Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    The effect of quercetin and kaempferol aglycones and glucuronides on peroxisome proliferator-activated receptor-gamma (PPAR-¿)
    Beekmann, K. ; Rubió, L. ; Haan, L.H.J. de; Actis Goretta, L. ; Burg, B. van der; Bladeren, P.J. van; Rietjens, I.M.C.M. - \ 2015
    Food & Function 6 (2015)4. - ISSN 2042-6496 - p. 1098 - 1107.
    mitotic clonal expansion - in-vitro - adipocyte differentiation - dietary flavonoids - gene-expression - 3t3-l1 cells - kappa-b - mediated inflammation - cholesterol efflux - molecular target
    The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-¿). Flavonoids are extensively metabolized during and after uptake and there is little known on the biological effects of these conjugated metabolites of flavonoids that are found in plasma. To investigate the effect of glucuronidation on the ability of flavonoids to activate PPAR-¿ we studied and compared the activity of quercetin, kaempferol and their relevant plasma conjugates quercetin-3-O-glucuronide (Q3G) and kaempferol-3-O-glucuronide (K3G) on different PPAR-¿ related endpoints. The flavonoid aglycones increased PPAR-¿ mediated gene expression in a stably transfected reporter gene cell line and glucuronidation diminished their effect. To study the intrinsic activity of the test compounds to activate PPAR-¿ we used a novel microarray technique to study ligand induced ligand binding domain (LBD) – nuclear receptor coregulator interactions. In this cell-free system we demonstrate that, unlike the known PPAR-¿ agonist rosiglitazone, neither the flavonoid aglycones nor the conjugates are agonistic ligands of the receptor. The increases in reporter gene expression in the reporter cells were accompanied by increased PPAR-¿ receptor-mRNA expression and quercetin synergistically increased the effect of rosiglitazone in the reporter gene assay. It is concluded that flavonoids affect PPAR-¿ mediated gene transcription by a mode of action different from agonist binding. Increases in PPAR-¿ receptor mRNA expression and synergistic effects with endogenous PPAR-¿ agonists may play a role in this alternative mode of action. Glucuronidation reduced the activity of the flavonoid aglycones
    Model Steatogenic Compounds (Amiodarone, Valproic Acid, and Tetracycline) Alter Lipid Metabolism by Different Mechanisms in Mouse Liver Slices
    Szalowska, E. ; Burg, B. van der; Man, H.Y. ; Hendriksen, P.J.M. ; Peijnenburg, A.A.C.M. - \ 2014
    PLoS ONE 9 (2014)1. - ISSN 1932-6203 - 15 p.
    gene-expression - rat-liver - hepatic steatosis - heparg cells - mitochondrial dysfunction - therapeutic targets - induced cholestasis - oxidative stress - fatty-acids - drug
    Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated-receptor (PPAR) signaling. Application of PPAR reporter assays classified AMI and VA as PPAR¿ and triple PPARa/(ß/d)/¿ agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions (i.e. TET). Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism
    Correlation between activation of PPAR¿ and resistin downregulation in a mouse adipocyte cell line by a series of thiazolidinediones.
    Sotiriou, A. ; Blaauw, R.H. ; Meijer, C. ; Gijsbers, L.H. ; Burg, B. van der; Vervoort, J. ; Rietjens, I.M.C.M. - \ 2013
    Toxicology in Vitro 27 (2013)5. - ISSN 0887-2333 - p. 1425 - 1432.
    insulin-resistance - adipose-tissue - antihyperglycemic agents - expression - receptor - glucose - metabolism - mechanisms - biology - obesity
    The present study shows significant correlations between the EC50 for PPAR¿ activation in a reporter gene cell line and resistin downregulation in mouse adipocytes, and between the IC50 for resistin downregulation and the already published minimum effective dose for antihyperglycemic activity in a mouse model. These correlations indicate that PPAR¿ mediated downregulation of resistin might promote insulin sensitivity and that downregulation of resistin in mouse adipocytes provides an adequate and possibly more direct bioassay for screening of newly developed antihyperglycemic compounds. Because of the higher throughput of the PPAR¿ the resistin downregulation assays seems most suitable to be used as a second tier in a tiered screening strategy.
    Short chain fatty acids stimulate Angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating PPARy
    Alex, S. ; Lange, K. ; Amolo, T. ; Grinstead, J.S. ; Haakonsson, A.K. ; Szalowska, E. ; Koppen, A. ; Mudde, C.M. ; Haenen, D. ; Al-Lahham, S. ; Roelofsen, H. ; Houtman, R. ; Burg, B. van der; Mandrup, S. ; Bonvin, A.M.J.J. ; Kalkhoven, E. ; Muller, M.R. ; Hooiveld, G.J.E.J. ; Kersten, A.H. - \ 2013
    Molecular and Cellular Biology 33 (2013)7. - ISSN 0270-7306 - p. 1303 - 1316.
    inflammatory-bowel-disease - ppar-gamma - transcriptional activity - lipoprotein-lipase - skeletal-muscle - gut microbiota - target gene - expression - protein-4 - butyrate
    Angiopoietin-like protein 4 (ANGPTL4/FIAF) has been proposed as a circulating mediator between the gut microbiota and fat storage. Here, we show that transcription and secretion of ANGPTL4 in human T84 and HT29 colon adenocarcinoma cells is highly induced by physiological concentrations of short-chain fatty acids (SCFA). SCFA induce ANGPTL4 by activating the nuclear receptor peroxisome proliferator activated receptor ¿ (PPAR¿), as demonstrated using PPAR¿ antagonist, PPAR¿ knockdown, and transactivation assays, which show activation of PPAR¿ but not PPARa and PPARd by SCFA. At concentrations required for PPAR¿ activation and ANGPTL4 induction in colon adenocarcinoma cells, SCFA do not stimulate PPAR¿ in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPAR¿ modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modeling. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin induced PPAR target genes and pathways in the colon. We conclude that (i) SCFA potently stimulate ANGPTL4 synthesis in human colon adenocarcinoma cells and (ii) SCFA transactivate and bind to PPAR¿. Our data point to activation of PPARs as a novel mechanism of gene regulation by SCFA in the colon, in addition to other mechanisms of action of SCFA.
    Towards a quick decision support tool for sustainable use of harvest residues
    Termorshuizen, A. ; Bodelier, P. ; Boer, W.I. de; Brouwer, B. ; Burg, B. van der; Erp, P. van; Helder, J. ; Henssen, M. ; Krooneman, J. ; Landeweert, R. ; Lieten, S. ; Molenaar, D. ; Pieterse, B. ; Putten, W.H. van der; Stam, H. ; Vedder, H. - \ 2013
    The continued growth of the world population requires increased amounts of agricultural products, including food and non-food products and energy. The potential problem of competition of land use between food- and energy-producing crops has been partially met by using non-food parts of food products as sources of energy or by growing energy crops on low-quality soils. Ultimately, high removal of organic matter from soils for energy production will result in decreasing levels of soil organic matter. Decreasing levels of organic matter in soil is risky, since organic matter comprises the basis of soil quality forming a stock of nutrients, which becomes available to the crop when soil organisms decompose the organic matter. This activity of soil organisms also brings about natural suppression of soilborne pathogens. Furthermore, organic matter functions as a 'gluing' component to stick mineral soil parts together, which prevents loss of soil by runoff or dust storms and organic matter facilitates root penetration of the soil and it acts as a buffer for water storage. Thus, soils with high organic matter removal typical for biomass production need careful management, primarily by maintaining and replenishing the pools of organic matter. Currently in biomass production large amounts of residues are available which are not optimally used. Therefore, we suggest constructing a decision tool to support the sustainable use of residues. In this support tool residue quality, soil requirement, and the risks, costs and revenues involved in the primary production of biomass are used as input parameters. The tool will include the results of research done within this project in which fast and for farmers financially affordable techniques will be developed to characterize the soil's needs and quality of the residues (e.g. nutrition supply and potential presence of toxics). These techniques are used to predict effects of residues on the soil food web, greenhouse gas emission potential, disease suppression, organic matter quality and nutrient supply to the crop after application of residues to soil. Summarizing, the tool will contribute to sustainable biomass production. This recently granted project has started 1 January 2013 and is scheduled to last for 4 years.
    Development and validation of two stable reporter cell lines for PPAR¿-mediated modulation of gene expression
    Haan, L.H.J. de; Gijsbers, L. ; Man, H. ; Kloet, S.K. ; Keijer, J. ; Rietjens, I.M.C.M. ; Burg, B. van der; Aarts, J.M.M.J.G. - \ 2012
    Induction of electrophile-responsive element (EpRE)-mediated gene expression by tomato extracts in vitro
    Gijsbers, L. ; Eekelen, H.D.L.M. van; Nguyen, T.H. ; Haan, L.H.J. de; Burg, B. van der; Aarts, J.M.M.J.G. ; Rietjens, I.M.C.M. ; Bovy, A.G. - \ 2012
    Food Chemistry 135 (2012)3. - ISSN 0308-8146 - p. 1166 - 1172.
    flavonoid intake - lung-cancer - activation - lycopene - cells - risk - phytochemicals - products - women
    The market for food products with additional health benefits is increasing rapidly and tools for identification of bio-functional characteristics of food items are essential. To facilitate the detection of beneficial effects of tomato on gene expression, methods to prepare tomato extracts suitable to test in the EpRE LUX assay and other cell-based reporter gene assays for health-related bioactivity mechanisms, were developed. An isoprenoid-containing chloroform extract of tomato fruit and most individual isoprenoids did not induce electrophile-responsive element (EpRE)-mediated gene expression. A semi-polar extract of tomato fruits, enzymatically hydrolysed to remove the glycosyl residues from the phenolic ingredients was able to induce EpRE-mediated luciferase expression at both mRNA and protein level, which might be partly due to the presence of quercetin, kaempferol, naringenin and naringenin chalcone. It was concluded that induction of EpRE-regulated genes, such as detoxifying phase II and antioxidant enzymes, may contribute to the beneficial health effects of tomato.
    BioBased Economy requires operationalization of the People Planet Profit principle
    Dinkla, I. ; Brouwer, B. ; Burg, B. van der; Termorshuizen, A.J. ; Erp, P. van; Landeweert, R. ; Stam, H. ; Putten, W.H. van der; Krooneman, J. - \ 2012
    Stable reporter cell lines for PPAR¿-mediated modulation of gene expression
    Gijsbers, L. ; Man, H. ; Kloet, S.K. ; Haan, L.H.J. de; Keijer, J. ; Rietjens, I.M.C.M. ; Burg, B. van der; Aarts, J.M.M.J.G. - \ 2011
    Stable reporter cell lines for PPAR¿-mediated modulation of gene expression
    Gijsbers, L. ; Man, H. ; Kloet, S.K. ; Haan, L.H.J. de; Keijer, J. ; Rietjens, I.M.C.M. ; Burg, B. van der; Aarts, J.M.M.J.G. - \ 2011
    Optimization and prevalidation of the in vitro ER alpha CALUX method to test estrogenic and antiestrogenic activity of compounds
    Burg, B. van der; Winter, R. ; Weimer, M. ; Berckmans, P. ; Suzuki, G. ; Gijsbers, L. ; Jonas, A. ; Linden, S. van der; Witters, H. ; Aarts, J.M.M.J.G. ; Legler, J. ; Kopp-Schneider, A. ; Bremer, S. - \ 2010
    Reproductive Toxicology 30 (2010)1. - ISSN 0890-6238 - p. 73 - 80.
    cell-line - transactivation assay - endocrine disruptors - bioassays - androgen - chemicals - panel - beta
    Estrogenicity of chemicals has received significant attention and is linked to endocrine-disrupting activities. However, there is a paucity of validated methods to assess estrogenicity in vitro. We have established a robust method to test estrogenic and antiestrogenic activity of compounds in vitro, as an alternative to using animal models such as the uterotrophic assay. To this end we optimized protocols to be used in combination with CALUX reporter gene assays and carried out an in house prevalidation, followed by two rounds of tests to establish transferability. Problems in the initial test with transferability were solved by isolation of a novel cell clone of the ER alpha CALUX line with greatly improved stability and luciferase levels. This cell line proved to be a very suitable and reliable predictor of estrogenicity of chemicals and was able to readily rank a range of chemicals on the basis of their EC50 values.
    An in vitro/in vovo screening assay as a sensitive tool to assess endocrine disruptive activity in surface water
    Bogers, R. ; Buitenweg, S. ; Geuijen, I. ; Waart, B. van de; Kuiper, R. ; Linden, S. van der; Puijker, L. ; Murk, A.J. ; Burg, B. van der; Legler, J. - \ 2007
    Environment International 33 (2007)3. - ISSN 0160-4120 - p. 292 - 301.
    minnow pimephales-promelas - vitellogenin messenger-rna - secondary sex characteristics - treated sewage effluent - medaka oryzias-latipes - fathead minnow - cyprinodon-variegatus - estrogenic activity - synthetic estrogen - rainbow-trout
    Adult male fathead minnow were exposed for 14 or 28-days under flow-through conditions to undiluted filtered water samples from the rivers Meuse and Rhine in the Netherlands. The experiment included two vessels per treatment each containing 10 fish and samples of five fish were taken after 14 and 28 days. Additional groups were exposed to 17¿-ethinylestradiol (EE2) as a reference and untreated drinking water as a negative control. Major endpoints examined included induction of vitellogenin (VTG) synthesis, VTG mRNA activity, hepato- and gonadosomatic indices (HSI and GSI) and gonadal histology. No significant difference was recorded in body weight or mean GSI values between the various treatments. Only exposure to Meuse water resulted in significantly higher HSI means after 14 days. Histological examination showed no apparent effects on gonadal tissue except for eosinophilic blood plasma in fish exposed to Meuse water or EE2. After 14 and 28 days, elevated VTG and VTG mRNA levels were measured in most livers of the fish exposed to Meuse water, but not in the fish exposed to Rhine water. This was confirmed by measuring estrogenic responses in the in vitro ER CALUX® assay. Induction of VTG synthesis proved to be the most sensitive endpoint in the Non Spawning Male Fish Assay for in vivo detection of bio-available estrogenic activity supplementary to a sensitive in vitro assay. The other endpoints examined varied too much and required a higher number of fish or replicates to achieve sufficient power for statistical testing making them less animal friendly.
    The in vivo transgenic zebrafish reporter gene assay for bioanalysis of exposure and effects of estrogenic chemicals in the aquatic environment
    Legler, J. ; Zee, M. van der; Ven, L.T.M. van der; Jonkers, C.C.H. ; Vethaak, A.D. ; Burg, B. van der; Murk, A.J. - \ 2006
    In: Estrogens and xenoestrogens in the aquatic environment: An integrated approach for field monitoring and effect assessment / Vethaak, D., Schrap, M, de Voogt, P., Pensacola : SETAC-scientific book (SETAC Technical Publications Series ) - ISBN 9781880611852 - 512 p.
    Estrogenic endpoints in fish early life-stage tests: luciferase and vitellogenin induction in estrogen-responsive transgenic zebrafish
    Bogers, R. ; Mutsaerds, E. ; Druke, J. ; Roode, D.F. de; Murk, A.J. ; Burg, B. van der; Legler, J. - \ 2006
    Environmental Toxicology and Chemistry 25 (2006)1. - ISSN 0730-7268 - p. 241 - 247.
    in-vivo - pimephales-promelas - fathead minnow - danio-rerio - sewage effluent - rainbow-trout - stw effluent - chemicals - exposure - vitro
    This study incorporated specific endpoints for estrogenic activity in the early life-stage (ELS) test, as described in Guideline 210 of the Organization for Economic Cooperation and Development and traditionally used for toxicity screening of chemicals. A transgenic zebrafish model expressing an estrogen receptor-mediated luciferase reporter gene was exposed to ethinylestradiol (EE2), and luciferase activity as well as vitellogenin (VTG) was measured. Concentrations of EE2 were tested at 1, 3, or 10 ng/L for 30 d from fertilization or during only the last 4 d with dimethylsulfoxide (DMSO) as presolvent (0.01%). Exposure to EE2 induced no toxic effects. Mean body weights were significantly higher in groups exposed for 30 d in the presence of DMSO, but condition factors were not affected. Significant luciferase and VTG induction occurred following 30-d exposure (3 and 10 ng EE2/L), while only VTG levels were affected in the 4-d exposure (10 ng EE2/L). This study demonstrated the usefulness of incorporating estrogenic endpoints in the OECD ELS test, fitting the requirements for screening estrogenic activity of chemicals. Quantitative measurement of both VTG and luciferase activity proved to be rapid and sensitive. Additional value of using transgenic zebrafish lies in combining VTG measurement with the more mechanistic approach of luciferase induction in one experiment.
    Detection of estrogenic activity in sediment-associated compounds using in vitro reporter gene assays
    Legler, J. ; Dennekamp, M. ; Vethaak, A.D. ; Brouwer, A. ; Koeman, J.H. ; Burg, B. van der; Murk, A.J. - \ 2002
    Science of the Total Environment 293 (2002). - ISSN 0048-9697 - p. 69 - 83.
    sediment - oestrogenen - toxische stoffen - afvalwater - organisch bodemmateriaal - hormonen - waterbodems - xenobiotica - waddenzee - sediment - oestrogens - hormones - toxic substances - waste water - soil organic matter - water bottoms - xenobiotics - wadden sea - in-vitro - saccharomyces-cerevisiae - polychlorinated-biphenyls - environmental estrogens - receptor - activation - metabolism - mechanism - system - transcription
    Sediments may be the ultimate sink for persistent (xeno-) estrogenic compounds released into the aquatic environment. Sediment-associated estrogenic potency was measured with an estrogen receptor-mediated luciferase reporter gene (ER-CALUX) assay and compared with a recombinant yeast screen. The ER-CALUX assay was more sensitive to 17beta-estradiol (E2) than the recombinant yeast screen, with an EC50 of 6 pM E2 compared to 100 pM in the yeast screen. Yeast cells were unable to distinguish the anti-estrogens ICI 182 780 and (4-hydroxy)tamoxifen, which were agonistic in the yeast. Acetone-soluble fractions of hexane/acetone extracts of sediments showed higher estrogenic potency than hexane-soluble extracts in the ER-CALUX assay. Sediments obtained from industrialized areas such as the Port of Rotterdam showed the highest estrogenic potency of the 12 marine sediments tested (up to 40 pmol estradiol equivalents per gram sediment). The estrogenic activity of individual chemicals that can be found in sediments including: alkylphenol ethoxylates and carboxylates; phthalates; and pesticides, was tested. Increasing sidechain length of various nonylphenol ethoxylates resulted in decreased estrogenic activity. Of the phthalates tested, butylbenzylphthalate was the most estrogenic, though with a potency approximately 100 000 times less than E2. The organochlorine herbicides atrazine and simazine failed to induce reporter gene activity. As metabolic activation may be required to induce estrogenic activity, a metabolic transformation step was added to the ER-CALUX assay using incubation of compounds with liver microsomes obtained from PCB-treated rats. Results indicate that metabolites of E2, NP and bisphenol A were less active than the parent compounds, while metabolites of methoxychlor were more estrogenic following microsomal incubations. (C) 2002 Elsevier Science B.V. All rights reserved.
    Comparison of in vivo and in vitro reporter gene assays for short-term screening of estrogenic activity
    Legler, J. ; Zeinstra, L.M. ; Schuitemaker, F. ; Lanser, P.H. ; Bogerd, J. ; Brouwer, A. ; Vethaak, A.D. ; Voogt, P. de; Murk, A.J. ; Burg, B. van der - \ 2002
    Environmental Science and Technology 36 (2002). - ISSN 0013-936X - p. 4410 - 4415.
    trout oncorhynchus-mykiss - medaka oryzias-latipes - rainbow-trout - alkylphenol ethoxylates - in-vitro - chemicals - receptor - nonylphenol - xenobiotics - disruption
    Functional in vitro and in vivo reporter gene assays have recently been developed for the rapid determination of exposure to (xeno)estrogens. The in vitro estrogen receptor (ER)-mediated chemically activated luciferase gene expression (ER-CALUX) assay uses T47D human breast cancer cells stably transfected with an ER-mediated luciferase gene construct. In the in vivo assay, transgenic zebrafish are used in which the same luciferase construct has been stably introduced. In both assays, luciferase reporter gene activity can be easily quantified following short-term exposure to chemicals activating endogenous estrogen receptors. The objective of this study was to compare responses by known (xeno)estrogenic compounds in both assays. Exposure to the (xeno)estrogens estradiol (E2), estrone, ethynylestradiol (EE2), o,p'-DDT, nonylphenol (NP), and di(2-ethylhexyl)phthalate (DEHP) revealed that EE2 was the most potent (xeno)estrogen tested and was 100 times more potent than E2 in the transgenic zebrafish assay, whereas in the in vitro ER-CALUX assay, EE2 and E2 were equipotent. Although the xenoestrogens o,p'-DDT and NP were full estrogen agonists in the in vitro ER-CALUX assay, only o,p'-DDT demonstrated weak dose-related estrogenic activity in vivo. To determine if differences in reporter gene activity maybe explained by differential affinity of (xeno)estrogens to human and zebrafish ERs, full-length sequences of the zebrafish ER subtypes alpha, beta, and gamma were cloned, and transactivation by (xeno)estrogens was compared to human ERalpha and ERbeta. Using transiently transfected recombinant ER and reporter gene constructs, EE2 also showed relatively potent activation of zebrafish ERalpha and ERbeta compared to human ERalpha and ERbeta. Zebrafish ERbeta and ERgamma showed higher transactivation by (xeno)estrogens relative to E2 than human ERbeta.
    Professor Ir. B. van der Burg : hoogleraar in de zuivelbereiding en melkkunde aan de Landbouwhogeschool te Wageningen van 1918 - 1949
    Burg, B. van der - \ 1949
    Wageningen : Landbouwhogeschool Wageningen - 8 p.
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