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  • 1.
    Aasa, Jenny
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cancer Risk Assessment of Glycidol: Evaluation of a Multiplicative Risk Model for Genotoxic Compounds2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Humans are exposed to chemical compounds in everyday life, both from the environment and from endogenous processes. Some compounds constitute a risk for cancer development. One such compound is glycidol, which is genotoxic and an animal carcinogen. It is the model compound of this work, partly due to its presence in food. Glycidol, often together with 3-monochloropropane-1,2-diol (3-MCPD), occurs in the form of esters particularly in refined cooking oils, which are used in a variety of food products. The esters are hydrolyzed in the gastrointestinal tract to form glycidol (and 3-MCPD).

    The aim of the thesis has been to evaluate an approach for cancer risk estimation of genotoxic carcinogens based on a multiplicative (relative) risk model and genotoxic potency. Further, the aim was to estimate the cancer risk for exposure to glycidol via food. Measurement of the internal doses (concentration × time) of glycidol in the studied biological systems, including humans, has been crucial. Glycidol is electrophilic and forms adducts with nucleophilic sites in proteins and DNA. The doses of glycidol were quantified by mass spectrometry: in vivo from adduct levels to hemoglobin (Hb); in vitro from adducts to cob(I)alamin.

    The first part of the thesis concerns the genotoxic potency (genotoxic response per internal dose) of glycidol, measured in vitro by mutation studies and in vivo by micronuclei as a biomarker for genotoxicity (short-term studies in mice). The results were compared to that of ionizing radiation, used as a standard, to estimate the relative genotoxic potency of glycidol: 10 and 15 rad-equ./mMh from mutations and micronuclei, respectively. No induction of micronuclei was observed for the related compound 3-MCPD.

    Tumor incidence from published carcinogenicity studies of glycidol in mice and rats, together with the measured in vivo doses, was evaluated with the relative cancer risk model. A good agreement between predicted and observed tumor incidence was shown, and no significant difference of the obtained cancer risk coefficients (risk per dose) between mice (5.1 % per mMh) and rats (5.4 % per mMh) was observed. The overall results support that the relative risk coefficient (β) is independent of sex, tumor site, and species, and indicated that it can be transferred also to humans. The doubling dose, expressed as 1/β, is the dose that is required to double the background tumor incidence. The mean of the doubling doses from mice and rats (19 mMh) was assumed valid for risk estimation for humans. Transfer of β of glycidol to rad-equ. via its relative genotoxic potency showed a risk coefficient in agreement with the relative cancer risk coefficient of ionizing radiation.

    In the final work, the lifetime (70 years) in vivo doses of glycidol were calculated from measured Hb adduct levels in blood from 50 children and 12 adults, and compared to the doubling dose. A fivefold variation was observed in the in vivo doses. The estimated lifetime excess cancer risk from glycidol exceeds 1/1000. This is much higher than what is considered as an acceptable risk.

    To conclude, the multiplicative (relative) risk model together with relative genotoxic potency is promising to use in an approach for cancer risk estimation and in line with 3R (reduce-refine-replace) initiatives.

  • 2.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. National Food Agency, Sweden.
    Measurement of micronuclei and internal dose in mice demonstrates that 3-monochloropropane-1,2-diol (3-MCPD) has no genotoxic potency in vivo2017In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 109, p. 414-420Article in journal (Refereed)
    Abstract [en]

    In this study 3-monochloropropane-1,2-diol (3-MCPD), a compound that appears as contaminant in refined cooking oils, has been studied with regard to genotoxicity in vivo (mice) with simultaneous measurement of internal dose using state-of-the-art methodologies. Genotoxicity (chromosomal aberrations) was measured by flow cytometry with dual lasers as the frequency of micronuclei in erythrocytes in peripheral blood from BalbC mice intraperitoneally exposed to 3-MCPD (0, 50, 75, 100, 125 mg/kg). The internal doses of 3-MCPD in the mice were calculated from N-(2,3-dihydroxypropyl)-valine adducts to hemoglobin (Hb), quantified at very low levels by high-resolution mass spectrometry.

    Convincing evidence for absence of genotoxic potency in correlation to measured internal doses in the mice was demonstrated, despite relatively high administered doses of 3-MCPD. The results are discussed in relation to another food contaminant that is formed as ester in parallel to 3-MCPD esters in oil processing, i.e. glycidol, which has been studied previously by us in a similar experimental setup. Glycidol has been shown to be genotoxic, and in addition to have ca. 1000 times higher rate of adduct formation compared to that observed for 3-MCPD. The conclusion is that at simultaneous exposure to 3-MCPD and glycidol the concern about genotoxicity would be glycidol.

  • 3.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Granath, Fredrik
    Cancer risk estimation of glycidol based on rodent carcinogenicity studies, a multiplicative risk model and in vivo dosimetryManuscript (preprint) (Other academic)
    Abstract [en]

    Here we evaluate a multiplicative (relative) risk model for more reliable cancer risk estimations of genotoxic compounds. According to this model, cancer risk is proportional to background tumor incidence and to internal dose of the genotoxic compound. A relative risk coefficient is considered to be common across species, sex, and tumor sites. The model has previously been shown to be successfully applied to rodent carcinogenicity data for a few genotoxic compounds. The aim of the present study was to evaluate this risk model for glycidol, a common food contaminant. Tumor data from published glycidol carcinogenicity studies in mice and rats were evaluated with the model, using internal doses estimated from hemoglobin adduct measurements in blood of B6C3F1 mice and Sprague Dawley rats treated with glycidol in short-term exposure studies.

    The evaluation demonstrated that the relative risk model is valid for glycidol. A good agreement between predicted and observed tumor incidence was demonstrated in the animals, supporting a relative risk coefficient that is independent of species, sex, and tumor site. There was no significant difference of the risk coefficients between mice (5.1 % per mMh) and rats (7.1 % per mMh) when the internal doses of glycidol were considered. Altogether, this mechanism-based risk model gives a common and more reliable risk coefficient which could be extrapolated to humans via internal dose measurements, and by considering the background cancer incidence.

  • 4.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Vryonidis, Efstathios
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Internal dose of glycidol in children and estimation of associated cancer riskManuscript (preprint) (Other academic)
    Abstract [en]

    Children are more susceptible to exposures to harmful compounds compared to adults. Monitoring of the actual exposures in vivo is important to enable risk mitigation actions. The general population, including children, is exposed to the carcinogen glycidol through food. A possible exposure source to glycidol is food containing refined cooking oils where it is present as a process-induced contaminant in the form of fatty acid esters.

    In the present study internal (in vivo) doses of the genotoxic and carcinogenic compound glycidol have been determined in a cohort of 50 children and in a reference group of 12 adults (non-smokers and smokers). The lifetime in vivo doses of glycidol have been calculated from the levels of the hemoglobin (Hb) adduct N-(2,3-dihydroxypropyl)-valine in blood samples from the subjects, demonstrating about a 5-fold variation between the children (71–322 µMh). This variation is likely due to different dietary habits and/or different genotypes/phenotypes of the enzymes involved in the detoxification of glycidol. Data from the adults indicate that the non-smoking subjects are exposed to about the same level as the children, whereas the smoking subjects have about double levels, likely due to the presence of glycidol in tobacco smoke. The estimated exposure to glycidol in the children is higher than those estimated by European Food Safety Authority.

    The calculated relative cancer risk increment due to glycidol exposure demonstrated an unacceptable risk for all subjects. The excess lifetime risk based on the estimated lifetime in vivo doses of glycidol exceeded 1/1000, which should be compared to a generally applied acceptable lifetime risk level of 1/100 000. A small contribution to the internal dose of glycidol from other precursors to the measured Hb adduct, and corresponding contribution to estimated risks from intake of glycidol from food cannot though be excluded.

  • 5.
    Aigars, Juris
    Stockholm University.
    The role of sediments in the biogeochemical cycles of nutrients in the Gulf of Riga2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The sediment biogeochemistry of C, N, P and biologic silica (BSi) plays an important role in cycling of these elements in aquatic ecosystems. In shallow coastal and estuarine systems, water-sediment nutrient dynamics can influence biological processes (e.g., primary production) in overlying waters.

    The objectives of this study are:

    • characterize C, N, P and BSi geochemistry of the surface sediments in the Gulf of Riga,
    • estimate the spatial distribution, including net flux and sink, for organic C, N and P in the Gulf of Riga,
    • examine if there are any appropriate bulk, regional and/or vertical relationships between the nutrients,
    • examine if nutrient biogeochemistry in surface sediments vary as a response to naturally occurring processes i.e., intensity of sedimentation and bioturbation, oxygen deficiency, variation of temperature

    Spatial and vertical distribution reveals that organic C and N ratio is almost independent of sediment characteristics and location, and exhibit a stable value down the sediment core. Over 90 % of carbon and nitrogen in sediments is organic. In contrast, organic P constitutes less than 50 % of the total phosphorus pool. The organic C:N:P ratio in sediments indicate that N and P are decomposed preferentially to C, whereas P is decomposed preferentially to N. The stable C:N ratio in sediments indicates that preferential N decomposition occurs in water column and/or immediately upon settling at sediment surface. Distribution pattern of BSi suggests that accumulation rate of sediments controls BSi concentration. Although nutrient loading from drainage area increased drastically over the past 100 years, vertical profiles of C, N and BSi show no variation in element concentrations except in the top few centimeters. A corresponding increase of benthic biomass most likely results in low elemental accumulation in these sediments.

    Although Gulf of Riga is one of the most productive areas in the Baltic Sea, seasonal alterations of C and N levels were limited. However, during spring and autumn algae blooms total C and N concentrations increased in the study area. Limited data suggests that burrowing amphipods directly impact the C and N concentrations in the top 2-3 cm of sediments. The vertical distribution of P is more dependent on oxygen concentration, which is largely controlled by bioturbation and sedimentation rates. Moreover, the results suggest that bioturbation is largely responsible for temporal accumulation of inorganic P in surface sediments.

    The low unidirectional fluxes of dissolved inorganic nitrogen (DIN) and dissolved inorganic phosphorus (DIP) in early spring is consistent with low water temperature and poor nutritional quality of experimentally added material. The high water temperature and better nutritional quality of material added in summer, comparatively to winter, resulted in large DIN and DIP fluxes. Moreover, flux experiments under low oxygen conditions and pulse input of large quantities of settling seston suggest that sediment surface might experience lack of oxygen despite availability of oxygen in the overlying water column.

  • 6. Alexander, Jan
    et al.
    Benford, Diane
    Boobis, Alan
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Scientific Opinion on Hexabromocyclododecanes (HBCDDs) in Food2011In: EFSA Journal, ISSN 1831-4732, Vol. 9, no 7, p. 2296-Article in journal (Other academic)
    Abstract [en]

    EFSA was asked by the European Commission to deliver a scientific opinion on hexabromocyclododecanes (HBCDDs) in food. HBCDDs are additive flame retardants primarily used in expanded and extruded polystyrene applied as construction and packing materials, and in textiles. Technical HBCDD predominantly consists of three stereoisomers (α-, β- and γ-HBCDD). Also δ- and ε-HBCDD may be present but at very low concentrations. HBCDDs are present in the environment and likewise in biota and in food and feed. Data from the analysis of HBCDDs in 1,914 food samples were provided to EFSA by seven European countries, covering the period from 2000 to 2010. The Panel on Contaminants in the Food Chain (CONTAM Panel) selected α-, β- and γ-HBCDD to be of primary interest. Since all toxicity studies were carried out with technical HBCDD, a risk assessment of individual stereoisomers was not possible. Main targets were the liver, thyroid hormone homeostasis and the reproductive, nervous and immune systems. HBCDDs are not genotoxic. The CONTAM Panel identified neurodevelopmental effects on behaviour as the critical endpoint, and derived a benchmark dose lower confidence limit for a benchmark response of 10 % (BMDL10) of 0.79 mg/kg body weight. Due to the limitations and uncertainties in the current data base, the CONTAM Panel concluded that it was inappropriate to use this BMDL to establish a health based guidance value, and instead used a margin of exposure (MOE) approach for the health risk assessment of HBCDDs. Since elimination characteristics of HBCDDs in animals and humans differ, the Panel used the body burden as starting point for the MOE approach. The CONTAM Panel concluded that current dietary exposure to HBCDDs in the European Union does not raise a health concern. Also additional exposure, particularly of young children, to HBCDDs from house dust is unlikely to raise a health concern

  • 7. Alexander, Jan
    et al.
    Benford, Diane
    Boobis, Alan
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food2011In: EFSA Journal, ISSN 1831-4732, Vol. 9, no 5, p. 2156-Article in journal (Other academic)
  • 8. Alexander, Jan
    et al.
    Benford, Diane
    Boobis, Alan
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Scientific Opinion on Tetrabromobisphenol A (TBBPA) and its derivatives in food: EFSA Panel on Contaminants in the Food Chain (CONTAM)2011In: EFSA Journal, ISSN 1831-4732, Vol. 9, no 12, p. 2477-Article in journal (Refereed)
    Abstract [en]

    EFSA was asked by the European Commission to deliver a scientific opinion on tetrabromobisphenol A (TBBPA) and its derivatives in food. TBBPA and its derivatives are widely used as flame retardants. TBBPA is primarily used as reactive flame retardant covalently bound to epoxy and polycarbonate resins. TBBPA derivatives are used as either reactive or additive intermediates in polymer manufacture. Data from the analysis of TBBPA in 344 food samples were submitted to EFSA by two European countries (Norway and Spain), covering the period from 2007 to 2010. All samples were in the food group “Fish and other seafood”, and all analytical results were reported as less than the limit of quantification (LOQ) (about 1 ng/g wet weight). Toxicological studies with TBBPA have been carried out using different experimental designs with single or repeated administration during gestation, postnatally or in adulthood. The main target is thyroid hormone homeostasis. TBBPA is not genotoxic. There are no indications that TBBPA might be carcinogenic. The Panel on Contaminants in the Food Chain (CONTAM Panel) identified a lower confidence limit for a benchmark response of 10 % (BMDL10) of 16 mg/kg b.w. reported for changes in thyroid hormones as the critical reference point. Due to the limitations and uncertainties in the database, the CONTAM Panel concluded that it was inappropriate to use this BMDL to establish a health based guidance value, and therefore used a margin of exposure (MOE) approach for the health risk assessment of TBBPA. In view of the large MOEs, the CONTAM Panel concluded that current dietary exposure to TBBPA in the European Union does not raise a health concern. Also exposure of infants via human milk does not raise a health concern. Additional exposure, particularly of young children, to TBBPA from house dust is unlikely to raise a health concern.

  • 9.
    Attoff, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm University.
    Kertika, Dimitra
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Oredsson, Stina
    Lund University.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5YManuscript (preprint) (Other academic)
  • 10.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Foreword2012In: Hormone-Disruptive Chemical Contaminants in Food / [ed] I. Pongratz and L. Vikström Bergander, London: Royal Society of Chemistry, 2012Chapter in book (Other academic)
  • 11.
    Bergqvist, Cecilia
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The role of nuclear membrane proteins in differentiation and chromatin organization2016Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nuclear envelope, consisting of an outer and an inner nuclear membrane, surrounds the genomic material. The genomic material (chromatin) is highly structured with (transcriptionally inactive) heterochromatin mostly found in the nuclear periphery and (transcriptionally active) euchromatin mostly found in the nuclear interior. Underlying the nuclear envelope is the nuclear lamina that consists of lamin proteins and nuclear envelope transmembrane proteins (NETs), which organize chromatin in the nuclear periphery. There are several hundred uncharacterized tissue-specific NETs, with only a few linked to cellular differentiation. Induced pluripotent stem cells (iPSCs) enable studies of early differentiation and are a promising tool for cell replacement therapies.

    In this licentiate thesis, we have focused on investigating the role of the inner nuclear membrane protein Samp1 in chromatin organization and cell differentiation. Overexpression of Samp1 induced a fast differentiation of iPSCs, suggesting that Samp1 may be involved in the differentiation process. We have also developed a novel image analysis method to be able to monitor chromatin organization in live cells. Depletion of Samp1 affected chromatin distribution and resulted in increased formation of peripheral heterochromatin, contradictory to what is expected of other characterized NETs. It is possible that Samp1 might have a role in both differentiation and chromatin organization and that future studies might link these two processes together.

  • 12.
    Bergqvist, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Figueroa, Ricardo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Markus, Robert
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Beckman, Marie
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Maxell, Danuta
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sousa, Paulo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jafferali, Mohammed Hakim
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Hallberg, Einar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Monitoring of the epigenetic state in live cellsManuscript (preprint) (Other academic)
  • 13.
    Bergqvist, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jafferali, Mohammed Hakim
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Santosh, Gudise
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Markus, Robert
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Hallberg, Einar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    An inner nuclear membrane protein induces rapid differentiation of human induced pluripotent stem cellsManuscript (preprint) (Other academic)
  • 14.
    Bogdanska, Jasna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sundström, Maria
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Bergström, Ulrika
    Institutionen för miljötoxikologi, Uppsala universitet.
    Borg, Daniel
    Institutet för miljömedicin, Karolinska institutet.
    Abedi-Valugerdi, Mauchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Nelson, Buck
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph
    Institutionen för biokemi och biofysik, Department of Biochemistry and Biophysics.
    Nobel, Stefan
    Department of molecular medicin and surgery, Karolinska institutet.
    Tissue distribution of 35S-labelled perfluorobutane sulfonic acid in adult mice following dietary exposure for 1-5 daysManuscript (preprint) (Other academic)
  • 15.
    Carlsson, Henrik
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholms Universitet, MMK.
    Development of an adductomic approach to identify electrophiles in vivo through their hemoglobin adducts2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Humans are exposed to electrophilically reactive compounds, both formed endogenously and from exogenous exposure. Such compounds could react and form stable reaction products, adducts, at nucleophilic sites in proteins and DNA. The formation of adducts constitutes a risk for effects, such as cancer and contact allergy, and plays a role in ageing processes. Adducts to proteins offer a possibility to measure electrophilic compounds in vivo.

    Adductomic approaches aim to study the totality of adducts, to specific biomolecules, by mass spectrometric screening. This thesis describes the development and application of an adductomic approach for the screening of unknown adducts to N-terminal valine (Val) in hemoglobin (Hb) by liquid chromatography tandem mass spectrometry (LC/MS/MS).

    The adductomic approach is based on the FIRE procedure, a modified Edman procedure for the analysis of adducts to N-terminal Val in Hb by LC/MS/MS. The adduct screening was performed by stepwise scanning of precursor ions in small mass increments and monitoring four fragments common for derivatives of detached Val adducts, in the multiple reaction monitoring mode. Samples from 12 smokers/nonsmokers were screened with the adductomic approach, and seven previously identified adducts and 19 unknown adducts were detected. A semiquantitative approach was applied for approximate quantification of adduct levels.

    A strategy for identifying unknown Hb adducts using adductome LC/MS/MS data was formulated and applied for the identification of unknown adducts. Identifications were based on the observed m/z of precursor ions and retention times combined with databases and Log P calculations. Hypothesized adducts were generated in vitro for comparison and matching with the corresponding unknown adducts. Five identified adducts correspond to the precursor electrophiles ethyl vinyl ketone (EVK), glyoxal, methylglyoxal, acrylic acid, and 1-octen-3-one. These adducts, except the adducts corresponding to glyoxal and methylglyoxal, have not been observed as protein adducts before.  Probable exposure sources to these electrophiles are diet and/or endogenous formation. The observation of these adducts motivate further studies to evaluate possible contributions to health risks, as well as their potential as biomarkers of exposure.

    The adduct from EVK was quantitatively assessed through different experiments to estimate the daily internal dose (area under the concentration-time-curve, AUC). EVK is about 2 × 103 more reactive than the reference compound acrylamide. The EVK adduct was shown to be unstable, with a relatively short half-life. The daily AUC in humans of EVK was estimated to be about 20 times lower than the corresponding AUC of acrylamide from intake via food.

    To confirm the observation of the detected unknown adducts and obtain a statistical foundation, analysis of unknown adducts were performed in large sets of blood samples (n = 50–120) from human cohorts. The majority of the previously detected unknown adducts were found in all analyzed samples, and the levels of many adducts showed large variations between individuals. The cause and significance of these observed variations are not yet clarified, but are of importance for the directions of future studies.

    In conclusion, a new approach for identification of unknown human exposure to electrophiles was developed and successfully applied. 

  • 16. Dingemans, Milou M L
    et al.
    de Groot, Aart
    van Kleef, Regina G D M
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    van den Berg, Martin
    Vijverberg, Henk P M
    Westerink, Remco H S
    Hydroxylation increases the neurotoxic potential of BDE-47 to affect exocytosis and calcium homeostasis in PC12 cells.2008In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 116, no 5, p. 637-43Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Oxidative metabolism, resulting in the formation of hydroxylated polybrominated diphenyl ether (PBDE) metabolites, may enhance the neurotoxic potential of brominated flame retardants. OBJECTIVE: Our objective was to investigate the effects of a hydroxylated metabolite of 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47; 6-OH-BDE-47) on changes in the intracellular Ca2+ concentration ([Ca2+]i) and vesicular catecholamine release in PC12 cells. METHODS: We measured vesicular catecholamine release and [Ca2+]i using amperometry and imaging of the fluorescent Ca2+-sensitive dye Fura-2, respectively. RESULTS: Acute exposure of PC12 cells to 6-OH-BDE-47 (5 microM) induced vesicular catecholamine release. Catecholamine release coincided with a transient increase in [Ca2+]i, which was observed shortly after the onset of exposure to 6-OH-BDE-47 (120 microM). An additional late increase in [Ca2+]i was often observed at > or =1 microM 6-OH-BDE-47. The initial transient increase was absent in cells exposed to the parent compound BDE-47, whereas the late increase was observed only at 20 microM. Using the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and thapsigargin to empty intracellular Ca2+ stores, we found that the initial increase originates from emptying of the endoplasmic reticulum and consequent influx of extracellular Ca2+, whereas the late increase originates primarily from mitochondria. CONCLUSION: The hydroxylated metabolite 6-OH-BDE-47 is more potent in disturbing Ca2+ homeostasis and neurotransmitter release than the parent compound BDE-47. The present findings indicate that bioactivation by oxidative metabolism adds considerably to the neurotoxic potential of PBDEs. Additionally, based on the observed mechanism of action, a cumulative neurotoxic effect of PBDEs and ortho-substituted polychlorinated biphenyls on [Ca2+]i cannot be ruled out.

  • 17. Eketjäll, Susanna
    et al.
    Jeppsson, Fredrik
    CNS and Pain iMed, AstraZeneca, Södertälje, Sweden; Operations Global Quality, AstraZeneca, Södertälje, Sweden.
    Cebers, Gvido
    AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 50, no 4, p. 1109-1123Article in journal (Refereed)
    Abstract [en]

    A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-beta peptide (A beta) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-beta protein precursor (A beta PP) to A beta peptides, with the soluble N terminal fragment of A beta PP (sA beta PP beta) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of A beta. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose-and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of A beta(40), A beta(42), and sA beta PP beta. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of A beta. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.

  • 18. Eketjäll, Susanna
    et al.
    Jeppsson, Fredrik
    Innovative Medicines AstraZeneca, CNS & Pain, Södertälje, Sweden.
    Fälting, Johanna
    AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 24, p. 10075-10084Article in journal (Refereed)
    Abstract [en]

    A beta, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). beta-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to A beta peptides. Small molecule BACE1 inhibitors are expected to decrease A beta-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of A beta production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.

  • 19.
    EL Andaloussi, Samir
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lehto, Taavi
    Laboratory of Molecular Biotechnology, Institute of Technology, Tartu University, Tartu, Estonia.
    Lundin, Per
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Application of PepFect peptides for the delivery of splice-correcting oligonucleotides2011In: Cell-penetrating peptides: Methods and Protocols, New York: Humana Press, 2011, p. 361-373Chapter in book (Other academic)
    Abstract [en]

    One oligonucleotide-based approach that appear very promising for the treatment of different genetic disorders are based on so-called splice-correcting oligonucleotides (SCOs) that are exploited to manipulate splicing patterns. In order to increase the bioavailability, cell-penetrating peptides (CPPs) have readily been covalently conjugated to SCOs to facilitate cellular internalization. While being a successful strategy for the delivery of uncharged oligonucleotides (ONs), it is extremely difficult to generate covalent conjugates between commonly used negatively charged ON analogs and cationic CPPs. Furthermore, high concentrations of ONs in the micromolar range are often needed to obtain biological responses, most likely as a result of endosomal entrapment of material. Therefore, exploring other vectorization methods using CPPs with endosomolytic properties are highly desired. A method of using stearyl modified CPP (i.e., TP10) analogs, named PepFect3 and PepFect4, are being described for the transfection of antisense SCOs using a simple one-step co-incubation procedure. These peptides form complexes with SCOs and efficiently promote cellular uptake by facilitating endosomal escape. This chapter describes the methods of how to form and characterize these nanoparticles and the cellular assay used to address the delivery.

  • 20.
    EL Andaloussi, Samir
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Said Hassane, Fatouma
    Université Montpellier, Motpellier, France.
    Boisguerin, Prisca
    Université Montpellier, Motpellier, France.
    Sillard, Rannar
    University of Tartu, Institute of Technology, Tartu, Estonia.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lebleu, Bernard
    Université Montpellier, Motpellier, France.
    Cell-penetrating peptides-based strategies for the delivery of splice redirecting antisense oligonucleotides2011In: Therapeutic Oligonucleotides: Methods and Protocols / [ed] John Goodchild, New York: Humana Press, 2011, p. 75-89Chapter in book (Other academic)
    Abstract [en]

    Progress in our understanding of the molecular pathogenesis of human malignancies has provided therapeutic targets amenable to oligonucleotide (ON)-based strategies. Antisense ON-mediated splicing regulation in particular offers promising prospects since the majority of human genes undergo alternative splicing and since splicing defects have been found in many diseases. However, their implementation has been hampered so far by the poor bioavailability of nucleic acids-based drugs. Cell-penetrating peptides (CPPs) now appear as promising non-viral delivery vector for non-permeant biomolecules. We describe here new CPPs allowing the delivery of splice redirecting steric-block ON using either chemical conjugation or non-covalent complexation. We also describe a convenient and robust splice redirecting assay which allows the quantitative assessment of ON nuclear delivery.

  • 21.
    Eriksson, Jonas
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gene therapy tools: oligonucleotides and peptides2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genetic mutations can cause a wide range of diseases, e.g. cancer. Gene therapy has the potential to alleviate or even cure these diseases. One of the many gene therapies developed so far is RNA-cleaving deoxyribozymes, short DNA oligonucleotides that specifically bind to and cleave RNA. Since the development of these synthetic catalytic oligonucleotides, the main way of determining their cleavage kinetics has been through the use of a laborious and error prone gel assay to quantify substrate and product at different time-points. We have developed two new methods for this purpose. The first one includes a fluorescent intercalating dye, PicoGreen, which has an increased fluorescence upon binding double-stranded oligonucleotides; during the course of the reaction the fluorescence intensity will decrease as the RNA is cleaved and dissociates from the deoxyribozyme. A second method was developed based on the common denominator of all nucleases, each cleavage event exposes a single phosphate of the oligonucleotide phosphate backbone; the exposed phosphate can simultaneously be released by a phosphatase and directly quantified by a fluorescent phosphate sensor. This method allows for multiple turnover kinetics of diverse types of nucleases, including deoxyribozymes and protein nucleases.

    The main challenge of gene therapy is often the delivery into the cell. To bypass cellular defenses researchers have used a vast number of methods; one of these are cell-penetrating peptides which can be either covalently coupled to or non-covalently complexed with a cargo to deliver it into a cell. To further evolve cell-penetrating peptides and understand how they work we developed an assay to be able to quickly screen different conditions in a high-throughput manner. A luciferase up- and downregulation experiment was used together with a reduction of the experimental time by 1 day, upscaling from 24- to 96-well plates and the cost was reduced by 95% compared to commercially available assays. In the last paper we evaluated if cell-penetrating peptides could be used to improve the uptake of an LNA oligonucleotide mimic of GRN163L, a telomerase-inhibiting oligonucleotide. The combination of cell-penetrating peptides and our mimic oligonucleotide lead to an IC50 more than 20 times lower than that of GRN163L.

  • 22. Florén, Anders
    et al.
    Mäger, Imre
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. Tartu University, Estonia.
    Uptake kinetics of cell-penetrating peptides2011In: Cell-penetrating peptides: Methods and Protocols, Humana Press, 2011, p. 117-128Chapter in book (Refereed)
    Abstract [en]

    As our knowledge increases about the diversity in uptake mechanisms displayed by cell-penetrating peptides (CPP), the concept of CPP uptake kinetics becomes increasingly complex. Here, we present three different assays that can be used for studying different kinetic aspects of CPP-mediated delivery: intracellular accumulation and membranolytical effects, intracellular CPP-cargo detachment, and finally a functional readout of a biological action from the delivered cargo. Unlike the traditional end-point measurements that give a static postincubation readout, these assays are all dynamic, real-time, in situ measurements obtained during incubation. A combination of some (or all) of these different assays gives us not only interesting kinetic information about the uptake routes but also provides a simple and valuable methodology for the evaluation of potential drug candidates based on the chemical modification of CPPs by cargo attachment.

  • 23.
    Grythe, Henrik
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Primary Marine Aerosol: Validation of sea spray source functions using observations and transport modeling2014Licentiate thesis, monograph (Other academic)
    Abstract [en]

    Sea spray aerosols (SSA) are an important part of the climate system through their effects on the global radiative budget, both directly as scatterers and absorbers of solar and terrestrial radiation, and indirectly as cloud condensation nuclei (CCN) influencing cloud formation, lifetime and precipitation. In terms of their global mass, SSA is the largest source and has the largest uncertainty of all aerosols. In this study I have reviewed 21 SSA source functions from the literature, several of which are used in current climate models, and as a result of this work  a new source function is proposed.

    The model FLEXPART was run in backward mode utilizing a large global set of observed SSA concentrations, comprised of several station networks and ship cruise measurement campaigns. FLEXPART backward calculations produce gridded emission sensitivity fields, which can subsequently be multiplied with gridded SSA production fluxes to obtain modeled SSA concentrations. This allows to efficiently evaluate all 21 source functions at the same time. Another advantage of this method is that source-region information on wind speed and sea surface temperatures (SSTs) could be stored and used for evaluating their influence on SSA production.

    The main driver of SSA production is wind, and the best fit to the observation data could be obtained when the SSA production is proportional to U103.5. A strong influence of SST on the production could be detected as well, although the underlying physical mechanisms of the SST influence remains unclear. For SST we obtain the best fit to the measurement data when SSA concentration is proportional to 0.031×T+0.39, where T is the source average SST. Based on the model source region average temperature and wind, an empirical fit was made to the data and a new source function obtained. The fit was made by using the model concentrations, observational data, ECMWF winds and the existing source function volume fluxes. Our new source function gives a global SSA production for particles smaller than 10μm of 9Pg yr-1 and is the best fit to the observed concentrations. The existing source functions display the large uncertainties, spanning from a global emitted mass of 1.9 to 100’s of Pg yr-1. Wind dependencies also range strongly and those far from U103.5, have poor correlation with observed values. It is also possible to add temperature dependence to an existing source function to come further towards observed values with the model results.

     Sea spray aerosols (SSA) are an important part of the climate system through their effects on the global radiative budget, both directly as scatterers and absorbers of solar and terrestrial radiation, and indirectly as cloud condensation nuclei (CCN) influencing cloud formation, lifetime and precipitation. In terms of their global mass, SSA is the largest source and has the largest uncertainty of all aerosols. In this study I have reviewed 21 SSA source functions from the literature, several of which are used in current climate models, and as a result of this work  a new source function is proposed.

    The model FLEXPART was run in backward mode utilizing a large global set of observed SSA concentrations, comprised of several station networks and ship cruise measurement campaigns. FLEXPART backward calculations produce gridded emission sensitivity fields, which can subsequently be multiplied with gridded SSA production fluxes to obtain modeled SSA concentrations. This allows to efficiently evaluate all 21 source functions at the same time. Another advantage of this method is that source-region information on wind speed and sea surface temperatures (SSTs) could be stored and used for evaluating their influence on SSA production.

    The main driver of SSA production is wind, and the best fit to the observation data could be obtained when the SSA production is proportional to U103.5. A strong influence of SST on the production could be detected as well, although the underlying physical mechanisms of the SST influence remains unclear. For SST we obtain the best fit to the measurement data when SSA concentration is proportional to 0.031×T+0.39, where T is the source average SST. Based on the model source region average temperature and wind, an empirical fit was made to the data and a new source function obtained. The fit was made by using the model concentrations, observational data, ECMWF winds and the existing source function volume fluxes. Our new source function gives a global SSA production for particles smaller than 10μm of 9Pg yr-1 and is the best fit to the observed concentrations. The existing source functions display the large uncertainties, spanning from a global emitted mass of 1.9 to 100’s of Pg yr-1. Wind dependencies also range strongly and those far from U103.5, have poor correlation with observed values. It is also possible to add temperature dependence to an existing source function to come further towards observed values with the model results.

    Sea spray aerosols (SSA) are an important part of the climate system through their effects on the global radiative budget, both directly as scatterers and absorbers of solar and terrestrial radiation, and indirectly as cloud condensation nuclei (CCN) influencing cloud formation, lifetime and precipitation. In terms of their global mass, SSA is the largest source and has the largest uncertainty of all aerosols. In this study I have reviewed 21 SSA source functions from the literature, several of which are used in current climate models, and as a result of this work  a new source function is proposed.

    The model FLEXPART was run in backward mode utilizing a large global set of observed SSA concentrations, comprised of several station networks and ship cruise measurement campaigns. FLEXPART backward calculations produce gridded emission sensitivity fields, which can subsequently be multiplied with gridded SSA production fluxes to obtain modeled SSA concentrations. This allows to efficiently evaluate all 21 source functions at the same time. Another advantage of this method is that source-region information on wind speed and sea surface temperatures (SSTs) could be stored and used for evaluating their influence on SSA production.

    The main driver of SSA production is wind, and the best fit to the observation data could be obtained when the SSA production is proportional to U103.5. A strong influence of SST on the production could be detected as well, although the underlying physical mechanisms of the SST influence remains unclear. For SST we obtain the best fit to the measurement data when SSA concentration is proportional to 0.031×T+0.39, where T is the source average SST. Based on the model source region average temperature and wind, an empirical fit was made to the data and a new source function obtained. The fit was made by using the model concentrations, observational data, ECMWF winds and the existing source function volume fluxes. Our new source function gives a global SSA production for particles smaller than 10μm of 9Pg yr-1 and is the best fit to the observed concentrations. The existing source functions display the large uncertainties, spanning from a global emitted mass of 1.9 to 100’s of Pg yr-1. Wind dependencies also range strongly and those far from U103.5, have poor correlation with observed values. It is also possible to add temperature dependence to an existing source function to come further towards observed values with the model results.

     

  • 24.
    Guterstam, Peter
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    EL Andaloussi, Samir
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Characterization of cellular internalization pathways for CPP-mediated oligonucleotide delivery2011In: Cell-penetrating peptides: Methods and Protocols / [ed] Ülo Langel, New York: Humana Press, 2011, p. 219-230Chapter in book (Other academic)
    Abstract [en]

    The methods for evaluating internalization pathways of cellular CPP-mediated ON delivery utilizing a pre-mRNA splice correction assay and fluorescence-based quantification are described. Examples for characterization of CPP uptake routes, employing various endocytosis inhibitors, and special treatment conditions are demonstrated. The methods are developed to characterize cellular delivery of pre-mRNA splice switching peptide nucleic acids conjugated to CPPs by disulfide bond.

  • 25.
    Henriksson, Linda
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structural and functional studies of a novel Botulinum neurotoxin and of MTH12018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    X-ray crystallography visualizes the three dimensional molecular structures of proteins at atomic resolution. Seeing the molecular structure of a biomedically interesting protein enables a higher understanding of its function. The process of producing pure protein from genetic material to generate crystals and determine the molecular structure can be a long and challenging process. My thesis involves structural and functional studies of two different proteins, which are both biomedically interesting and important to learn about. X-ray crystallography is the method which has been used to determine the majority of the protein structures that we know of today and is also the method used in the results presented in my thesis. 

    Today there are no cancer therapies defeating all types of cancers and they do not come without side effects. Battling cancer diseases often include long and painful treatments. Finding an anti-cancer drug targeting phenotypes characteristic of cancer cells is a compelling thought. MutT homolog-1 (MTH1) is an enzyme present in all proliferating cells. The enzyme seems to be crucial for cancer cell survival but not for the viability of normal cells. MTH1 cleans out oxidized and thereby damaged nucleotides from the free nucleotide pool and stops them from being used in DNA synthesis. This process is very important in fast proliferating cancer cells. The hypothesis is to inhibit MTH1 and thereby allow a limitless amount of DNA damage in the cancer cells. This action will eventually kill cancer cells while not affecting normal cells. The molecular structure of MTH1 with (PDB ID: 3ZR0) and without a product bound (PDB ID: 3ZR1) was determined and is presented in my thesis. These two structures aided in the synthesis of inhibitors. 

    Botulinum neurotoxins (BoNTs) are the most potent toxins known. As little as one gram of pure toxin could potentially kill one million people. Due to its potency BoNT is a potential  bioterrorism threat. The toxin is also a very potent drug used clinically to relieve the symptoms of an array of neuromuscular disorders. Most people know this neurotoxin by one of its commercial names: Botox™. Additionally BoNTs are the cause of botulism. BoNTs are neuro-specific enzymes that target neuromuscular signaling, inducing flaccid paralysis and potentially death. It is of importance to learn more about these toxins to enable the development of new countermeasures, vaccines or more efficient neuroparalytic drugs. BoNTs consist of three domains with different functions, all crucial for intoxication. The toxins are fragile and can easily be destroyed by harsh surroundings if not protected by non-toxic non-hemagglutinin (NTNH) proteins. The complex of some BoNT serotypes and their protective NTNH have proven to be pH-dependent. Parts of the intoxication process are not yet clear and their mechanisms are still puzzling researchers. Until recently seven BoNT serotypes were identified. We have now identified and characterized a novel serotype called BoNT/X. The molecular structure of the active domain is presented here (PDB ID: 6F47). The pH-dependent mechanism forming a complex as seen in other serotypes, is confirmed to be present in BoNT/X as well.

  • 26. Houde, Magali
    et al.
    Pacepavicius, Grazina
    Darling, Colin
    Fair, Patricia A
    Alaee, Mehran
    Bossart, Gregory D
    Solomon, Keith R
    Letcher, Robert J
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Marsh, Göran
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Muir, Derek C G
    POLYBROMINATED DIPHENYL ETHERS AND THEIR HYDROXYLATED ANALOGS IN PLASMA OF BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS) FROM THE UNITED STATES EAST COAST.2009In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 28, no 10, p. 2061-2068Article in journal (Refereed)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) and hydroxylated-PBDEs (OH-PBDE) were determined in plasma of free-ranging bottlenose dolphins (Tursiops truncatus) from Charleston (CHS), South Carolina, and the Indian River Lagoon (IRL), Florida, US. Significantly lower sum (Sigma) of PBDE concentrations (sum of 12 congeners) were found in animals from the IRL [arithmetic mean: 5.454.63 ng/g wet weight (ww)] compared to CHS (3040 ng/g ww). BDE-47 was the predominant PBDE in dolphins from the IRL (50% of the SigmaPBDEs) and CHS (58%). SigmaPBDE concentrations in plasma of dolphins were negatively correlated with age at both locations. Fifteen and sixteen individual OH-PBDE congeners could be quantified in plasma of dolphins from IRL and CHS, respectively. Similar to SigmaPBDE, mean SigmaOH-PBDE concentrations were significantly higher in plasma of dolphins at CHS (1150708 pg/g ww) compared to IRL (624393 pg/g ww). The predominant congener at both locations was 6-OH-PBDE 47 (IRL: 384319 pg/g ww; CHS: 541344 pg/g ww) representing 61.5% of total SigmaOH-PBDE at IRL and 47.0% at CHS. Concentrations of SigmaOH-PBDEs were weakly negatively correlated with age in dolphins from both locations (P<0.05; IRL, R2=0.048; CHS, R2=0.021). In addition to the OH-PBDE congeners identified with technical standards, eight and four unidentified OH-PBDEs were detected and quantified respectively in animals from CHS (sum of unidentified OH-PBDEs=1.350.90 pg/g ww) and IRL (0.730.40 pg/g ww). Our results suggest that, unlike OH-PCBs, OH-PBDEs in bottlenose dolphins are minor products in plasma relative to SigmaPBDEs and a significant proportion may be a consequence of the dietary uptake of naturally produced methoxylated- and OH-PBDEs.

  • 27. Jakobsson, K.
    et al.
    Fång, Johan
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Athanasiadou, Maria
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Rignell-Hydbom, A.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Polybrominated diphenyl ethers in maternal serum, umbilical cord serum, colostrum and mature breast milk: Insights from a pilot study and the literature2012In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 47, p. 121-130Article in journal (Refereed)
    Abstract [en]

    Human serum and mother's milk are frequently used to assess exposure to polybrominated diphenyl ethers (PBDEs), including transplacental transfer to the foetus. However, little is known about the kinetics of PBDEs, especially the highly brominated BDE congeners.

    In this pilot study, maternal serum samples were collected from 10 women at delivery and five to six weeks post partum. Umbilical serum was also obtained. Milk was donated two to five days, and five to six weeks after delivery. The amount of PBDEs in these samples was determined using liquid–liquid extraction and GC/MS.

    Low, moderately and highly brominated diphenyl ethers were present in umbilical cord serum, indicating placental transfer. The lipid-adjusted levels of BDE-47, BDE-207 and BDE-209 were similar in maternal and umbilical cord serum, whereas the cord serum levels for the penta- to octa-BDEs quantified were lower than in maternal serum.

    Marked changes were seen in the congener pattern in breast milk during the first month of lactation, whereas maternal serum levels did not change significantly. The general pattern was an enrichment of low to moderately brominated congeners (i.e. from BDE-17 to BDE-154, with the exception of BDE-28) in colostrum compared with maternal serum. In contrast, more highly brominated congeners were found at similar, or lower levels in colostrum than in maternal serum. After the transition from colostrum to mature milk, the levels of BDE-153 and BDE-209 were substantially reduced, and BDE‐209 was below the limit of detection in 6 out of 9 samples.

    A literature review on the design and reporting of studies on the transfer of PBDEs from mother to infant revealed a lack of transparency in many cases. The use of the recently published STROBE-ME guidelines is therefore recommended.

  • 28.
    Jeppsson, Fredrik
    et al.
    Innovative Medicines AstraZeneca, CNS and Pain, Södertälje, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden.
    Falting, Johanna
    Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 49, p. 41245-41257Article in journal (Refereed)
    Abstract [en]

    beta-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid beta peptide (A beta species. Because cerebral deposition of A beta species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, A beta and sAPP beta release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose-and time-dependent lowering of plasma, brain, and cerebrospinal fluid A beta levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of A beta in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.

  • 29. Johnson, Allan E.
    et al.
    Jeppsson, Fredrik
    Molecular Pharmacology, AstraZeneca R&D, Södertälje, Sweden.
    Svensson, Samuel P. S.
    AZD2184: a radioligand for sensitive detection of beta-amyloid deposits2009In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 108, no 5, p. 1177-1186Article in journal (Refereed)
    Abstract [en]

    The presence of beta-amyloid plaques in brain is a hallmark of Alzheimer's disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Positron emission tomography (PET) radioligands such as Pittsburgh compound B ([(11)C]-2-(3-fluoro-4-methylamino-phenyl)-benzothiazol-6-ol) (PIB) binds selectively to beta-amyloid and are promising new tools supporting the clinical diagnoses of AD. In addition, such methodology may be useful for evaluation of new drugs aiming at reduction of amyloid plaque load. The objective of this study is to develop a new amyloid selective PET radioligand with higher signal-to-background ratio when compared with existing amyloid PET ligands. The lead compound, AZD2184, (2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol) was found to have high affinity for amyloid fibrils in vitro (K(d): 8.4 +/- 1.0 nM). Two minutes after i.v. administration in rats, about 1% of the dose was in brain. In vitro autoradiography on cortical brain sections from amyloid-beta precursor protein/presenilin 1 (APP/PS1) mice and AD patients showed that while [(3)H]AZD2184 and [(3)H]PIB are mutually displaceable, [(3)H]AZD2184 displays a higher signal-to-background ratio primarily by virtue of lower background binding levels. The ratio of binding ability in prefrontal cortex (high plaque load) to subcortical white matter (background) was 4.5 for [(3)H]AZD2184 and 0.8 for [(3)H]PIB at 1 nM. In adjacent cortical sections from APP/PS1 mouse as well as from AD cortical tissue, [(3)H]AZD2184 and antibodies to human beta-amyloid labeled identical structures. In vivo administration of [(3)H]AZD2184 to APP/PS1 mice further showed that [(3)H]AZD2184 labels amyloid deposits with low non-specific background binding. Taken together, the pre-clinical profile of AZD2184 in relation to the reference ligand PIB, suggests that (11)C-labeled AZD2184 is a potential radioligand for PET-visualization of beta-amyloid deposits in the living human brain.

  • 30. Juréus, Anders
    et al.
    Jeppsson, Fredrik
    Department of Neuroscience, AstraZeneca R&D Södertälje, Södertälje, Sweden.
    Svensson, Samuel P. S.
    Characterization of AZD4694, a novel fluorinated Abeta plaque neuroimaging PET radioligand2010In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 114, no 3, p. 784-794Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography (PET) radioligands that bind selectively to β-amyloid plaques (Aβ) are promising imaging tools aimed at supporting the diagnosis of Alzheimer’s disease and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use, there is a particular need for PET tracers labeled with fluorine-18, a radionuclide with 110 min half-life allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is, however, challenging because of the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high non-specific white matter binding. We have here developed the new benzofuran-derived radioligand containing fluorine, AZD4694 that shows high affinity for β-amyloid fibrils in vitro (Kd = 2.3 ± 0.3 nM). In cortical sections from human Alzheimer’s disease brain [3H]AZD4694 selectively labeled β-amyloid deposits in gray matter, whereas there was a lower level of non-displaceable binding in plaque devoid white matter. Administration of unlabeled AZD4694 to rat showed that it has a pharmacokinetic profile consistent with good PET radioligands, i.e., it quickly entered and rapidly cleared from normal rat brain tissue. Ex vivo binding data in aged Tg2576 mice after intravenous administration of [3H]AZD4694 showed selective binding to β-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [3H]AZD4694 could still be detected 80 min after i.v. administration. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labeled AZD4694 may have potential for PET-visualization of cerebral β-amyloid deposits in the living human brain.

  • 31.
    Konn, Cécile
    Stockholm University, Faculty of Science, Department of Geology and Geochemistry.
    Origin of organic compounds in fluids from ultramafic-hosted hydrothermal vents of the Mid-Atlantic Ridge2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Natural gas, primarily methane (CH4), is produced in substantial amounts in ultramafic-hosted hydrothermal systems. These systems could also generate oil (heavier hydrocarbons) and the first building blocks of life (prebiotic molecules). In the presence of iron bearing minerals, serpentinisation reactions generate H2. Subsequently, CH4 could be synthesised by Fischer-Tropsch Type (FTT) reaction (4H2 + CO2 → CH4 + 2H2O) which is an abiotic process. This has lead to the idea of abiotic formation of larger organic molecules. Both thermodynamics and laboratory work support this idea, yet field data have been lacking. This study focuses on determining the organic content of fluids from ultramafic-hosted hydrothermal systems from the Mid-Atlantic Ridge (MAR) and the origin of the compounds. Fluids were collected from the Lost City, Rainbow, Ashadze and Logatchev vent fields during the EXOMAR (2005), SERPENTINE (2007), MoMARDREAMnaut (2007) and MOMAR08-Leg2 (2008) cruises conducted by IFREMER, France. A SBSE-TD-GC-MS technique was developed and used to extract, concentrate, separate and identify compounds in the fluids. Hydrothermally derived compounds appeared to consist mainly of hydrocarbons and O-bearing molecules. In addition, some amino acids were detected in the fluids by ULPC-ESI-QToF-MS but their origin will need to be determined. The organic content of the Rainbow fluids did not show intra field variability unlike differences could be noted over the years. In order to address the question of the source of the molecules, compound specific carbon isotopic analyses were carried out and completed with a bacterial (Pyrococcus abyssi) hydrothermal degradation experiment. The δ13C data fall in the range of -40 to -30‰ (vs. V-PDB), but individual δ13C values preclude the identification of a biogenic or abiogenic origin of the compounds. The degradation experiment, however, suggests an abiogenic origin of a portion of saturated hydrocarbons whereas carboxylic acids would be biogenic, and aromatic compounds would be thermogenic.

  • 32.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Preface2011In: Cell-Penetrating Peptides: Methods and Protocols / [ed] Ûlo Langel, Humana Press, 2011Chapter in book (Other academic)
  • 33.
    Lindqvist, Dennis
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Hydroxylated polybrominat­ed diphenyl ethers in Baltic Sea biota: Natural production, food web distribution and biotransformation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are naturally produced in aquatic ecosystems e.g. by algae. Many OH-PBDEs have been observed to be highly bioactive and to cause adverse effects through several pathways, e.g. via disrupting oxidative phosphorylation (OXPHOS). The levels of some OH-PBDEs have increased in Baltic biota over the past decades. This may be associated with the nutrient enrichment of the Baltic Sea, which has favored growth of some of the OH-PBDE producers.

    Ceramium tenuicorne has been suggested to be a producer of OH-PBDEs in the Baltic Sea, which is supported by the results presented in this thesis. The levels of OH-PBDEs were observed to fluctuate greatly in C. tenuicorne over the summer season, and to correlate with the levels of pigments in the algae. However, the observed congener pattern in C. tenuicorne questioned theories regarding the mechanism of their biosynthesis. The results indicate a much more selective pathway for biosynthesis than previously suggested for the production of OH-PBDEs.

    One of the most abundant OH-PBDEs in C. tenuicorne, 6-OH-BDE137, has previously been observed to be toxic to bacteria, fungi, and crustaceans. Furthermore, Baltic gammarids seemed to change their feeding preferences towards less grazing on C. tenuicorne during the production peek of OH-PBDEs in the alga. This suggests that OH-PBDEs may serve as allelochemical defense agents for C. tenuicorne.

    The transport and fate of OH-PBDEs through a Baltic food chain was also studied, including C. tenuicorne, Gammarus spp., three-spined stickleback (Gasterosteus aculeatus), and perch (Perca fluviatilis). A small portion of the OH-PBDEs were observed to be methylated in the alga, or by associated bacteria. The methylated OH-PBDEs biomagnified in the food chain up to perch, in which they were converted back to the OH-PBDEs via demethylation. The OH-PBDEs and their methylated counterparts were also partially debrominated in the food chain, which resulted in high concentration of 6-OH-BDE47 in the perch. This congener is the most toxic OH-PBDE with regards to OXPHOS disruption.

    Another biotransformation of OH-PBDEs was identified in Baltic Sea blue mussels (Mytilus edulis). High concentrations of OH-PBDEs were conjugated with lipophilic moieties, e.g. fatty acids. This increases the residence time of the OH-PBDEs in the mussels. Mussels have been suggested to conjugate steroids with fatty acids as a means to regulate hormone levels. The conjugation of OH-PBDEs to fatty acids may occur due to intrusion into this pathway. Methods were developed to include quantification of conjugated OH-PBDEs in the analysis of mussels.

    OH-PBDEs were also quantified in blood from Baltic Sea grey seals (Halichoerus grypus). Seals originating from the Baltic proper were observed to be more highly exposed to 6-OH-BDE47 than seals from the Gulf of Bothnia. However, the levels of OH-PBDEs were generally low. A major effort was invested into securing these results, including development of a new analytical method. Blood obtained from dead seals is a difficult matrix for quantification of OH-PBDEs, and previous attempts using an established method yielded unsatisfactory results.

  • 34.
    Ljungberg, Mathias P.
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Nilsson, Anders
    Stockholm University, Faculty of Science, Department of Physics.
    Pettersson, Lars G.M.
    Stockholm University, Faculty of Science, Department of Physics.
    Semi-classical description of nuclear dynamics in x-ray emission of water2010In: Physical Review B Condensed Matter, ISSN 0163-1829, E-ISSN 1095-3795, Vol. 82, no 24, p. 245115-Article in journal (Refereed)
    Abstract [en]

    In this article we present a semi-classical approximation to the Kramers-Heisenberg formula for calculating x-ray emission (XES) spectra, including vibrational effects. We compare the method to the quantum Kramers-Heisenberg formula for a test system consisting of a model water dimer where the hydrogen-bond donor is core-ionized and obtain excellent agreement. In the semi-classical approach we average spectra from classical trajectories where the core-hole-induced dynamics is performed with initial conditions sampling the quantum zero-point position and momentum probability distributions in the O-H vibration. We find very similar time-evolution of the squared quantum wave packet compared to the probability distribution under classical dynamics until the proton interacts with the next water. We compare our semi-classical approach with other methods to compute the XES spectra of water that have been used in the past and conclude that our approach gives superior results while requiring the same computational effort.

  • 35.
    Lundin, Per
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    EL Andaloussi, Samir
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Toxicity methods for CPPs2011In: Cell-penetrating peptides: Methods and Protocols, New York: Humana Press, 2011, p. 195-205Chapter in book (Other academic)
    Abstract [en]

    CPPs have for numerous years been utilized as delivery vectors of various pharmaceutically interesting cargoes, both in vitro and in vivo. As CPPs are gradually approaching the bedsides, investigating toxicity associated with these highly interesting peptides becomes increasingly important and thorough initial assessment of cytotoxicity in vitro is a first step towards advancing these delivery vehicles in to the clinics. The present chapter describes protocols for four cytotoxicity assays in order to provide a toolbox for toxicity assessment of CPPs. The foci lie on membrane integrity (deoxyglucose leakage and propidium iodide assays) and cell viability (the MTT assay), but the chapter also provides a protocol for assessing an important parameter for future clinical applications, namely the hemolytic properties of CPPs.

  • 36.
    Lundkvist, Johan
    Stockholm University.
    Role of IL-1RAcP and IL-1ra in IL-1 signalling: molecular biological and transgenic studies1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    IL-1 is a proinflammatory cytokine which causes systemic responses such as fever, increased neuroendocrine activity, sympathetic outflow and increased immune responses. Activation of the transcription factor NFkB is one of the molecular mechanisms involved in IL-1 signalling.

    We have shown that the IL-1binduced fever response is regulated the hypothalamic - pituitary - adrenal axis (HPA-axis), as either the nonpeptidic CRF receptor antagonist CP154,526, or a subchronic glucocorticoid treatment, respectively, blocked the ability of peripheral IL-1bto induce fever in rats. The subchronic glucocorticoid treatment caused a dampened IL-1aand IL-1bmRNA expression in the hypothalamus whereas IL-6 mRNA was induced by the same glucocorticoid treatment. Both the glucocorticoid altered cytokine mRNA levels and IL-1 induced fever responses, respectively, were reversed to normal upon the removal of exogenous glucocorticoids. Both IL-1 receptor antagonist (IL-1ra) mRNA and protein were detectable in adrenal chromaffin cells. Adrenal IL-1ra mRNA levels were furthermore rapidly induced by a peripheral lipopolysaccharide (LPS) challenge.

    Type II IL-1R (IL-1RII) is a negative regulator of IL-1 bioactivities by being a nonsignaling, IL-1 binding protein. Here we present evidence that IL-1RII also can interact with IL-1R accessory protein (IL-1RAcP), thus extending the previously known IL-1 suppressing activity of IL-1RII to encompass the sequestering of IL-1RAcP from the signaling IL-1RI complex. IL-1RAcP was shown to be a necessary component of the murine (m) IL-1RI complex in transducing the IL-1 signal to NFkB activation in murine fibroblast C127 cells and in primary mouse astrocyte cultures. In addition, heterologous murine IL-1RAcP and human IL-1RI complexes formed functional IL-1bsignaling complexes.

    Transgenic mice deficient in IL-RAcP did not respond with fever to either a peripheral injection of IL-1aor to IL-1b, thus implicating IL-1RAcP as a necessary component of the IL-1RI complex in vivo.

    To examine the role of central IL-1ra in suppressing IL-1signaling, the cDNA encoding the human secretable form of IL-1ra (hsIL-1ra) was expressed under the control of the glia fibrillary acidic protein (GFAP) promoter in transgenic mice. The expression of hsIL-1ra mRNA and protein were exclusively restricted to CNS, as measured by RT-PCR and ELISA, respectively. The GFAP-hsIL-1ra (GILRA) mice did not exhibit fever upon a central injection of IL-1b, while a peripheral LPS injection caused a hypersensitive fever response in these mice. These mice strains provide a model for studies on IL-1R occupancy and systemic responses.

  • 37. Mattsson, Anna
    et al.
    Jeppsson, Fredrik
    Stockholm University, Faculty of Science, Department of Neurochemistry. AstraZeneca CNS and Pain iMed, Södertälje, Sweden.
    Juréus, Anders
    Altered amyloid PET ligand binding to ApoE-containing plaques in Alzheimer´s disease brain in vitro Article in journal (Refereed)
  • 38.
    Moustiakimov, Marat
    Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry.
    X-ray structural studies of lanthanide alkoxides2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [sv]

    A number of homo- and hetero-metallic lanthanide (oxo-)isopropoxides with the general composition LnxMyO(OiPr)p(HOiPr)q has been structurally characterized by means of single crystal X-ray diffraction. The studied compounds may be divided into five groups by the geometry of their metal-oxygen core.

    1) M5O(OiPr)13 (M = Er, Eu, Gd) and [(Eu2+)(Eu3+)4O(OiPr)12(HOiPr)]*(HOiPr). In this system the flexibility of the close-packed molecular framework with respect to orientation of the molecules and the possibility to incorporate solvent molecules has been shown.

    2) (Tb0.9Er0.1)4TiO(OiPr)14, Er4SbO(OiPr)13 and Er2M2TiO(OiPr)14 (M = La, Sc). Three geometrically distinct metal positions may be identified in the common M4TiO(OiPr)14 system, so that metal composition may be stated as M2M’2Ti. The successful substitution in the Er4TiO(OR)14 molecule of Ti for Sb and of two Er atoms for La has been performed.

    3) M[Al(OiPr)4]3 (M = Nd, Eu). The phase transition from orthorhombic modification at room temperature to monoclinic at 110 K has been observed when M = Nd. Both compounds form pseudo-merohedrally twinned crystals at low temperature.

    4) [(Eu3+)2(Eu2+)2(OiPr)10(HOiPr)3]*2(HOiPr) is probably the first mixed valence Eucontaining alkoxide structurally characterized. It also exhibits rare four-dentate [OiPr]1- ligand.

    5) Er4Cs2O(OiPr)12 and Er4(Na0.75Er0.25)2O(OiPr)13(HOiPr). The two chemically related phases display similar molecular geometry with distorted octahedral configuration of metal atoms. Yet the relative arrangement of two alkali elements within the octahedron is different: trans for Na and cis for Cs.

  • 39.
    Norrgran Engdahl, Jessica
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cats as a biomarker for exposure to POPs in home environments: – with focus on brominated chemicals and associations to feline hyperthyroidism2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, body burden of brominated chemicals such as polybrominated diphenyl ethers (PBDEs) and brominated phenolic substances are explored. The external exposure of cats to these compounds from house dust and their food was also investigated. The analytical methodology used for serum extractions was validated for analysis of OH-PBDEs in cat serum.

    Cats are highly exposed to dust and thereby also to chemicals accumulated in dust, due to their grooming behavior. This makes pet cats, a suitable biomarker for exposure to chemicals in house dust in home environments. Thereby, cats’ exposure to dust is somewhat similar to toddlers, due their hand-to-mouth behavior. Thus, cats’ internal exposure may be used to access that of toddlers. The PBDE pattern in Swedish pet cats show exposure to Penta-, Octa- and DecaBDE and their profile matches that of dust from their homes, suggesting dust to be an important exposure source. Serum concentrations of BDE-47 in the cats were also shown to correlate with house dust from their living rooms.

    Feline hyperthyroidism (FH) is a common endocrine disease in elderly cats worldwide, still the actual cause(s) has not been established even though environmental pollutants such as PBDEs have been suggested. Difference in contamination load between cats with normal thyroid status and cats diagnosed with FH was performed and higher serum concentrations for some PBDEs (BDE-99, 153, -183) were found in the hyperthyroid cats.

    Further, the presence of the longtime discontinued flame retardant, decabromobiphenyl (BB-209) in all sampled cats indicates that it is still being circulated. A significant correlation between serum concentrations of BB-209 and matched cat food samples was found.

    Very few OH-PBDEs were indeed shown in cat serum and the dominating compound, 6-OH-BDE47, is believed to be of natural origin rather than being a metabolite of BDE-47. A significant correlation between serum concentration of 6-OH-BDE47 and cat food was found.

  • 40.
    Norrgran Engdahl, Jessica
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Jones, Bernt
    Athanassiadis, Ioannis
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Bignert, Anders
    Weiss, Jana
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cats’ internal exposure to selected BFRs and organochlorines correlated to house dust and cat foodManuscript (preprint) (Other academic)
  • 41.
    Nyberg, Elisabeth
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Swedish Museum of Natural History.
    Improved Assessment in Environmental Monitoring of POPs: Using monitoring data from the aquatic ecosystem and human milk2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The thesis deals with several aspects of monitoring of persistent organic contaminants (POPs) in biological matrices, for example choice of sample, sampling design, and statistical treatment of data both for temporal and spatial trends and for compliance towards a set target value. The efficiency has been evaluated through statistical power analyses. Contaminant data from more than 4 decades from the Swedish National Monitoring Programs for monitoring of contaminants in biota (marine, freshwater and human health), has been quantitatively evaluated both temporally and spatially and for compliance. The aim was also to evaluate the suitability of different matrices, i.e. herring (Clupea harengus), guillemot (Uria aalge) egg, cod (Gadus morhua), perch (Perca fluviatilis), eelpout (Zoarces viviparous), blue mussel (Mytilus edulis), pike (Esox lucius), Arctic char (Salvelinus alpinus) and human milk, for monitoring of POPs with the overall aim to improve the assessment within monitoring programs.

    The results show that variation can be reduced by using pooled samples including more specimens but fewer chemical analyses, which in turn generate a higher statistical power to a lower cost, at least in cases where the cost of collection and sampling is considerably lower than the cost of chemical analysis. However, there are also a number of advantages using individual samples, such as information of sample variance and maximum value, which allows the choice of an appropriate central measure and direct adjustment of confounding factors.

    Generally, the levels of polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethanes (DDTs), hexachlorocyclohexanes (HCHs) and hexachlorobenzene (HCB) have decreased both in marine and freshwater biota but concentrations are still higher in the Baltic compared to e.g. the North Sea. The levels of dioxinlike-PCBs and polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDD/Fs) have decreased in human milk over time, but not to the same extent in fish and guillemot egg from the Baltic and the freshwater environment. This may be explained by the dietary advice developed by the Swedish Food Administration with the goal that girls, reproductive aged, and pregnant women should eat less food containing high levels of PCDD/Fs. Thus the levels in milk could continue to decrease at the same rate although the temporal trend in the environment has slowed down or leveled out.

    The most essential regarding the choice of species and matrices for contaminant monitoring, is that the species and organ fit the purpose of the monitoring.

  • 42.
    Rydén, Andreas
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Synthesis of organobromines as a tool for their characterisation and environmental occurrence assessment2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) have been intensively used as flame retardants (FRs) and have become ubiquitous environmental pollutants. PBDEs form hydroxylated PBDEs (OH-PBDEs) as metabolites. Further, some OH-PBDEs and methoxy-PBDEs (MeO-PBDEs) are natural products. These are all compounds of environmental and health concern and it is therefore important to confirm their identity and to assess their environmental levels and toxicities. Hence, it is vital to obtain authentic reference standards of individual PBDEs and OH/MeO-PBDEs. The thesis main aim was to develop synthesis methods of congener specific PBDEs, OH- and MeO-PBDEs. The second aim was to identify and quantify PBDEs, OH- and MeO-PBDEs in environmental samples. The third was to propose an abbreviation system for FRs.

    O-Arylation of brominated phenols, using either symmetrical or unsymmetrical brominated diphenyliodonium salts, was selected for synthesis of PBDEs and OH-/MeO-PBDEs. A total of 16 MeO-PBDEs, 11 OH-PBDEs, 1 diMeO-PBDE and 1 EtO-MeO-PBDE were synthesised. Three novel unsymmetrical diaryliodonium triflates were synthesised and used in synthesis. Optimisations were made to construct a reliable general method for congener specific PBDE synthesis, which was used in the synthesis of 8 representative PBDE congeners. The products were generally characterised by electron ionisation mass spectrometry (EIMS) and nuclear magnetic resonance (NMR) spectroscopy.

    Identification of PBDEs and OH-PBDEs in various matrixes was based on gas chromatographic and mass spectrometric analyses. Fourteen OH-PBDE congeners were identified in a pooled human blood sample. One previously uncharacterised natural PBDE analogue was identified as 6-OH-6’-MeO-BDE-194, and quantified in Swedish blue mussels. PBDE congeners and other BFRs were identified and quantified in workers and dust from a smelter in Sweden.

    A structured and practical abbreviation system was developed for halogen- and phosphorus containing FRs.

  • 43.
    Rydén, Andreas
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Marsh, Göran
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Synthesis of polybrominated diphenyl ethers via unsymmetrical diaryliodonium triflatesManuscript (preprint) (Other academic)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants due to theirpersistent character and extensive use as additive flame retardants. In order to assess theirbiological effects, fate, environmental concentrations and other parameters related to riskassessment, authentic PBDE congers are needed for research purposes. In the present work anew general method for the preparation of individual PBDE congeners is presented. Themethodology used is based on recent advances in unsymmetrical diaryliodonium saltsynthesis as well as advances in O-arylation of phenols with these types of salts. Accordingly,three brominated diphenyliodonium triflates were prepared i.e. phenyl(2,4,5-tribromophenyl)iodonium triflate, phenyl(2,4,6-tribromophenyl)iodonium triflate andphenyl(2,3,4,6-tetrabromophenyl)iodonium triflate from 1,2,4-tribromo-5-iodobenzene, 1,3,5-tribromo-2-iodobenzene and 1,2,3,5-tetrabromo-4-iodobenzene, respectively. Yields indiaryliodonium salt syntheses ranged from 69-96%. These salts were further used to O-arylatevarious brominated phenols giving individual tetra- to octa-BDE congeners in yields rangingfrom 64-98%. The O-arylation method used was given after a minor optimisation study, regarding reaction time and temperature, which is reported herein. In addition, this O-arylationmethod was also used with two brominated methoxyphenols in the syntheses of twomethoxylated PBDEs.

  • 44.
    Srimanee, Artita
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Peptide-based delivery to glioblastoma cells studied by the blood-brain barrier model2016Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Crossing the blood-brain barrier (BBB) is a great challenge for delivery of highly charged macromolecules such as nucleic acids and proteins to the brain. Cell-penetrating peptides (CPPs) are promising vectors to deliver various cargoes ranging from small molecules to large molecules such as antibodies, proteins, and nucleic acids. The BBB limits the passage of all large molecules to central nervous system (CNS), thus, CPP is a potential vector to use for oligonucleotide delivery across the BBB. In paper I, various CPPs were covalently conjugated with two different glioma-targeting peptides, glioma-homing peptide (gHo) and angiopep-2 (ANG). PepFect 32 (PF32), a conjugation between truncated PepFect 14 and ANG, was the most efficient vector to deliver plasmid DNA (pDNA) across a setup in vitro model of the BBB and showed the highest transfection in glioma cells. LRP-1 receptors, which are over-expressed in brain endothelial cells and glioma cells, were speculated to mediate the transcytosis of PF32:pDNA complexes across the BBB model since the ANG could target to LRP-1. In paper II, scavenger receptors class A and B (SCARA3, SCARA5, and SR-BI) were found to be expressed in the brain endothelial cells. Inhibition of these scavenger receptors led to a reduction of the transfection of PF32:pDNA complexes in the brain endothelial cells. Therefore, in the BBB model scavenger receptors also played a vital role as well as LRP-1 in the transport of oligonucleotides in the complex with peptide-based vector PF32.

    In conclusion, PF32 is a potential vector to deliver pDNA across the BBB model and target to the glioma cells. The complexes of PF32:pDNA transport across the brain endothelial cells via receptor-mediated endocytosis pathway recognized by scavenger receptors and LRP-1. To improve the specificity and enhance the transport into the brain, the brain-homing devices are considered as a promising strategy for CNS drug delivery.

  • 45.
    Sundgren Andersson, Anna
    Stockholm University.
    On Fever Mechanisms & Preoptic Signalling1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fever, a 1-4 °C elevation of the body temperature, is part of the systemic inflammatory response to infection or tissue damage, and it is believed to be a potent host defence. The underlying physiological mechanisms of the febrile response are one of the two main objectives in this thesis, where studies conducted in whole animals (rats and mice), chiefly aimed at clarifying the cytokine cascade in fever. The other principal objective of this thesis was to gain a general understanding on the signalling properties of neurons in the thermoregulatory region of the brain, the preoptic area, through electrophysiological investigations in vitro of ion channels and impulse firing behaviour of medial preoptic neurons of rat. From these studies it was concluded that:

    The endogenous pyrogen tumour necrosis factor _ (TNF_) injected intraperitoneally causes fever independent of interleukin-1_ (IL-1_), but dependent on interleukin-6 (IL-6) in the central nervous system. The TNF__induced fever is triggered through release endoperoxides, since pre-administration of the cyclooxygenase inhibitor indomethacin, efficiently blocks the increased body temperature.

    An intraperitoneal injection of lipopolysaccharide (LPS) induces fever that is independent on central IL-1 binding to its receptors, since occupancy of central IL-1 receptors of the IL-1 receptor antagonist (IL-1ra), is unable to block the febrile response.

    The temperature in the central nervous system and in the peritoneum are similar during the febrile response with respect to onset, temporal characteristics and fever amplitude.

    The neurons of the medial preoptic nucleus respond to glutamate application with currents that can be attributed to ion channels of the AMPA-receptor type as well as of the NMDA-receptor type. The functional characteristics of these channels comprise fast activation and desensitization of the AMPA-receptor channel, as well as glycine dependency, Mg2+dependent outward rectification and slow desensitization kinetics of the NMDA-receptor channel.

    The medial preoptic neurons display two types of Ca2+ spikes, that result in two types of firing behaviour. First, low-threshold spikes depend on T-type Ca2+ channels and are generated from membrane potentials < -75 mV. They may induce short bursts of fast Na+ spikes. Second, high-threshold spikes can be generated from more depolarized levels, and depend on Ca2+channels that are mainly of the L, N and P -types. One role of these channels is to sustain long-burst firing.

    Medial preoptic neurons spontaneously fire with several types of temporal firing patterns. Apart from burst firing, neurons are silent or discharge regularly as well as irregularly. The type of firing pattern can be manipulated with steady current injection and possibly also by PGE2.

  • 46.
    Thornton, Brett F.
    et al.
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Burdette, Shawn C.
    Chemistry’s Decision Point: Isotopes2017In: Elements Old and New: Discoveries, Developments, Challenges, and Environmental Implications / [ed] Mark A. Benvenuto, Tracy Williamson, American Chemical Society (ACS), 2017, p. 119-140Chapter in book (Refereed)
    Abstract [en]

    Although the modern periodic table barely resembles the one constructed by Dmitri Mendeleev, every chemistry student learns that the placement of missing elements in the open slots of Mendeleev’s table was a scientific triumph. The discovery of isotopes in the early 1900s was an inflection point in periodicity, and chemistry as a discipline. Chemists once characterized each new isotope as a unique element—but as isotopes proliferated, fitting them into the existing periodic table became impossible. Several decades passed before the concept of isotopy fully developed. At that point, scientists seemingly concluded that chemistry occurred at the atomic level, and isotopic differences were the purview of physics. Had a different understanding of isotopy prevailed, the direction of chemistry could have changed dramatically. While the trajectory of synthetic chemistry might have remained constant, ‘chemists’ may have dominated the discovery of new superheavy elements by appropriating the modern conventional definition of ‘nuclear physicist’.

  • 47.
    Thornton, Brett F.
    et al.
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Burdette, Shawn C.
    University of Connecticut.
    Finding eka-iodine: discovery priority in modern times2010In: Bulletin for the History of Chemistry, ISSN 1053-4385, Vol. 35, no 2, p. 86-96Article in journal (Refereed)
  • 48.
    Thornton, Brett F.
    et al.
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Burdette, Shawn C.
    Frantically forging fermium2017In: Nature Chemistry, ISSN 1755-4330, E-ISSN 1755-4349, Vol. 9, p. 724-724Article in journal (Other academic)
    Abstract [en]

    Brett F. Thornton and Shawn C. Burdette relate how element 100 was first identified in a nuclear weapons test, but that was classified information, so researchers had to ‘discover’ it again using other methods.

  • 49.
    Thornton, Brett F.
    et al.
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Burdette, Shawn C.
    Nobelium non-believers2014In: Nature Chemistry, ISSN 1755-4330, E-ISSN 1755-4349, Vol. 6, p. 652-652Article in journal (Other academic)
  • 50.
    Thornton, Brett F.
    et al.
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Burdette, Shawn C.
    Worcester Polytechnic Institute.
    Recalling radon's recognition2013In: Nature Chemistry, ISSN 1755-4330, E-ISSN 1755-4349, Vol. 5, no 9, p. 804-Article in journal (Other academic)
12 1 - 50 of 57
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