subsample of 287 subjects. The less chlorinated polychlorinated biphenyl (PCB) congeners (105 and 118), and the pesticides dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB), and trans-nonachlordane (TNC) were positively related to both VAT and SAT, whereas the more highly chlorinated PCBs (153, 156, 157, 169, 170, 180, 194, 206, and 209) were inversely related to both VAT and SAT. PCB189 was related to the VAT/SAT ratio in an inverted U-shaped manner (P = 0.0008). In conclusion, the results were in accordance with our previous studies using waist circumference and fat mass as obesity measure. However, the novel finding that PCB189 was related to the VAT/SAT ratio deserves further investigation since exposure to this PCB congener, which has previously been linked to diabetes development, might thereby play a role in the distribution of abdominal adipose tissue.

  • 10.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Environmental Contaminants and Obesity2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Obesity is a worldwide problem affecting both children and adults. Genetic, physiological, environmental, psychological, social and economic factors interact in varying degrees, influencing body weight and fat distribution and the progress of obesity. Moreover, some anthropogenic chemicals have proven to be endocrine disrupting chemicals (EDCs) with the potential to interfere with different actions of hormones in the body. EDCs may thereby disrupt homeostasis, modifying developmental, behavioral and immune functions in humans and animals, and also promoting adiposity. Because hormones generally act at low concentrations, small changes in the endocrine system may lead to extensive effects. Based on data from experimental and epidemiological studies this thesis elucidates the relationship between a large number of environmental contaminants and obesity.

    The experimental studies demonstrated that fructose supplementation in the drinking water resulted in unfavorable metabolic alterations such as a higher liver somatic index (LSI), an increase in plasma triglycerides and increased plasma levels of apo A-I. Fructose in combination with exposure to bisphenol A (BPA) increased liver fat content and plasma levels of apo A-I in juvenile female Fischer 344 rats. The experimental studies also showed that the retro-peritoneal fat, which in rats is a distinct fat depot easy to distinguish and dissect, correlated well with the measurements of total fat mass analyzed with MRI, and could therefore be used as a substitute for total fat mass in rats.

    The epidemiological studies showed that circulating levels of persistent organic pollutants (POPs) were related to fat mass measured by DXA. OCDD, HCB, TNC, DDE and the less chlorinated PCBs were positively related to fat mass, while the more highly chlorinated PCBs showed a negative association. Further, circulating levels of BPA were positively associated with levels of the hormones adiponectin and leptin, but negatively related with ghrelin, hormones which are involved in the regulation of hunger and satiety. However, serum BPA levels were not related to measures of fat mass in the elderly individuals in the PIVUS cohort.

    This thesis concludes that environmental contaminants such as BPA and POPs most likely are contributors, along with genetic, social and behavioral factors, to the development of obesity.

    List of papers
    1. Quantification of total and visceral adipose tissue in fructose-fed rats using water-fat separated single echo MRI
    Open this publication in new window or tab >>Quantification of total and visceral adipose tissue in fructose-fed rats using water-fat separated single echo MRI
    Show others...
    2013 (English)In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, no 9, p. E388-E395Article in journal (Refereed) Published
    Abstract [en]

    Objective: The aim of this study was to setup a rodent model for modest weight gain and an MRI-based quantification of body composition on a clinical 1.5 T MRI system for studies of obesity and environmental factors and their possible association. Design and Methods: Twenty-four 4-week-old female Fischer rats were divided into two groups: one exposed group (n=12) and one control group (n 12). The exposed group was given drinking water containing fructose (5% for 7 weeks, then 20% for 3 weeks). The control group was given tap water. Before sacrifice, whole body MRI was performed to determine volumes of total and visceral adipose tissue and lean tissue. MRI was performed using a clinical 1.5 T system and a chemical shift based technique for separation of water and fat signal from a rapid single echo acquisition. Fat signal fraction was used to separate adipose and lean tissue. Visceral adipose tissue volume was quantified using semiautomated segmentation. After sacrifice, a perirenal fat pad and the liver were dissected and weighed. Plasma proteins were analyzed by Western blot. Results: The weight gain was 5.2% greater in rats exposed to fructose than in controls (P=0.042). Total and visceral adipose tissue volumes were 5.2 cm(3) (P=0.017) and 3.1 cm(3) (P=0.019) greater, respectively, while lean tissue volumes did not differ. The level of triglycerides and apolipoprotein A-I was higher (P=0.034, P=0.005, respectively) in fructose-exposed rats.

    National Category
    Medical Image Processing Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-209508 (URN)10.1002/oby.20229 (DOI)000325426600007 ()
    Available from: 2013-10-21 Created: 2013-10-21 Last updated: 2017-12-06Bibliographically approved
    2. Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats
    Open this publication in new window or tab >>Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats
    Show others...
    2013 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 303, no 1, p. 125-132Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Prenatal exposure to bisphenol A (BPA) has been shown to induce obesity in rodents. To evaluate if exposure also later in life could induce obesity or liver damage we investigated these hypothesises in an experimental rat model.

    METHODS:

    From five to fifteen weeks of age, female Fischer 344 rats were exposed to BPA via drinking water (0.025, 0.25 or 2.5mgBPA/L) containing 5% fructose. Two control groups were given either water or 5% fructose solution. Individual weight of the rats was determined once a week. At termination magnetic resonance imaging was used to assess adipose tissue amount and distribution, and liver fat content. After sacrifice the left perirenal fat pad and the liver were dissected and weighed. Apolipoprotein A-I in plasma was analyzed by western blot.

    RESULTS:

    No significant effects on body weight or the weight of the dissected fad pad were seen in rats exposed to BPA, and MRI showed no differences in total or visceral adipose tissue volumes between the groups. However, MRI showed that liver fat content was significantly higher in BPA-exposed rats than in fructose controls (p=0.04). BPA exposure also increased the apolipoprotein A-I levels in plasma (p<0.0001).

    CONCLUSION:

    We found no evidence that BPA exposure affects fat mass in juvenile fructose-fed rats. However, the finding that BPA in combination with fructose induced fat infiltration in the liver at dosages close to the current tolerable daily intake (TDI) might be of concern given the widespread use of this compound in our environment.

    Keywords
    MRI, Liver fat, Rat, Bisphenol A, Obesity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-185549 (URN)10.1016/j.tox.2012.09.013 (DOI)000314856800014 ()23142792 (PubMedID)
    Available from: 2012-11-08 Created: 2012-11-26 Last updated: 2017-12-07Bibliographically approved
    3. Circulating levels of persistent organic pollutants associate in divergent ways to fat mass measured by DXA in humans
    Open this publication in new window or tab >>Circulating levels of persistent organic pollutants associate in divergent ways to fat mass measured by DXA in humans
    Show others...
    2011 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 85, no 3, p. 335-343Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Environmental contaminants have recently been implicated in the pathogenesis of obesity.

    OBJECTIVE:

    To explore relations between persistent organic pollutants (POPs) and fat mass independently of body stature, using a cross-sectional design.

    METHODS:

    In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), fat mass was determined in 70-year-old subjects (n=890) by dual-energy X-ray absorptiometry (DXA). The plasma levels of 21 POPs (including 16 PCB congeners, 3 OC pesticides, 1 BDE47, and 1 dioxin) were measured by high resolution chromatography coupled with high resolution mass spectrometry (HRGC/HRMS).

    RESULTS:

    Lipid-standardized plasma concentrations of octachlorodibenzo-p-dioxin (OCDD), the PCBs 74, 99, 105 and 118, and the pesticides HCB, TNK, and DDE were all positively related to fat mass (p=0.03-0.0001). Subjects in the fifth quintile for PCB 105 showed a mean fat mass that was 4.8kg more than subjects in the first quintile. On the other hand, the PCBs 156, 157, 169, 170, 180, 189, 194, 206, and 209 were negatively related to fat mass (p=0.0001). For PCB 194, subjects in the fifth quintile showed a mean fat mass that was 10.8kg less than subjects in the first quintile. Following adjustment for smoking, physical activity, education level, height, lean mass, and gender, these results remained significant (p=0.01-0.0001) except for the PCBs 74 and 99. For some PCBs, the associations vs. fat mass were more pronounced in women than in men.

    CONCLUSION:

    Plasma concentrations of some pesticides are positively related to fat mass, while divergent associations are seen for the PCBs. These results implicate a complex role of POPs in obesity.

    Keywords
    DXA, Dioxin, Fat mass, Obesity, Persistent organic pollutants (POPs), Pesticides
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-161503 (URN)10.1016/j.chemosphere.2011.06.095 (DOI)000297661900007 ()21767864 (PubMedID)
    Available from: 2011-11-14 Created: 2011-11-14 Last updated: 2017-12-08Bibliographically approved
    4. Bisphenol A is related to circulating levels of adiponectin, leptin and ghrelin, but not to fat mass or fat distribution in humans
    Open this publication in new window or tab >>Bisphenol A is related to circulating levels of adiponectin, leptin and ghrelin, but not to fat mass or fat distribution in humans
    Show others...
    2014 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 112, p. 42-48Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: Since bisphenol A (BPA) has been shown to induce obesity in experimental studies, we explored the associations between BPA and fat mass, fat distribution and circulating levels of adiponectin, leptin and ghrelin in humans.

    METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), fat mass and fat distribution were determined in 70-year-old men and women (n=890) by dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) (n=287). Serum levels of BPA were analyzed using isotope liquid chromatography/tandem mass spectrometer (API4000LC-MS/MS). Hormone levels were analyzed with radioimmunoassays (RIA) or enzyme-linked immunosorbent assay (ELISA). Imaging was performed approximately two years following collection of other data.

    RESULTS: Serum concentrations of BPA were not related to adipose tissue measurements by DXA or MRI. BPA associated positively with adiponectin and leptin, but negatively with ghrelin, following adjustments for sex, height, fat mass, lean mass, smoking, alcohol consumption, physical activity, energy intake, and educational levels (p<0.001, p=0.009, p<0.001, respectively). The relationship between BPA and ghrelin was stronger in women than in men.

    CONCLUSION: Although no relationships between BPA levels and measures of fat mass were seen, BPA associated strongly with the adipokines adiponectin and leptin and with the gut-hormone ghrelin suggesting that BPA may interfere with hormonal control of hunger and satiety.

    Keywords
    BPA; Adiponectin; Leptin; Ghrelin; Adipose tissue
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-229030 (URN)10.1016/j.chemosphere.2014.03.042 (DOI)000340688300006 ()25048886 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Research Council Formas
    Note

    Correction in Chemosphere, 2015, vol 139, pp. 1, DOI: 10.1016/j.chemosphere.2015.05.050

    Available from: 2014-07-27 Created: 2014-07-27 Last updated: 2017-12-05Bibliographically approved
  • 11.
    Rönn, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Karlsson, Helen
    Berglund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Malmberg, Filip
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats2013In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 303, no 1, p. 125-132Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prenatal exposure to bisphenol A (BPA) has been shown to induce obesity in rodents. To evaluate if exposure also later in life could induce obesity or liver damage we investigated these hypothesises in an experimental rat model.

    METHODS:

    From five to fifteen weeks of age, female Fischer 344 rats were exposed to BPA via drinking water (0.025, 0.25 or 2.5mgBPA/L) containing 5% fructose. Two control groups were given either water or 5% fructose solution. Individual weight of the rats was determined once a week. At termination magnetic resonance imaging was used to assess adipose tissue amount and distribution, and liver fat content. After sacrifice the left perirenal fat pad and the liver were dissected and weighed. Apolipoprotein A-I in plasma was analyzed by western blot.

    RESULTS:

    No significant effects on body weight or the weight of the dissected fad pad were seen in rats exposed to BPA, and MRI showed no differences in total or visceral adipose tissue volumes between the groups. However, MRI showed that liver fat content was significantly higher in BPA-exposed rats than in fructose controls (p=0.04). BPA exposure also increased the apolipoprotein A-I levels in plasma (p<0.0001).

    CONCLUSION:

    We found no evidence that BPA exposure affects fat mass in juvenile fructose-fed rats. However, the finding that BPA in combination with fructose induced fat infiltration in the liver at dosages close to the current tolerable daily intake (TDI) might be of concern given the widespread use of this compound in our environment.

  • 12.
    Rönn, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Bavel, Bert van
    Salihovic, Samira
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Circulating levels of persistent organic pollutants associate in divergent ways to fat mass measured by DXA in humans2011In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 85, no 3, p. 335-343Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Environmental contaminants have recently been implicated in the pathogenesis of obesity.

    OBJECTIVE:

    To explore relations between persistent organic pollutants (POPs) and fat mass independently of body stature, using a cross-sectional design.

    METHODS:

    In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), fat mass was determined in 70-year-old subjects (n=890) by dual-energy X-ray absorptiometry (DXA). The plasma levels of 21 POPs (including 16 PCB congeners, 3 OC pesticides, 1 BDE47, and 1 dioxin) were measured by high resolution chromatography coupled with high resolution mass spectrometry (HRGC/HRMS).

    RESULTS:

    Lipid-standardized plasma concentrations of octachlorodibenzo-p-dioxin (OCDD), the PCBs 74, 99, 105 and 118, and the pesticides HCB, TNK, and DDE were all positively related to fat mass (p=0.03-0.0001). Subjects in the fifth quintile for PCB 105 showed a mean fat mass that was 4.8kg more than subjects in the first quintile. On the other hand, the PCBs 156, 157, 169, 170, 180, 189, 194, 206, and 209 were negatively related to fat mass (p=0.0001). For PCB 194, subjects in the fifth quintile showed a mean fat mass that was 10.8kg less than subjects in the first quintile. Following adjustment for smoking, physical activity, education level, height, lean mass, and gender, these results remained significant (p=0.01-0.0001) except for the PCBs 74 and 99. For some PCBs, the associations vs. fat mass were more pronounced in women than in men.

    CONCLUSION:

    Plasma concentrations of some pesticides are positively related to fat mass, while divergent associations are seen for the PCBs. These results implicate a complex role of POPs in obesity.

  • 13.
    Rönn, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Söderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden; Umea Univ, Ctr Heart, Umea, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bisphenol A is related to circulating levels of adiponectin, leptin and ghrelin, but not to fat mass or fat distribution in humans2014In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 112, p. 42-48Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Since bisphenol A (BPA) has been shown to induce obesity in experimental studies, we explored the associations between BPA and fat mass, fat distribution and circulating levels of adiponectin, leptin and ghrelin in humans.

    METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), fat mass and fat distribution were determined in 70-year-old men and women (n=890) by dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) (n=287). Serum levels of BPA were analyzed using isotope liquid chromatography/tandem mass spectrometer (API4000LC-MS/MS). Hormone levels were analyzed with radioimmunoassays (RIA) or enzyme-linked immunosorbent assay (ELISA). Imaging was performed approximately two years following collection of other data.

    RESULTS: Serum concentrations of BPA were not related to adipose tissue measurements by DXA or MRI. BPA associated positively with adiponectin and leptin, but negatively with ghrelin, following adjustments for sex, height, fat mass, lean mass, smoking, alcohol consumption, physical activity, energy intake, and educational levels (p<0.001, p=0.009, p<0.001, respectively). The relationship between BPA and ghrelin was stronger in women than in men.

    CONCLUSION: Although no relationships between BPA levels and measures of fat mass were seen, BPA associated strongly with the adipokines adiponectin and leptin and with the gut-hormone ghrelin suggesting that BPA may interfere with hormonal control of hunger and satiety.

  • 14.
    Rönn, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Monica P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karlsson, Helen
    Cvek, Katarina
    Berglund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Malmberg, Filip
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ortiz-Nieto, Francisco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Quantification of total and visceral adipose tissue in fructose-fed rats using water-fat separated single echo MRI2013In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, no 9, p. E388-E395Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to setup a rodent model for modest weight gain and an MRI-based quantification of body composition on a clinical 1.5 T MRI system for studies of obesity and environmental factors and their possible association. Design and Methods: Twenty-four 4-week-old female Fischer rats were di