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  • 1. Alvarez-Lloret, Pedro
    et al.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Nyberg, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Rodríguez-Navarro, Alejandro B
    Effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) on vertebral bone mineralization and on thyroxin and vitamin D levels in Sprague-Dawley rats2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 187, no 2, p. 63-68Article in journal (Refereed)
    Abstract [en]

    The aim of the present study is to use Fourier transform infrared spectrometry (FTIR), and transmission electron microscopy (TEM) techniques, to make a more detailed description of toxic effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) on bone tissue at the microstructural and at the molecular level as a result of an altered bone metabolism. We have analysed potential changes on vitamin D and thyroxin serum levels since these hormones represent endocrine endpoints that are critical for bone growth and development. For this purpose Sprague-Dawley rats were exposed (n=10) to PCB126 (i.p.) for 3 months (total dose, 384microg/kg bodyweight), while control rats (n=10) were injected with corn oil (vehicle). Results from FTIR showed that vertebrae from the exposed rats had an overall lower degree of mineralization (-8.5%; p<0.05) compared with the controls. In addition, results from peripheral quantitative computed tomography (pQCT) analyses showed significant increases in the trabecular bone mineral density (+12%; p<0.05) in the exposed group compared with the controls. The TEM analyses also showed an alteration in the crystallinity properties of vertebral bone mineral with a significant decrease in the size and crystallinity of apatite crystal forming the bone tissue in the exposed vs. non-exposed rats. Serum analysis revealed lower levels of thyroid hormones, FT4 (-42%; p<0.005), TT4 (-26%; p<0.005), and vitamin D (-21%; p<0.005) in exposed group compared to control animals. The complementary techniques (TEM and FTIR) used in this study have revealed insights into possible bone mineralization alteration due to PCB126 exposure. The lowering of both the thyroxin and vitamin D serum levels might be an underlying explanation for the observed effects on bone mineralization.

  • 2.
    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)
  • 3.
    Ax, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Lampa, Erik
    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.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    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 environmental contaminants are associated with dietary patterns in older adults2015In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 75, p. 93-102Article in journal (Refereed)
    Abstract [en]

    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.

  • 4. Bergman, Ake
    et al.
    Andersson, Anna-Maria
    Becher, Georg
    van den Berg, Martin
    Blumberg, Bruce
    Bjerregaard, Poul
    Bornehag, Carl-Gustaf
    Bornman, Riana
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Brian, Jayne V.
    Casey, Stephanie C.
    Fowler, Paul A.
    Frouin, Heloise
    Giudice, Linda C.
    Iguchi, Taisen
    Hass, Ulla
    Jobling, Susan
    Juul, Anders
    Kidd, Karen A.
    Kortenkamp, Andreas
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Martin, Olwenn V.
    Muir, Derek
    Ochieng, Roseline
    Olea, Nicolas
    Norrgren, Leif
    Ropstad, Erik
    Ross, Peter S.
    Ruden, Christina
    Scheringer, Martin
    Skakkebaek, Niels Erik
    Soder, Olle
    Sonnenschein, Carlos
    Soto, Ana
    Swan, Shanna
    Toppari, Jorma
    Tyler, Charles R.
    Vandenberg, Laura N.
    Vinggaard, Anne Marie
    Wiberg, Karin
    Zoeller, R. Thomas
    Science and policy on endocrine disrupters must not be mixed: a reply to a "common sense" intervention by toxicology journal editors2013In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 12, p. 69-Article in journal (Other academic)
    Abstract [en]

    The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU.

  • 5.
    Bergman, Åke
    et al.
    Swedish Toxicol Sci Res Ctr Swetox, Sodertalje, Sweden..
    Becher, Georg
    Norwegian Inst Publ Hlth, Oslo, Norway..
    Blumberg, Bruce
    Univ Calif Irvine, Irvine, CA USA..
    Bjerregaard, Poul
    Univ Southern Denmark, Odense, Denmark..
    Bornman, Riana
    Univ Pretoria, Sch Hlth Syst & Publ Hlth, ZA-0002 Pretoria, South Africa..
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Casey, Stephanie C.
    Univ Calif Irvine, Irvine, CA USA..
    Frouin, Heloise
    Vancouver Aquarium Marine Sci Ctr, Vancouver, BC, Canada..
    Giudice, Linda C.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Heindel, Jerrold J.
    Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA..
    Iguchi, Taisen
    Natl Inst Basic Biol, Okazaki, Aichi 444, Japan..
    Jobling, Susan
    Brunel Univ London, Uxbridge, Middx, England..
    Kidd, Karen A.
    Univ New Brunswick, New Brunswick, NJ USA..
    Kortenkamp, Andreas
    Brunel Univ London, Uxbridge, Middx, England..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Muir, Derek
    Environm Canada, Burlington, ON L7R 4A6, Canada..
    Ochieng, Roseline
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Ropstad, Erik
    Norwegian Univ Life Sci, Oslo, Norway..
    Ross, Peter S.
    Vancouver Aquarium Marine Sci Ctr, Vancouver, BC, Canada..
    Skakkebaek, Niels Erik
    Univ Copenhagen, Copenhagen Univ Hosp, Copenhagen, Denmark..
    Toppari, Jorma
    Univ Turku, Turku, Finland..
    Vandenberg, Laura N.
    Univ Massachusetts, Amherst, MA 01003 USA..
    Woodruff, Tracey J.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Zoeller, R. Thomas
    Univ Massachusetts, Amherst, MA 01003 USA..
    Manufacturing doubt about endocrine disrupter science - A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012"2015In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 73, no 3, p. 1007-1017Article in journal (Other academic)
    Abstract [en]

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.

  • 6.
    Bjermo, Helena
    et al.
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Aune, Marie
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Cantillana, Tatiana
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Glynn, Anders
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Darnerud, Per Ola
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Serum levels of brominated flame retardants (BFRs: PBDE, HBCD) and influence of dietary factors in a population-based study on Swedish adults2017In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 167, p. 485-491Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate associations between serum concentrations of brominated flame retardants and personal characteristics, including diet, in adults participating in a population-based study in Sweden 2010-11. Moreover, observed concentrations were used in a health risk assessment, using published health-based reference values. Serum samples of 170 adult individuals of both sexes were analyzed for 10 PBDE congeners and HBCD by GC-MS. When including concentrations between LOD and LOQ, highest median serum concentration was observed for BDE-153 (1.2 ng/g serum lipid), followed by BDE-209 (0.95 ng/g lipid), BDE-47 (0.49 ng/g lipid) and BDE-100 (0.21 ng/g lipid). Median concentration of HBCD was 0.10 ng/g lipid. A few markedly elevated concentrations of BDE-209, HBCD (77-78 ng/g lipid) and BDE-47 (44 ng/g lipid) were observed. The only statistical significant findings were higher BDE-153 concentrations in men than in women, and positive associations between serum BDE-153 concentrations and consumption of fish (total), beef, mutton and poultry. PBDE concentrations were in accordance with concentrations reported in other European countries but generally lower than those found in North America. Median PBDE serum concentrations observed in adults from Sweden suggest sufficient health protection, when compared with published health-based reference values, although some outliers with high serum concentrations had lower safety margins.

  • 7.
    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.

  • 8. Cedervall, Therese
    et al.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Savendahl, Lars
    Expression of the Aryl Hydrocarbon Receptor in Growth Plate Cartilage and the Impact of Its Local Modulation on Longitudinal Bone Growth2015In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, no 4, p. 8059-8069Article in journal (Refereed)
    Abstract [en]

    Although dioxin has been reported to impair bone growth in both humans and animals, the underlying mechanisms have not been clarified. We conducted this study to rule out if dioxin may directly target the growth plate, via local modulation of the aryl hydrocarbon receptor (AhR). Initial studies in rare tissue samples of the human growth plate confirmed that the AhR protein is widely expressed in growth plate cartilage. To explore the local role of the AhR, mechanistic studies were performed in a well-established model of cultured fetal rat metatarsal bones. The longitudinal growth of these bones was monitored while being exposed to AhR modulators. The AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin, did not affect bone growth at any concentrations tested (1 pM-10 nM). In contrast, the AhR antagonist, alpha-naphthoflavone, suppressed bone growth and increased chondrocyte apoptosis, although only at a high, potentially cytotoxic concentration (50 mu M). We conclude that although the AhR is widely expressed in the growth plate, bone growth is not modulated when locally activated, and therefore, dioxin-induced growth failure is likely mediated through systemic rather than local actions.

  • 9. Evans, N. P.
    et al.
    Bellingham, M.
    Sharpe, R. M.
    Cotinot, C.
    Rhind, S. M.
    Kyle, C.
    Erhard, H.
    Hombach-Klonisch, S.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Fowler, P. A.
    Does grazing on biosolids-treated pasture pose a pathophysiological risk associated with increased exposure to endocrine disrupting compounds?2014In: Journal of Animal Science, ISSN 0021-8812, E-ISSN 1525-3163, Vol. 92, no 8, p. 3185-3198Article in journal (Refereed)
    Abstract [en]

    Biosolids (processed human sewage sludge), which contain low individual concentrations of an array of contaminants including heavy metals and organic pollutants such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB), and polychlorinated dibenzodioxins/polychlorinated dibenzofurans known to cause physiological disturbances, are increasingly being used as an agricultural fertilizer. This could pose a health threat to both humans and domestic and wild animal species. This review summarizes results of a unique model, used to determine the effects of exposure to mixtures of environmentally relevant concentrations of pollutants, in sheep grazed on biosolids-treated pastures. Pasture treatment results in nonsignificant increases in environmental chemical (EC) concentrations in soil. Whereas EC concentrations were increased in some tissues of both ewes and their fetuses, concentrations were low and variable and deemed to pose little risk to consumer health. Investigation of the effects of gestational EC exposure on fetal development has highlighted a number of issues. The results indicate that gestational EC exposure can adversely affect gonadal development (males and females) and that these effects can impact testicular morphology, ovarian follicle numbers and health, and the transcriptome and proteome in adult animals. In addition, EC exposure can be associated with altered expression of GnRH, GnRH receptors, galanin receptors, and kisspeptin mRNA within the hypothalamus and pituitary gland, gonadotroph populations within the pituitary gland, and regional aberrations in thyroid morphology. In most cases, these anatomical and functional differences do not result in altered peripheral hormone concentrations or reproductive function (e.g., lambing rate), indicating physiological compensation under the conditions tested. Physiological compensation is also suggested from studies that indicate that EC effects may be greater when exposure occurs either before or during gestation compared with EC exposure throughout life. With regard to human and animal health, this body of work questions the concept of safe individual concentration of EC when EC exposure typically occurs as complex mixtures. It suggests that developmental EC exposure may affect many different physiological systems, with some sex-specific differences in EC sensitivity, and that EC effects may be masked under favorable physiological conditions.

  • 10. Fletcher, Nick
    et al.
    Giese, Norbert
    Schmidt, Carsten
    Stern, Natalia
    Lind, Monica
    Institute of Environmental Medicine, Karolinska Institutet.
    Viluksela, Matti
    Tuomisto, Jouni T
    Tuomisto, Jouko
    Nau, Heinz
    Håkansson, Helen
    Altered retinoid metabolism in female Long-Evans and Han/Wistar rats following long-term 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treatment2005In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 86, no 2, p. 264-272Article in journal (Refereed)
    Abstract [en]

    This study investigated the effects of long-term low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on retinoid, thyroid hormone, and vitamin D homeostasis in Long-Evans and Han/Wistar rats using a tumor promotion exposure protocol. Female rats (ten/group) were partially hepatectomized, initiated with nitrosodiethylamine (NDEA), and given TCDD once per week by sc injection for 20 weeks at calculated daily doses of 0, 1, 10, 100, or 1000 ng/kg bw/day. Groups of nonhepatectomized/uninitiated rats (five/group) were identically maintained. After 20 weeks, the rats were killed, and apolar retinoid levels were determined in the liver and kidneys. No consistent differences were seen between partially hepatectomized/initiated and nonhepatectomized/uninitiated animals with respect to apolar retinoid levels or hepatic TCDD concentration. Further analyses of polar and apolar retinoid levels in liver, plasma, and kidney, as well as free thyroxine (FT4) and vitamin D (25-OH-D(3)) concentrations were carried out in partially hepatectomized/inititated animals. In Long-Evans rats, TCDD exposure dose-dependently decreased hepatic retinyl ester concentrations at doses of 1-100 ng/kg bw/day. Likewise, hepatic all-trans-retinoic acid (all-trans-RA) concentration was decreased 39 and 54% at 10 and 100 ng/kg bw/day respectively, whereas 9-cis-4-oxo-13,14-dihydro-retinoic acid (9-cis-4-oxo-13,14-dihydro-RA), a recently discovered retinoic acid metabolite, was decreased approximately 60% in the liver at 1 ng/kg bw/day. TCDD dose-dependently increased plasma retinol and kidney retinol concentrations, whereas all-trans-RA concentration was also increased in the plasma and kidney at 10 and 100 ng/kg bw/day. Plasma 9-cis-4-oxo-13,14-dihydro-RA was decreased to below detection limits from doses of 1 ng/kg bw/day TCDD. A qualitatively similar pattern of retinoid disruption was observed in the Han/Wistar rat strain following TCDD exposure. FT4 was decreased to a similar extent in both strains, whereas 25-OH-D(3) was decreased only at 100 ng/kg bw/day in Long-Evans rats. Together these results show that TCDD disrupts both retinoid storage and metabolism of retinoic acid and retinoic acid metabolites in liver, kidney, and plasma from doses as low as 1 ng/kg bw/day. Furthermore, 9-cis-4-oxo-13,14-dihydro-RA was identified as a novel and sensitive indicator of TCDD exposure, in a resistant and sensitive rat strain, thereby extending the database of low-dose TCDD effects.

  • 11.
    Fox, Glen A
    et al.
    Canadian Wildlife Service, National Wildlife Research Centre, Carleton University, Ottawa, Ontario, Canada.
    Lundberg, Rebecca
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Wejheden, Carolina
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Lind, Monica
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Health of herring gulls (Larus argentatus) in relation to breeding location in the early 1990s: III. Effects on the bone tissue2008In: Journal of Toxicology and Environmental Health, ISSN 1528-7394, E-ISSN 1087-2620, Vol. 71, no 21, p. 1448-1456Article in journal (Refereed)
    Abstract [en]

    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.

  • 12. Glynn, A. Wicklund
    et al.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology.
    Wolk, Alicja
    Aune, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Atuma, S.
    Darnerud, P.O.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Organochlorines and bone mineral density in Swedish men from the general population2000In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 11, no 12, p. 1036-1042Article in journal (Refereed)
    Abstract [en]

    Persistent organochlorines (POCs), such as polychlorinated biphenyls (PCBs) and DDT, are present at relatively high concentrations in food and show estrogenic, anti-estrogenic or anti-androgenic activity in biological test systems. Because bone mineral density (BMD) in men is influenced by sex hormones, we looked for associations between BMD and serum concentrations of POCs in 115 men (mean age 63 years, range 40-75 years) from the general Swedish population. Ten PCB congeners, five DDT isomers, hexachlorobenzene, three hexachlorocyclohexane isomers, trans-nonachlor and oxychlordane were analyzed by gas chromatography. Quantitative bone measurements were performed by dual-energy X-ray absorptiometry at three sites: whole body, the L2-L4 region of the lumbar spine, and the neck region of the proximal femur, as well as by quantitative ultrasound on the left os calcis (broadband ultrasound attenuation (BUA) and speed of sound (SOS)). After adjustment for confounding factors in linear regression analyses we found no strong association between serum concentrations of single POCs and the five BMD and ultrasound variables. When POCs were grouped according to hormonal activity (estrogenic, anti-estrogenic, anti-androgenic) and the study subjects were divided into organochlorine concentration quartiles, a weak association was indicated between increased serum concentrations of p,p'-DDE (antiandrogenic) and decreased BMD, BUA and SOS. This may suggest that p,p'-DDE could cause negative effects on bone density, but the findings might also be due to chance since multiple comparisons were made in the statistical analysis. Overall our results do not suggest that the studied POCs caused major effects on bone density in our study group.

  • 13. Gutleb, Arno C.
    et al.
    Arvidsson, Dan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Skaare, Janneche Utne
    Aleksandersen, Mona
    Ropstad, Erik
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Effects on bone tissue in ewes (Ovies aries) and their foetuses exposed to PCB 118 and PCB 1532010In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 192, no 2, p. 126-133Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to investigate whether low levels of mono-ortho PCB 118 and di-ortho PCB 153, affect bone composition and strength in ewes (Dala breed) and their foetuses following exposure starting at conception and ending a week before expected delivery. In male foetuses, trabecular bone mineral content at the metaphysis was almost 30% lower in the PCB 118 (49mug/kg body wt/day) group compared to the control group (corn oil) (ANCOVA, P<0.05). In female foetuses of the PCB 153 (98mug/kg body wt/day) group trabecular cross-sectional area at the metaphysis was 19% smaller than in the controls (ANCOVA, P<0.05). At the diaphysis a smaller marrow cavity area (up to 24% reduction) was observed in female and male foetuses exposed to PCB 153 compared with controls (ANCOVA, P<0.05). There were also significant differences at the mid diaphyseal measure point between the PCB 153 and the control group females (ANCOVA, P<0.05). Cortical and total bone mineral density, cortical thickness were significantly higher, endosteal circumference shorter and marrow cavity significantly smaller in the PCB 153 group (ANCOVA, P<0.05). In conclusion there were gender dependent effects on bone tissue and cortical bone was more affected than trabecular bone.

  • 14. Herlin, Maria
    et al.
    Kalantari, Fereshteh
    Stern, Natalia
    Sand, Salomon
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Viluksela, Matti
    Tuomisto, Jouni T.
    Tuomisto, Jouko
    Tuukkanen, Juha
    Jämsä, Timo
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Håkansson, Helen
    Quantitative characterization of changes in bone geometry, mineral density and biomechanical properties in two rat strains with different Ah-receptor structures after long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin2010In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 273, no 1-3, p. 1-11Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Both industrial chemicals and environmental pollutants can interfere with bone modeling and remodeling. Recently, detailed toxicological bone studies have been performed following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which exerts most of its toxic effects through the aryl hydrocarbon receptor (AhR). OBJECTIVES: The aims of the present study were to quantitatively evaluate changes in bone geometry, mineral density and biomechanical properties following long-term exposure to TCDD, and to further investigate the role of AhR in TCDD-induced bone alterations. To this end, tissue material used in the study was derived from TCDD-exposed Long-Evans (L-E) and Han/Wistar (H/W) rats, which differ markedly in sensitivity to TCDD-induced toxicity due to a strain difference in AhR structure. METHODS: Ten weeks old female L-E and H/W rats were administered TCDD s.c. once per week for 20 weeks, at doses corresponding to calculated daily doses of 0, 1, 10, 100 and 1000ngTCDD/kgbw (H/W only). Femur, tibia and vertebra from the L-E and H/W rats were analyzed by peripheral quantitative computed tomography (pQCT) and biomechanical testing at multiple sites. Dose-response modeling was performed to establish benchmark doses for the analyzed bone parameters, and to quantify strain sensitivity differences for those parameters, which were affected by TCDD exposure in both rat strains. RESULTS: Bone geometry and bone biomechanical parameters were affected by TCDD exposure, while bone mineral density parameters were less affected. The trabecular area at proximal tibia and the endocortical circumference at tibial diaphysis were the parameters that showed the highest maximal responses. Significant strain differences in response to TCDD treatment were observed, with the L-E rat being the most sensitive strain. For the parameters that were affected in both strains, the differences in sensitivity were quantified, showing the most pronounced (about 49-fold) strain difference for cross-sectional area of proximal tibia. CONCLUSION: The study provides novel information about TCDD-induced bone alterations at doses, which are of relevance from a health risk assessment point of view. In addition, the obtained results provide further support for a distinct role of the AhR in TCDD-induced bone alterations, and suggest that the benchmark dose modeling approach is appropriate for quantitative evaluation of bone toxicity parameters.

  • 15. Hermsen, Sanne A. B.
    et al.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Arima, Akihiro
    Muneoka, Atsunobu
    Ihara, Toshio
    Sumida, Hiroshi
    Fukusato, Toshio
    Kubota, Shunichiro
    Yasuda, Mineo
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects bone tissue in rhesus monkeys2008In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 253, no 1-3, p. 147-152Article in journal (Refereed)
    Abstract [en]

    Bone tissue is one of the target tissues for dioxins and dioxin-like compounds. Therefore, the aim of this study was to investigate effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), oil bone tissue in rhesus monkey, the most human-like experimental model available, Pregnant rhesus monkeys (Macaca mulatta; age 4-10 years) were exposed to TCDD with a total dose of 40.5-42.0 or 405-420 ng/kg bodyweight by repeated subcutaneous injections starting at gestational day 20 and followed by injections every 30 days until 90 clays after delivery. At a mean age of 7 years the offspring were sacrificed and the femur bone dissected. Results from peripheral Quantitative Computed Tomography (pQCT) analyses of the metaphyseal part of the femur bones in female offspring showed significant increases in trabecular bone mineral content (BMC; +84.6%, p < 0.05, F-value (F)=5.9) in the low-dose treatment group compared with the controls. In the same animals, analysis of the mid-diaphyseal part revealed increases in total BMC (+21.3%. p < 0.05, F = 5.2) and cortical cross-sectional area (CSA; +16.4%. p < 0.01, F=7.4) compared with the controls. In males, changes in biomechanical properties indicating more fragile bone were observed. Displacement at failure were significantly increased in the male low-dose group compared to the controls (+38.0%, p, < 0.05, F=11). The high dose of TCDD did not induce any significant changes in bone morphology.

  • 16. Hodgson, Susan
    et al.
    Thomas, Laura
    Fattore, Elena
    Lind, Monica
    Institute of Environmental Medicine, Karolinska Institutet.
    Alfven, Tobias
    Hellström, Lennart
    Håkansson, Helen
    Carubelli, Grazia
    Fanelli, Roberto
    Jarup, Lars
    Bone mineral density changes in relation to environmental PCB exposure2008In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 116, no 9, p. 1162-1166Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bone toxicity has been linked to organochlorine exposure following a few notable poisoning incidents, but epidemiologic studies in populations with environmental organochlorine exposure have yielded inconsistent results.

    OBJECTIVES: The aim of this study was to investigate whether organochlorine exposure was associated with bone mineral density (BMD) in a population 60-81 years of age (154 males, 167 females) living near the Baltic coast, close to a river contaminated by polychlorinated biphenyls (PCBs).

    METHODS: We measured forearm BMD in participants using dual energy X-ray absorptiometry; and we assessed low BMD using age- and sex-standardized Z-scores. We analyzed blood samples for five dioxin-like PCBs, the three most abundant non-dioxin-like PCBs, and p,p'-dichloro-phenyldichloroethylene (p,p'-DDE).

    RESULTS: In males, dioxin-like chlorobiphenyl (CB)-118 was negatively associated with BMD; the odds ratio for low BMD (Z-score less than -1) was 1.06 (95% confidence interval, 1.01-1.12) per 10 pg/mL CB-118. The sum of the three most abundant non-dioxin-like PCBs was positively associated with BMD, but not with a decreased risk of low BMD. In females, CB-118 was positively associated with BMD, but this congener did not influence the risk of low BMD in women.

    CONCLUSIONS: Environmental organochlorine exposures experienced by this population sample since the 1930s in Sweden may have been sufficient to result in sex-specific changes in BMD.

  • 17. Hong, N-S
    et al.
    Kim, K-S
    Lee, I-K
    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.
    Jacobs, D R
    Lee, D-H
    The association between obesity and mortality in the elderly differs by serum concentrations of persistent organic pollutants: a possible explanation for the obesity paradox2011In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 36, no 9, p. 1170-1175Article in journal (Refereed)
    Abstract [en]

    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.

  • 18.
    Johansson, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology.
    Håkansson, Helen
    Oxlund, Hans
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology.
    Subclinical hypervitaminosis A causes fragile bones in rats2002In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 31, no 6, p. 685-689Article in journal (Refereed)
    Abstract [en]

    Excessive intake of vitamin A has been associated with an increased risk of hip fracture in humans. This finding has raised the question of whether long-term intake of relatively moderate doses ("subclinical" hypervitaminosis A) contributes to fracture risk. Although it has been known for more than half a century that toxic doses of vitamin A lead to spontaneous fractures in rats, the lowest intake that induces adverse effects is not known, and the result of exposure to excessive doses that do not cause general toxicity has been rarely investigated. In this study, mature female rats were fed a standard diet with 12 IU vitamin A/g pellet (control, C), or standard diet supplemented with either 120 IU ("10 x C") or 600 IU ("50 x C") vitamin A/g pellet for 12 weeks. Fifteen animals were included in each group. The supplemented diets correspond to a vitamin A intake of approximately 1800 IU/day and 9000 IU/day, respectively. The latter dose is about one third of that previously reported to cause skeletal lesions. At the end of the study, serum retinyl esters were elevated 4- (p < 0.01) and 20-fold (p < 0.001) and the total amount of liver retinoid had increased 3- (p < 0.001) and 7-fold (p < 0.001) in the 10 x C and 50 x C group, respectively. The animals showed no clinical signs of general toxicity, and there were no significant bone changes in the 10 x C group. However, in the 50 x C group, a characteristic thinning of the cortex (cortical area -6.5% [p < 0.001]) and reduction of the diameter of the long bones were evident (bone cross-sectional area -7.2% [p < 0.01] at the midshaft and -11.0% [p < 0.01] at the metaphysis), as measured by peripheral quantitative computed tomography. In agreement with these data and a decreased polar strength strain index (-14.0%, p < 0.01), the three-point bending breaking force of the femur was reduced by 10.3% (p < 0.01) in the 50 x C group. These data indicate that the negative skeletal effects appear at a subchronic vitamin A intake of somewhere between 10 and 50 times the standard diet. This level is considerably lower than previously reported. Our results suggest that long-term ingestion of modest excesses of vitamin A may contribute to fracture risk.

  • 19.
    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.

  • 20.
    Kumar, Jitender
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample of men and women2014In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 134, no SI, p. 251-256Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Persistent organic pollutants (POPs) are stable organic compounds generated through different industrial activities. Liver is involved in the metabolism of POPs, and hence exposure to POPs may interfere with liver function. Although a few studies have shown adverse effects of POPs on liver function, large-scale studies involving humans are lacking. We performed this large population-based cross-sectional study to assess the associations between different POPs and liver dysfunction biomarkers.

    METHODS: A total of 992 individuals (all aged 70 years, 50% males) were recruited as part of Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. The total toxic equivalency (TEQ) value was calculated for seven mono-ortho and two non-ortho substituted polychlorinated biphenyls (PCBs) and octachloro-p-dibenzodioxin (OCDD) to assess their toxicological effects. The association of TEQ values, summary measures of 16 PCBs (sum of PCBs) and three organochlorine pesticides (sum of OC pesticides) with liver dysfunction biomarkers (bilirubin; alkaline phosphatase, ALP; alanine aminotransferase, ALT; and gamma-glutamyltransferase, GGT) was analyzed utilizing linear regression analysis.

    RESULTS: The mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=0.71, P=0.008), while sum of OC pesticide concentrations was negatively associated with ALP (β=-0.02, P=0.002) after adjusting for various potential confounders. When analyzed individually, a number of different POPs were associated with ALP, ALT and bilirubin. No such association with GGT was observed.

    CONCLUSION: Various POPs including PCBs, OCDD and pesticides were associated with the liver dysfunction biomarkers bilirubin, ALT and ALP, suggesting adverse effects on liver function from these environmental pollutants.

  • 21.
    Kumar, Jitender
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Monica P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Influence of persistent organic pollutants on oxidative stress in population-based samples2014In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 114, p. 303-309Article in journal (Refereed)
    Abstract [en]

    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.

  • 22.
    Kumar, Jitender
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    van Bavel, Bert
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Persistent Organic Pollutants and Inflammatory Markers in a Cross-Sectional Study of Elderly Swedish People: The PIVUS Cohort2014In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 122, no 9, p. 977-983Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Persistent organic pollutants (POPs) are compounds that are generated through various industrial activities and released in the surrounding environment. Different animal studies have shown effects of different POPs on various inflammatory markers. OBJECTIVE: Because very few studies have been conducted in humans, we assessed the associations between different POPs and inflammatory markers in a large population-based sample of elderly men and women (all 70 years of age) from Sweden. METHODS: This cross-sectional study investigated the concentrations of several polychlorinated biphenyls (PCBs), organochlorine pesticides, polychlorinated dibenzo-p-dioxin, and brominated diphenyl ether congeners and their association with a number of inflammatory markers [vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, C-reactive protein (CRP), total leucocyte count, tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1), and interleukin 6 (IL-6)] in 992 individuals. These individuals were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. We used a total toxic equivalency (TEQ) value that measures toxicological effects with the relative potencies of various POPs. RESULTS: Following adjustment for potential confounders, the TEQ value (driven mainly by PCB-126) was significantly associated with levels of ICAM-1 (p < 10(-5)). A similar trend was also observed between sum of PCBs and VCAM-1 (p < 0.001). No significant associations were observed between levels of POPs and other inflammatory markers. CONCLUSIONS: TEQ values were associated with levels of ICAM-1, to a lesser degree also with VCAM-1, but not with CRP and several other inflammatory markers. These findings suggest an activation of vascular adhesion molecules by POPs, and particularly by PCB-126.

  • 23.
    Kumar, Jitender
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Influence of persistent organic pollutants on the complement system in a population-based human sample2014In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 71, p. 94-100Article in journal (Refereed)
    Abstract [en]

    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.

  • 24.
    La Merrill, M A
    et al.
    Department of Environmental Toxicology, University of California, Davis, CA, USA.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden, and Norwegian Institute for Water Research, NIVA, Oslo, Norway.
    van Bavel, B
    MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden, and Norwegian Institute for Water Research, NIVA, Oslo, Norway.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    The association between p,p'-DDE levels and left ventricular mass is mainly mediated by obesity2018In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 160, p. 541-546, article id S0013-9351(17)31176-3Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: The pesticide metabolite p,p'-DDE has been associated with left ventricular (LV) mass and known risk factors for LV hypertrophy in humans and in experimental models. We hypothesized that the associations of p,p'-DDE with LV hypertrophy risk factors, namely elevated glucose, adiposity and hypertension, mediate the association of p,p'-DDE with LV mass.

    METHODS: p,p'-DDE was measured in plasma from 70-year-old subjects (n = 988) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). When these subjects were 70-, 75- and 80- years old, LV characteristics were measured by echocardiography, while fasting glucose, body mass index (BMI) and blood pressure were assessed with standard clinical techniques.

    RESULTS: We found that p,p'-DDE levels were associated with increased fasting glucose, BMI, hypertension and LV mass in separate models adjusted for sex. Structural equation modeling revealed that the association between p,p'-DDE and LV mass was almost entirely mediated by BMI (70%), and also by hypertension (19%).

    CONCLUSION: The obesogenic effect of p,p'-DDE is a major determinant responsible for the association of p,p'-DDE with LV mass.

  • 25.
    Lampa, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bornefalk-Hermansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    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.
    Mixture Effects of Multiple Environmental Contaminants on the Metabolic Syndrome in a Human Population-based SampleManuscript (preprint) (Other academic)
  • 26.
    Lampa, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bornefalk-Hermansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, P. 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.
    Atherosclerosis in Humans and the Association to Environmental Contaminant MixturesManuscript (preprint) (Other academic)
  • 27.
    Lampa, Erik
    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.
    Bornefalk Hermansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Salihovic, Samira
    van Bavel, Bert
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    An investigation of the co-variation in circulating levels of a large number of environmental contaminants2012In: Journal of Exposure Science and Environmental Epidemiology, ISSN 1559-0631, E-ISSN 1559-064X, Vol. 22, no 5, p. 476-482Article in journal (Refereed)
    Abstract [en]

    We are daily exposed to many different environmental contaminants. Mixtures of these contaminants could act together to induce more pronounced effects than the sum of the individual contaminants. To evaluate the effects of such mixtures, it is of importance to assess the co-variance amongst the contaminants. Thirty-seven environmental contaminants representing different classes were measured in blood samples from 1016 individuals aged 70 years. Hierarchical cluster analysis and principal component analysis were used to assess the co-variation among the contaminants. Within each identified cluster, possible marker contaminants were sought for. We validated our findings using data from the National Health and Nutrition Examination Survey (NHANES) 2003--2004 study. Two large clusters could be identified, one representing low/medium chlorinated polychlorinated biphenyls (PCBs) (<= 6 chlorine atoms), as well as two pesticides and one representing medium/high chlorinated PCBs (>= 6 chlorine atoms). PCBs 118 and 153 could be used as markers for the low/medium chlorinated cluster and PCBs 170 and 209 could be used as markers for the medium/high chlorinated cluster. This pattern was similar to data from the NHANES study. Apart from the PCBs, little co-variation was seen among the contaminants. Thus, a large number of chemicals have to be measured to adequately identify mixtures of environmental contaminants.

  • 28.
    Lampa, Erik
    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.
    Lind, Monica P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bornefalk-Hermansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    The identification of complex interactions in epidemiology and toxicology: a simulation study of Boosted Regression Trees2014In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 13, p. 57-Article in journal (Refereed)
    Abstract [en]

    Background: There is a need to evaluate complex interaction effects on human health, such as those induced by mixtures of environmental contaminants. The usual approach is to formulate an additive statistical model and check for departures using product terms between the variables of interest. In this paper, we present an approach to search for interaction effects among several variables using boosted regression trees. Methods: We simulate a continuous outcome from real data on 27 environmental contaminants, some of which are correlated, and test the method's ability to uncover the simulated interactions. The simulated outcome contains one four-way interaction, one non-linear effect and one interaction between a continuous variable and a binary variable. Four scenarios reflecting different strengths of association are simulated. We illustrate the method using real data. Results: The method succeeded in identifying the true interactions in all scenarios except where the association was weakest. Some spurious interactions were also found, however. The method was also capable to identify interactions in the real data set. Conclusions: We conclude that boosted regression trees can be used to uncover complex interaction effects in epidemiological studies.

  • 29. Lee, Duk-Hee
    et al.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Jacobs, David R., Jr.
    Salihovic, Samira
    van Bavel, Bert
    Lind, Monica P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Does Mortality Risk of Cigarette Smoking Depend on Serum Concentrations of Persistent Organic Pollutants?: Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e95937-Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is an important cause of preventable death globally, but associations between smoking and mortality vary substantially across country and calendar time. Although methodological biases have been discussed, it is biologically plausible that persistent organic pollutants (POPs) like polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides can affect this association. This study was performed to evaluate if associations of cigarette smoking with mortality were modified by serum concentrations of PCBs and OC pesticides. We evaluated cigarette smoking in 111 total deaths among 986 men and women aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) with mean follow-up for 7.7 years. The association between cigarette smoking and total mortality depended on serum concentration of PCBs and OC pesticides (P value for interaction = 0.02). Among participants in the highest tertile of the serum POPs summary score, former and current smokers had 3.7 (95% CI, 1.5-9.3) and 6.4 (95% CI, 2.3-17.7) times higher mortality hazard, respectively, than never smokers. In contrast, the association between cigarette smoking and total mortality among participants in the lowest tertile of the serum POPs summary score was much weaker and statistically nonsignificant. The strong smoking-mortality association observed among elderly people with high POPs was mainly driven by low risk of mortality among never smokers with high POPs. As smoking is increasing in many low-income and middle-income countries and POPs contamination is a continuing problem in these areas, the interactions between these two important health-related issues should be considered in future research.

  • 30. Lee, Duk-Hee
    et al.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jacobs, David R
    Salihovic, Samira
    van Bavel, Bert
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Associations of persistent organic pollutants with abdominal obesity in the elderly: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study2012In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 40, p. 170-178Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: In animal experiments, persistent organic pollutants (POPs) have induced visceral obesity. To address this possibility in humans, we evaluated associations between POPs and abdominal obesity both cross-sectionally and prospectively.

    METHODS: Twenty-one plasma POPs (16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured at baseline in 970 participants aged 70years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), with prospective analyses in 511 participants re-examined after 5years. Abdominal obesity was defined by an increased waist circumference.

    RESULTS: In the cross-sectional analyses, concentrations of the less chlorinated PCBs, OC pesticides such as p,p'-DDE and dioxin had adjusted odds ratios of 2 to 3 for abdominal obesity. Many relations had inverted U-shapes rather than being linear, particularly in women. In contrast, concentrations of highly chlorinated PCBs were strongly inversely associated with abdominal obesity. In a single model including summary measures of the less chlorinated PCBs, highly chlorinated PCBs, and OC pesticides, both the positive associations and inverse associations strengthened. Similar but somewhat weaker associations were seen between POPs and risk of development of abdominal obesity in the prospective analyses.

    CONCLUSION: Using both a cross-sectional and a prospective design, low-dose exposure to less chlorinated PCBs, p,p'-DDE, and dioxin, were associated with existence or development of abdominal obesity, while highly chlorinated PCBs had an opposite association in an elderly population, despite the previous observation of higher incident diabetes associated with these same PCBs.

  • 31. Lee, Duk-Hee
    et al.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Jacobs, David R
    Salihovic, Samira
    van Bavel, Bert
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Polychlorinated biphenyls and organochlorine pesticides in plasma predict development of type 2 diabetes in the elderly: the prospective investigation of the vasculature in Uppsala Seniors (PIVUS) study2011In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 34, no 8, p. 1778-1784Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Persistent organic pollutants (POPs), lipophilic chemicals that accumulate mainly in adipose tissue, have recently been linked to type 2 diabetes. However, evidence from prospective studies is sparse. This study was performed to evaluate prospective associations of type 2 diabetes with selected POPs among the elderly.

    RESEARCH DESIGN AND METHODS: Nineteen POPs (14 polychlorinated biphenyl [PCB] congeners, 3 organochlorine pesticides, 1 brominated diphenyl ether, and 1 dioxin) were measured in plasma collected at baseline in 725 participants, aged 70 years, of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).

    RESULTS: After adjusting for known type 2 diabetes risk factors, including obesity, odds ratios (ORs) (95% CIs) for type 2 diabetes at age 75 years (n = 36) according to the quintiles of a summary measure of concentrations of PCBs (vs. the lowest quintile) were 4.5, 5.1, 8.8 (1.8-42.7), and 7.5 (1.4-38.8) (P(trend) <0.01). Among organochlorine pesticides, adjusted ORs across concentrations of trans-nonachlor showed that P(trend) = 0.03. Adjusted ORs (95% CIs) across quintiles of the sum of three organochlorine pesticides were 1.1, 1.6, 1.5, and 3.4 (1.0-11.7) (P(trend) = 0.03). Neither brominated diphenyl ether 47 nor dioxin was significantly associated with incident diabetes. The sum of PCBs improved reclassification significantly when added to traditional risk factors for diabetes.

    CONCLUSIONS: Despite the small number of incident cases, this study found that environmental exposure to some POPs substantially increased risk of future type 2 diabetes in an elderly population.

  • 32.
    Lee, Duk-Hee
    et al.
    Kyungpook Natl Univ, Sch Med, Dept Prevent Med, Daegu, South Korea.;Kyungpook Natl Univ, Dept Biomed Sci, Plus KNU Biomed Convergence Program BK21, Daegu, South Korea..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Jacobs, David R., Jr.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Salihovic, Samira
    Univ Orebro, Sch Sci & Technol, MTM Res Ctr, SE-70182 Orebro, Sweden..
    van Bavel, Bert
    Univ Orebro, Sch Sci & Technol, MTM Res Ctr, SE-70182 Orebro, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Association between background exposure to organochlorine pesticides and the risk of cognitive impairment: A prospective study that accounts for weight change2016In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 89-90, p. 179-184Article in journal (Refereed)
    Abstract [en]

    Background: Background exposure to organochlorine (OC) pesticides was recently linked to cognitive impairment and dementia in cross-sectional and case-control studies. This prospective study was performed to evaluate if OC pesticides at baseline are associated with the future risk of cognitive impairment in elderly, with particular focus on weight change. Methods: Plasma concentrations of 3 OC pesticides (p,p'-DDE, trans-nonachlor, and hexachlorobenzene) were measured among 989 men and women aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Cognitive impairment was validated by reviewing medical records. During the ten year follow-up, cognitive impairment was developed in 75 subjects. When weight change from age 70 to 75 was considered in analyses, elderly with incident cases before age 75 were excluded to keep the prospective perspective, leaving 795 study subjects and 44 incident cases. Results: The summary measure of 3 OC pesticides predicted the development of cognitive impairment after adjusting for covariates, including weight change. Compared to subjects with OC pesticides <25th percentile, adjusted hazard ratios (HRs) in those with 25th-<75th and >= 75th percentiles were 3.5 (95% confidence interval: 1.5-8.5) and 3.2 (1.1-7.6), respectively (P-trend = 0.04). Among 506 subjects who maintained or gained body weight, adjusted HRs were 6.9 and 11.6 (1.4-92.6) among the elderly in the 25th-<75th and >= 75th percentiles compared to <25th percentile (P-trend < 0.01). Conclusions: This prospective study demonstrates that background exposure to OC pesticides are linked to the risk of developing cognitive impairment in elderly. The role of the chronic exposure to low dose OC pesticides in the development of dementia should be further evaluated in other populations.

  • 33. Lee, Duk-Hee
    et al.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Jacobs, David R., Jr.
    Salihovic, Samira
    van Bavel, Bert
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Background exposure to persistent organic pollutants predicts stroke in the elderly2012In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 47, p. 115-120Article in journal (Refereed)
    Abstract [en]

    Background exposure to persistent organic pollutants (POPs), lipophilic xenobiotics that accumulate mainly in adipose tissue, has recently emerged as a new risk factor for cardiovascular diseases. This prospective study was performed to evaluate if plasma concentrations of selected POPs predict incident stroke among the elderly. Twenty-one POPs (including 16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured in plasma collected at baseline in 898 participants aged 70 years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Stroke diagnosis was validated by hospital records. During the five year follow-up, 35 subjects developed hospital-treated stroke. After adjusting for known stroke risk factors, most PCBs with 4, 5, or 6 chlorine atoms, p,p'-DDE, trans-nonachlor, and octachlorodibenzo-p-dioxin significantly predicted the risk of stroke. Across quartiles of summary measures of PCBs and OC pesticides, the adjusted ORs were 1.0, 0.8 (95% confidence interval: 0.2-2.5), 1.2 (0.4-3.4), and 2.1 (0.7-6.2) for PCBs and 1.0, 1.2 (0.3-4.2), 2.3 (0.7-6.9), and 3.0 (1.0-9.4) for OC pesticides (P for trend = 0.11 and 0.03, respectively). The adjusted ORs among participants >= 90th percentile of the summary measures were 5.5 (1.7-18.1) for PCBs and 4.0 (1.1-14.6) for OC pesticides; corresponding ORs for those >= 95th percentile were 7.8 (2.1-29.6) and 9.5 (2.3-38.9). Background exposure to POPs may play an important role in development or progression of stroke in the elderly.

  • 34. Lee, Duk-Hee
    et al.
    Porta, M
    Lind, L
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Jacobs, D
    Neurotoxic chemicals in adipose tissue: a role in puzzling findings on obesity and dementia.In: NeurologyArticle in journal (Refereed)
  • 35.
    Lee, Duk-Hee
    et al.
    Kyungpook Natl Univ, Sch Med, Dept Prevent Med, Daegu, South Korea.
    Porta, Miquel
    Univ Autonoma Barcelona, Sch Med, Hosp del Mar, Inst Med Res IMIM, Barcelona, Spain.
    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.
    Jacobs, David R
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA.
    Neurotoxic chemicals in adipose tissue: A role in puzzling findings on obesity and dementia2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90, no 4, p. 176-182Article in journal (Refereed)
    Abstract [en]

    Midlife obesity is associated with increased risk of dementia, whereas late-life obesity is commonly associated with a lower risk of dementia. Although methodologic issues are often discussed in this apparent risk reversal, chronic exposure to low-dose organochlorine pesticides (OCPs), an emerging risk factor for dementia in general populations, may contribute to a direct explanation for these differences. OCPs are strong lipophilic chemicals with very long half-lives (several years), primarily stored in adipose tissue and very slowly released and metabolized over years. As serum concentrations of neurotoxic OCPs strongly correlate with brain OCPs (r = 0.95), any condition enhancing the release of OCPs from the adipose tissue into circulation would increase the risk of dementia. Increased release of OCPs from adipose tissue typically occurs in (1) dysfunctional adipocytes accompanied by uncontrolled lipolysis and (2) weight loss. Weight gain may help sequester circulating OCPs in adipose tissue. As obesity is the most common reason that adipocytes become dysfunctional, midlife obesity can increase dementia risk through the chronic release of OCPs into circulation. However, late-life obesity potentially decreases dementia risk because weight loss after midlife will increase the release of OCPs while weight gain may actually decrease the release. These countervailing forces may underlie paradoxical associations with dementia of obesity in midlife vs late life which is influenced by weight change after midlife. This hypothesis should be tested in future experimental and human studies on obesity and dementia.

  • 36.
    Lejonklou, Margareta H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Christiansen, S.
    Tech Univ Denmark, Div Diet Dis Prevent & Toxicol, Morkhoj Bygade 19, DK-2860 Soborg, Denmark..
    Örberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Shen, Ling
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Boberg, J.
    Tech Univ Denmark, Div Diet Dis Prevent & Toxicol, Morkhoj Bygade 19, DK-2860 Soborg, Denmark..
    Hass, U.
    Tech Univ Denmark, Div Diet Dis Prevent & Toxicol, Morkhoj Bygade 19, DK-2860 Soborg, Denmark..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Low-dose developmental exposure to bisphenol A alters the femoral bone geometry in wistar rats2016In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 164, p. 339-346Article in journal (Refereed)
    Abstract [en]

    Background: Bisphenol A (BPA) is a chemical produced in large volumes for use in manufacturing of consumer products and industrial applications, and an endocrine disruptor known to affect several hormonal systems. Bone produces hormones and is additionally a sensitive hormone target tissue, and is thus potentially sensitive to low doses of endocrine disruptors such as BPA, especially during development. Methods: 110 pregnant Wistar rats were gavaged with 0; 25 mu g; 250 mu g; 5000 mu g or 50,000 mu g BPA/kg bodyweight (bw)/day from gestational day 7 until weaning at postnatal day 22. The three-month-old offspring were sacrificed and right femurs collected for length measurements, geometrical measurements by peripheral quantitative computed tomography (pQCT), as well as for analyses of biomechanical properties using the three-point-bending method. Results: The femur was elongated in female offspring of dams exposed to 25 or 5000 mu g BPA/kg bw/day (1.8% and 2.1%, respectively), and increased cortical thickness (4.7%) was observed in male offspring of dams exposed to 25 mu g BPA/kg bw/day, compared to controls (p < 0.005). The biomechanical properties of the bone were not significantly altered. Conclusions: In utero and lactational exposure to the lowest BPA dose used in this study altered femoral geometry in both male and female offspring. This was observed at 25 mu g BPA/kg bw/day, a dose lower than the Human Equivalent Dose (HED) applied by EFSA to set a temporary TDI (609 mu g BPA/kg bw/day), and far lower than the No-Observed-Adverse-Effect-Level (NOAEL) (5000 mu g BPA/kg bw/day) on which the US FDA TDI is based.

  • 37.
    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.

  • 38.
    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)
  • 39.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Bisphenol A increases cortisol production by enhancing phosphorylation of CREB in normal human adrenocortical cells2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S243-S243Article in journal (Other academic)
  • 40.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Induction of LINE-1 promoter hypomethylation, a hallmark of tumorigenesis, in normal human adrenocortical cells by Bisphenol A2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S149-S149Article in journal (Other academic)
  • 41.
    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)
  • 42.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Developmental low-dose exposure to bisphenol A results in gender-specific and non-monotonic effects on Fischer F344 rat bone2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S255-S255Article in journal (Other academic)
  • 43.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Can Persistent Organic Pollutants And Plastic-Associated Chemicals Cause Cardiovascular Disease?2012In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 271, no 6, p. 537-553Article, review/survey (Refereed)
    Abstract [en]

    During the last decade, associations between persistent organic pollutants (POPs), such as polychlorinated biphenyls, dioxins and pesticides, and cardiovascular (CV) risk factors and overt CV disease (CVD) have been reported in humans. Recently, associations between plastic-associated chemicals (PACs), such as bisphenol A and phthalates, and CVD have also begun to emerge. Several approaches to evaluating such associations have been used: accidents with a high level of exposure, occupational exposure studies, geographical studies of subjects living near a contaminated area and traditional case-control or cohort studies with measurements of circulating levels of different environmental contaminants in the general population. Exposure to POPs has consistently been associated with diabetes using all the approaches described above, including prospective studies. The evidence regarding associations between exposure to POPs and other CV risk factors, such as hypertension, obesity and lipids, is less strong, and is mainly based on cross-sectional data. Associations between overt CVD and POPs have been reported using all the above approaches, but prospective data from population-based studies are still lacking to provide firm evidence of an important and independent role of POP exposure in the pathogenesis of CVD. Nevertheless, taken together, current evidence suggests that further longitudinal and experimental studies should be conducted to investigate the effect of exposure to both POPs and PACs, such as bisphenol A and phthalates.

  • 44.
    Lind, Lars
    et al.
    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.
    Lejonklou, Margareta H
    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.
    Bergman, Åke
    Guerrero-Bosagna, Carlos
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lee, Hong Kyu
    Legler, Juliette
    Nadal, Angel
    Pak, Youngmi Kim
    Phipps, Richard P
    Vandenberg, Laura N
    Zalko, Daniel
    Ågerstrand, Marlene
    Öberg, Mattias
    Blumberg, Bruce
    Heindel, Jerrold J
    Birnbaum, Linda S
    Uppsala Consensus Statement on Environmental Contaminants and the Global Obesity Epidemic2016In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, no 5, p. A81-A83Article in journal (Refereed)
    Abstract [en]

    From the lectures presented at the 2nd International Workshop on Obesity and Environmental Contaminants, which was held in Uppsala, Sweden, on 8–9 October 2015, it became evident that the findings from numerous animal and epidemiological studies are consistent with the hypothesis that environmental contaminants could contribute to the global obesity epidemic. To increase awareness of this important issue among scientists, regulatory agencies, politicians, chemical industry management, and the general public, the authors summarize compelling scientific evidence that supports the hypothesis and discuss actions that could restrict the possible harmful effects of environmental contaminants on obesity.

  • 45.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ng, Esther
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
    Lindgren, Cecilia
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, Sweden.
    Mahajan, Anubha
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Morris, Andrew P
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UK.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p'-dde levels in a population-based sample2017In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 98, p. 212-218Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p'-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.

    METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p,p'-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.

    RESULTS: Evidence for genome-wide significant association with p,p'-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472ng/g lipid, while the corresponding level for those being homozygote for the T allele was 192ng/g lipid (p=1.5×10(-31)). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19:41520351; p=2.2×10(-8)). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p=6.2×10(-9)) located 7kb downstream the CYP2B6 gene (cg27089200, position chr19:41531976). This CpG-site was also related to the lead SNP (p=3.8×10(-35)), but mediated only 4% of the effect of the lead SNP on p,p'-DDE levels.

    CONCLUSION: Circulating levels of p,p'-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p,p'-DDE levels.

  • 46.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Penell, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Luttropp, Karin
    Nordfors, Louise
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    van Bavel, Bert
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, P Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population2013In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 59, p. 456-461Article in journal (Refereed)
    Abstract [en]

    Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p=0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p=0.009) only in subjects with one G-allele (n=103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p=0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis.

  • 47.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Penell, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morris, Andrew P
    Lindgren, Cecilia
    Salihovic, Samira
    van Bavel, Bert
    Lind, P Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample2014In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 133, p. 135-140Article in journal (Refereed)
    Abstract [en]

    Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures >80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003-0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005-0.05 range. Very few associations with p<0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs.

  • 48.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Mixture effects of 30 environmental contaminants on incident metabolic syndrome: A prospective study2017In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 107, p. 8-15Article in journal (Refereed)
    Abstract [en]

    Background: Several cross-sectional studies have linked different environmental contaminants to the metabolic syndrome (MetS). However, mixture effects have not been investigated and no prospective studies exist regarding environmental contaminants and the MetS.

    Objectives: To study mixture effects of contaminants on the risk of incident MetS in a prospective fashion.

    Methods: Our sample consisted of 452 subjects from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years) free from the MetS at baseline, being followed for 10 years. At baseline, 30 different environmental contaminants were measured; 6 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, one dioxin, one polybrominated diphenyl ether (all in plasma), 8 perfluoroalkyl substances (in plasma) and 11 metals (in whole blood). The MetS was defined by the ATPIII/NCEP criteria. Gradient boosted Classification and Regression Trees (CARTs) was used to evaluate potential synergistic and additive mixture effects on incident MetS.

    Results: During 10-year follow-up, 92 incident cases of the MetS occurred. PCB126, PCB170, hexachlorobenzene (HCB) and PCB118 levels were all associated with incident MetS in an additive fashion (OR 1.73 for a change from 10th to 90th percentile (95% CI 1.24-3.04) for PCB126, OR 0.63 (0.42-0.78) for PCB170, OR 1.44 (1.09-2.20) for HCB and OR 1.46 (1.13-2.43) for PCB118). No synergistic effects were found.

    Conclusion: A mixture of environmental contaminants, with PCB126, PCB170, HCB and PCB118 being the most important, showed associations with future development of the MetS in an additive fashion in this prospective study. Thus, mixture effects of environmental contaminants could contribute to the development of cardiometabolic derangements.

  • 49.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Univ Orebro, Orebro.
    Van Bavel, B.
    Univ Orebro, Orebro, Switzerland..
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Circulating levels of perfluorinated compounds and left ventricular geometry2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S93-S93Article in journal (Other academic)
  • 50.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Lind, Monica P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Circulating levels of perfluoroalkyl substances and prevalent diabetes in the elderly2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 3, p. 473-479Article in journal (Refereed)
    Abstract [en]

    Several environmental contaminants, such as polychlorinated biphenyls, dioxins, bisphenol A and phthalates, have been linked to diabetes. We therefore investigated whether other kinds of contaminants, perfluoroalkyl substances (PFAS), also called perfluorinated compounds (PFCs), are also associated with diabetes. The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study investigated 1,016 men and women aged 70 years. Seven PFAS were detected in almost all participant sera by ultra-high performance liquid chromatograph/tandem mass spectrometry. Diabetes was defined as use of hypoglycaemic agents or fasting glucose > 7.0 mmol/l. 114 people had diabetes. In the linear analysis, no significant relationships were seen between the seven PFAS and prevalent diabetes. However, inclusion of the quadratic terms of the PFAS revealed a significant non-linear relationship between perfluorononanoic acid (PFNA) and diabetes, even after adjusting for multiple confounders (OR 1.96, 95% CI 1.19, 3.22, p = 0.008 for the linear term and OR 1.25, 95% CI 1.08, 1.44, p = 0.002 for the quadratic term). Perfluorooctanoic acid (PFOA) also showed such a relationship (p = 0.01). PFOA was related to the proinsulin/insulin ratio (a marker of insulin secretion), but none of the PFAS was related to the HOMA-IR (a marker of insulin resistance) following adjustment for multiple confounders. PFNA was related to prevalent diabetes in a non-monotonic fashion in this cross-sectional study, supporting the view that this perfluoroalkyl substance might influence glucose metabolism in humans at the level of exposure seen in the general elderly population.

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