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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    Rekenregels schapen en geiten voor de Landbouwtelling : verantwoording van het gebruik van het Identificatie & Registratiesysteem
    Os, J. van; Jeurissen, J.L.L. ; Verkaik, J.C. - \ 2020
    Wageningen : Wettelijke Onderzoekstaken Natuur & Milieu (WOt-technical report 185) - 52
    Om te voldoen aan statistische verplichtingen voor veehouderij en bedrijfsstructuur en voor de registratie van emissies is informatie nodig over de schapen- en geitenhouderij in Nederland. Daartoe vraagt de Rijksoverheid bij veehouders op hoeveel van deze dieren aanwezig zijn, uitgesplitst in verschillende diergroepen; dit is een onderdeel van de jaarlijkse landbouwtelling. De Rijksoverheid streeft naar beperking van administratieve lastendruk bij ondernemers. Wageningen Environmental Research heeft op verzoek van het ministerie van Landbouw, Natuur en Voedselkwaliteit onderzocht in welke mate het mogelijk is om de benodigde gegevens af te leiden uit het bestaande Identificatie & Registratiesysteem (I&R) voor Schapen en Geiten (een systeem voor identificatie en registratie van dieren voor dier- en volksgezondheid). Dat blijkt in principe goed mogelijk; het I&R-systeem voor schapen en geiten bevat iets minder onderscheid tussen diergroepen dan nodig is voor de Landbouwtelling of Emissieregistratie. Maar door bij de betreffende veehouders nog wel het productiedoel op te vragen en een enkele aanname te doen, kunnen voor de meeste bedrijven alle benodigde aantallen schapen en geiten uit I&R worden afgeleid. Deze nieuwe werkwijze leidt niet alleen tot lagere administratieve lasten, maar ook tot een kwaliteitsverbetering van de gegevens over schapen en geiten.---Information on cattle farming in the Netherlands is needed for the national statistics on sheep and goat farms and farm structure. To obtain this information the national government asks farmers to submit information on the number of sheep and goats on their farms, divided into the various animal classes, as part of the annual agricultural census. The government also wants to minimise the administrative burden on farmers. Wageningen Environmental Research has studied to what extent it would possible to derive the required information from the existing identification and registration system (I&R) for sheep and goat (a system for identifying and registering livestock for animal and human health purposes). The results show that this is largely possible: for most farms all the animal classes can be automatically derived from the I&R. For some farms it is necessary to make an additional division of animal classes by product category. This new way of working will not only reduce the administrative burden, but it will also lead to better quality data on sheep and goats.
    Rekenregels pluimvee voor de Landbouwtelling: verantwoording van het gebruik van het Identificatie- & Registratiesysteem
    Os, J. van; Jeurissen, L.J.J. ; Ellen, H.H. - \ 2019
    Wageningen : Wettelijke Onderzoekstaken Natuur & Milieu (WOt-technical report 154) - 62
    Information on poultry farming in the Netherlands is needed for national statistics on livestock farming and farm structure. To obtain this information the national government asks farmers to submit information on the number of poultry on their farms, divided into the various animal classes, as part of the annual agricultural census. The government also wants to minimise the administrative burden on farmers. At the request of the Ministry of Agriculture, Nature and Food Quality, Wageningen Environmental Research has studied to what extent it would possible to derive the required information from the existing identification and registration system (I&R) for poultry (a system for identifying and registering livestock for animal and human health purposes). The results of the study indicate that, in principle, this can be done; the I&R system for poultry farming contains a more detailed breakdown into animal classes than is necessary for the agricultural census or emissions inventory. In addition, stocking densities per livestock shed, a key input for calculating emissions, can be determined by linking the I&R for poultry farming to the Register of Addresses and Buildings. This new way of working will not only reduce the administrative burden, but it will also lead to better quality of data on poultry.
    Planten voor een prima binnenklimaat : Industriële spoor
    Hermans, Tia ; Vries, Sjerp de; Jeurissen, Leonn ; Kraan, Jolanda ; Oppedijk, Berry ; Duijn, Bert van - \ 2019
    Wageningen : Wageningen Environmental Research (Wageningen Environmental Research rapport 2952) - 167
    A conceptual model was developed, describing the short-term, medium and long-term effects of plants on the indoor climate and the health and well-being of people. The model was tested by means of intervention research at three companies and eight homes for the elderly. The effect of plants on the physical indoor climate was measured with sensors, the effect on the health and well-being of employees with questionnaires. In principle, a ‘Before After Control Impact’ approach was used at the locations. A control room and an intervention room were selected for each location. After a pre-measurement, plants were placed in the intervention room and up to three post-measurements were conducted. At the companies, significant effects were found on relative humidity (up), attractiveness of the workplace (more attractive), state of mind (more positive), satisfaction with own functioning (higher) and sickness absence reporting (less). The need for recovery after a working day showed a reversed effect (rising). No significant effects were found for the other variables in the model. Similar effects were not observed in the homes for the elderly. Possible reasons for the latter are: the small number of employees working in the same room (i.e., living room for clients), a low willingness amongst these employees to participate in the study (high work pressure), a high mobility amongst employees and working in both the intervention and the control room.
    Broeikasgasemissie van de Gelderse land- en tuinbouw in 2016
    Jeurissen, Leonne ; Voogd, Jan Cees ; Kros, Hans ; Lesschen, Jan Peter - \ 2019
    Wageningen : Wageningen Environmental Research (Wageningen Environmental Research rapport 2947) - 53
    Geur bekennen: combi-luchtwassers, varkenshouderijen en geurhinder
    Biesheuvel, Pieter Jan ; Groothuijse, Frank ; Jeurissen, Ellis ; Melse, Roland W. ; Poll, Ric van - \ 2019
    Den Haag : Overlegorgaan Fysieke Leefomgeving - 53
    Urban food security at the crossroads between metropolitan food planning and global trade : the case of the Antwerp–Rotterdam–Düsseldorf region
    Wascher, Dirk Michael ; Jeurissen, Leonne - \ 2017
    Agroecology and Sustainable Food Systems 41 (2017)8. - ISSN 2168-3565 - p. 944 - 964.
    Ecological footprint - food consumption - spatial planning - sustainable cities
    Making use of Life Cycle Thinking, the Metropolitan Foodscape Planner (MFP) tool provides ecological footprint maps and supply/demand data showing a large potential for metropolitan food supplies. In the discussion, we examine these results in the light of recent research on the impacts of the prevailing global trade agro-food systems for the impact areas land use change, competition for space, biodiversity, and climate change, paying special attention to the Dutch approach toward global agro-food-chains. Finally, we put forward recommendations for developing sustainable foodscapes in metropolitan regions based on food-oriented spatial planning devices addressing aspects such as climate change, biodiversity, cross-border collaboration, food chain innovation, and footprint assessments.
    Rekenregels rundvee voor de Landbouwtelling : verantwoording van het gebruik van het Identificatie & Registratiesysteem
    Os, J. van; Bartholomeus, M.G.T.M. ; Jeurissen, L.J.J. ; Reenen, C.G. van - \ 2017
    Wageningen : Wettelijke Onderzoekstaken Natuur & Milieu (WOt-technical report 91) - 68
    rundveehouderij - rundvee - landbouwtellingen - emissie - registratie - identificatie - bedrijfsstructuur in de landbouw - nederland - cattle husbandry - cattle - agricultural censuses - emission - registration - identification - farm structure - netherlands
    Om te voldoen aan statistische verplichtingen voor veehouderij en bedrijfsstructuur en voor de registratievan emissies is informatie nodig over de rundveehouderij in Nederland. Daartoe vraagt de Rijksoverheid bijveehouders op hoeveel rundvee aanwezig is, uitgesplitst in verschillende diergroepen; dit is een onderdeelvan de jaarlijkse landbouwtelling. De Rijksoverheid streeft naar beperking van administratieve lastendruk bijondernemers. Wageningen Environmental Research heeft op verzoek van het ministerie van EconomischeZaken onderzocht in welke mate het mogelijk is om de benodigde gegevens af te leiden uit het bestaandeIdentificatie & Registratiesysteem (I&R) Rundveehouderij (een systeem voor identificatie en registratie vandieren voor dier- en volksgezondheid). Dat blijkt grotendeels goed haalbaar; voor de meeste bedrijvenkunnen alle diergroepen automatisch uit I&R bepaald worden. Voor sommige bedrijven is een aanvullendeverdeling van diergroepen over productiedoelen nodig. Deze nieuwe werkwijze leidt niet alleen tot lagereadministratieve lasten, maar ook tot een kwaliteitsverbetering van de rundveegegevens.---Information on cattle farming in the Netherlands is needed for the national statistics on beef and dairy farmsand farm structure. To obtain this information the national government asks farmers to submit informationon the number of cattle on their farms, divided into the various animal classes, as part of the annualagricultural census. The government also wants to minimise the administrative burden on farmers. At therequest of the Ministry of Economic Affairs, Wageningen Environmental Research has studied to what extentit would possible to derive the required information from the existing identification and registration system(I&R) for beef and dairy farms (a system for identifying and registering livestock for animal and humanhealth purposes). The results show that this is largely possible: for most farms all the animal classes can beautomatically derived from the I&R. For some farms it is necessary to make an additional division of animalclasses by product category. This new way of working will not only reduce the administrative burden, but itwill also lead to better quality data on beef and dairy cattle.
    Towards an index for sustainable regional food provision (i-SRPF) by linking global and regional food system assessment tools
    Wascher, D.M. ; Jeurissen, L.J.J. - \ 2016
    Wageningen : Wageningen University & Research - 18 p.
    Afstand tussen veehouderij en woningen : een onderzoek naar aantallen veehouderijen en woningen op minder dan 250 meter van elkaar
    Os, J. van; Smidt, R.A. ; Jeurissen, L.J.J. - \ 2016
    Wageningen : Alterra, Wageningen-UR (Alterra-rapport 2658) - 51
    veehouderij - landbouwbedrijven - woningen - milieu - milieufactoren - nederland - livestock farming - farms - dwellings - environment - environmental factors - netherlands
    Ter voorbereiding op een debat in de Tweede Kamer op 15 september 2014 heeft het ministerie van Economische Zaken aan Alterra gevraagd om te bepalen hoeveel veehouderijen er liggen op een afstand van 250 m of minder van burgerwoningen, niet zijnde agrarische bedrijfswoningen. Achtergrond van deze vraag is de mogelijke negatieve beïnvloeding van de omgevingskwaliteit van woningen door veehouderijen. Naar aanleiding van het debat en het eerste gepubliceerde document heeft het ministerie van Economische Zaken Alterra gevraagd om een actualisatie en nadere detaillering te maken van de eerste resultaten. Met behulp van GIS heeft Alterra daarop zowel voor de jaren 2011 en 2013 bepaald dat ca. 70-90% van de veehouderijen op minder dan 250 m van een woning ligt. Andersom geredeneerd ligt ca. 30-40% van de woningen in het buitengebied op minder dan 250 m van een veehouderij; voor woningen in bevolkingskernen is dat 3%. Binnen Nederland zijn er aanzienlijke verschillen tussen regio’s, vooral veroorzaakt door verschillen in dichtheid van veehouderijen en woningen.
    Geografisch informatiesysteem voor de emissieregistratie van landbouwbedrijven; : GIABplus-bestand 2013 – Status A
    Os, J. van; Jeurissen, L.J.J. ; Naeff, H.S.D. - \ 2016
    Wageningen : Wettelijke Onderzoekstaken Natuur & Milieu (WOt-technical report 66) - 65
    landbouwbedrijven, bedrijfslocaties, emissies, Landbouwtelling, veehouderij, rundvee, varkens, pluimvee, schapen, geiten, kippen - landbouwbedrijven - veehouderij - emissie - registratie - landbouwtellingen - geografische informatiesystemen - nederland - farms - livestock farming - emission - registration - agricultural censuses - geographical information systems - netherlands
    Voor de nationale emissieregistratie van het RIVM is het nodig om een goed beeld te hebben van de bedrijfslocaties van veehouderijbedrijven in Nederland. Vanaf 2009 is daarvoor niet alleen gebruik gemaakt van de jaarlijkse Landbouwtelling, maar ook van bedrijfslocaties die bekend zijn via dierregistraties voor dier- en volksgezondheid. Daarmee wordt het zogenaamde GIABplus-bestand gemaakt: Geografische Informatie Agrarische Bedrijven, waarbij de dieraantallen van de Landbouwtelling zijn herverdeeld over veehouderijlocaties vanuit de dierregistraties en gekoppeld aan de staltypen die in de Landbouwtelling bekend zijn. Dit rapport geeft aan hoe het GIABplus-bestand 2013 is samengesteld en wat de gebruiksmogelijkheden zijn. Behalve voor het lokaliseren van emissies uit de veehouderij is het bestand ook toepasbaar in regionale onderzoeken naar de landbouwstructuur en onderzoek naar verspreiding van dierziekten.
    Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and biphenyls (PCBs) in home-produced eggs
    Hoogenboom, L.A.P. ; Dam, G. ten; Bruggen, Mark van; Jeurissen, Suzanne ; Leeuwen, S.P.J. van; Theelen, R.M.C. ; Zeilmaker, M.J. - \ 2016
    Chemosphere 150 (2016). - ISSN 0045-6535 - p. 311 - 319.
    Home produced eggs from 62 addresses in the Netherlands were investigated for the levels of polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and biphenyls (PCBs), both dioxin-like (dl) and non-dioxin-like (ndl). Compared to commercial eggs, levels were relatively high with a median of 4.6 pg TEQ g−1 fat for the sum of PCDD/Fs and dl-PCBs, and a highest level of 18.9 pg TEQ g−1 fat. A number of samples showed clearly elevated ndl-PCB levels with a median of 13 ng g−1 fat and a highest level of 80 ng g−1 fat. There were no clear regional differences, even though part of the samples were derived from the rather industrial Rotterdam/Rijnmond area. Based on the congener patterns, former backyard burning of waste seems the most likely source for most eggs, with two exceptions where other sources contributed to the contamination. Similar is true for the ndl-PCBs. The study shows that average levels are about ten-fold higher than commercial eggs and may substantially contribute to the intake of PCDD/Fs and dl-PCBs by consumers. Intervention measures to reduce the intake of these contaminants by laying hens are advised.
    FOODMETRES – Metropolitan food planning connecting the local with the global
    Wascher, D.M. ; Piorr, A. ; Pintar, M. ; Kneafsey, M. ; Sali, G. ; Corsi, S.L. ; Mbatia, T. ; Jeurissen, L.J.J. ; Arciniegas, G. ; Glavan, M. ; Doernberg, A. ; Zasada, I. ; Groot, J. ; Schmutz, U. ; Bos, E. ; Venn, L. ; Monaco, F. ; Simiyu, R. ; Owour, S. ; Asselt, E.D. van; Fels, H.J. van der; Eupen, M. van - \ 2015
    Urban Agriculture Magazine (2015)29. - ISSN 1571-6244 - p. 41 - 44.
    Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr-/- mice
    Hendrikx, Tim ; Jeurissen, M.L.J. ; Gorp, P.J. Van; Gijbels, M.J. ; Walenbergh, S.M.A. ; Houben, Tom ; Gorp, Rick Van; Pöttgens, C.C. ; Stienstra, Rinke ; Netea, M.G. ; Hofker, M.H. ; Donners, M.M.P.C. ; Shiri-Sverdlov, Ronit - \ 2015
    FEBS Journal 282 (2015)12. - ISSN 1742-464X - p. 2327 - 2338.
    atherosclerosis - cardiovascular diseases - caspase-1/11 - inflammasome - macrophage

    Recent investigations have suggested that inflammasome activation plays an important role during atherosclerosis. Upon activation, the inflammasome induces processing and release of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) via activation of caspase-1/11. Previously, it was shown that complete caspase-1 deficiency is protective against atherosclerosis development. However, while macrophages are the main inflammatory cells involved in atherosclerosis, the exact role of macrophage-specific caspase-1/11 activation during development of cardiovascular disease has never been investigated. We hypothesized that hematopoietic caspase-1/11 deficiency leads to reduced atherosclerosis development. To investigate the specific contribution of hematopoietic caspase-1/11 activation to atherosclerosis development, Ldlr-/- mice received a transplant (tp) of wild-type (WT) or caspase-1/11-/- bone marrow, to create WT-tp mice and caspase-1/11-/--tp mice, and fed a high-fat, high-cholesterol diet for 12 weeks. Our results showed an increase in anti-inflammatory blood leukocytes in caspase-1/11-/--tp mice compared with WT-tp mice, as indicated by a decreased level of Ly6Chigh monocytes and an increased level of Ly6Clow monocytes. In line with our hypothesis, hematopoietic deletion of caspase-1/11 resulted in a strong reduction in atherosclerotic plaque size. Furthermore, necrotic core content was dramatically decreased in caspase-1/11-/--tp mice. Our data indicate that hematopoietic caspase-1/11 activation is involved in vascular inflammation and atherosclerosis, and plays an important role in cardiovascular disease progression. In this study, we investigated the contribution of hematopoietic caspase-1/11 to atherosclerosis development by transferring wild-type or caspase-1/11 deficient bone marrow cells into hyperlipidemic Ldlr-/- recipient mice. Hematopoietic deletion of caspase-1/11 resulted in smaller plaque size and reduced cell death in the plaque area compared to controls. These data indicate that hematopoietic caspase-1/11 activation plays an important role in vascular inflammation and atherosclerosis.

    Dioxins, PCBs and heavy metals in Chinese mitten crabs from Dutch rivers and lakes
    Hoogenboom, L.A.P. ; Kotterman, M.J.J. ; Hoek - van Nieuwenhuizen, M. ; Lee, M.K. van der; Mennes, W.C. ; Jeurissen, S.M.F. ; Leeuwen, S.P.J. van - \ 2015
    Chemosphere 123 (2015). - ISSN 0045-6535 - p. 1 - 8.
    dr-calux(r) bioassay - netherlands - biphenyls - exposure - eel
    Chinese mitten crab is an invasive species in many European rivers and lakes. Data from the UK indicated high levels of dioxins and PCBs, in particular in the brown meat in the body. This was confirmed by studies in the Netherlands, showing average levels of dioxins and PCBs in the meat in the body of 43 pg TEQ g-1 ww in crabs caught in the large rivers. Levels in crab of lakes in the Northern part of the Netherlands were on average 3.7-fold lower. Consumption of crabs from polluted areas results in a relatively high dose of dioxins and dl-PCBs and could significantly increase the intake above the TWI. However, in general consumption of these crabs is low, even in the Asian sub-population in the Netherlands. Cadmium and lead levels were higher in crabs from contaminated areas, but for mercury and arsenic there was no clear difference. Consumption of crabs would not result in significant risks for cadmium and mercury. For lead the daily intake could be raised above the BMDL01 for neurodevelopmental toxicity, but this would only occur on a limited number of days. For arsenic the exposure would exceed the lower end of the BMDL01 values for certain cancers, but again, the infrequent consumption by most consumers reduces this risk. Furthermore, speciation showed that most arsenic in crabs was probably not a toxic inorganic form, but likely to be in an organic form.
    Land-Applied Goat Manure as a Source of Human QFever in the Netherlands, 2006–2010
    Hermans, C.M.L. ; Jeurissen, L.J.J. ; Hackert, V. ; Hoebe, C. - \ 2014
    PLoS ONE 9 (2014)5. - ISSN 1932-6203 - 9 p.
    coxiella-burnetii - infection - epidemic - outbreak
    Studies have shown a link between Q-fever positive farms (QFPFs) and community cases of human Q-fever. Our study is the first to investigate the potential role of contaminated land-applied manure in human Q-fever, based on a large set of nationwide notification and farm management data. Time between manure application and disease onset in geographically linked notified human cases coincided with the incubation period of Q-fever. Proximity of contaminated land parcels predicted human cases better than proximity of QFPFs (80% vs. 58%, 0–5 km in 2009). Incidence around QFPFs and contaminated land parcels decreased with distance, but not around non-contaminated land parcels. Incidence was higher around contaminated land parcels than non-contaminated land parcels (RR = [10],95%CI = [7], [1]–[14,2]). Our findings deliver evidence that, apart from QFPFs, land-applied contaminated manure may be another source of human Q-fever.
    Afstand veehouderij tot woningen
    Os, J. van; Smidt, R.A. ; Jeurissen, L.J.J. - \ 2014
    Wageningen : Alterra - 5
    veehouderij - landbouwbedrijfsgebouwen - woningen - intensieve veehouderij - ruimtelijke ordening - livestock farming - farm buildings - dwellings - intensive livestock farming - physical planning
    Ter voorbereiding van het debat in de Tweede Kamer met staatssecretaris Dijksma over een initiatiefnota van de SP heeft het ministerie van EZ aan Alterra gevraagd om te bepalen hoeveel veehouderijbedrijven er liggen op een afstand van 250 m of minder van burgerwoningen. Daarbij blijven de agrarische bedrijfswoningen buiten beschouwing. In paragraaf 2 staat de aanpak vermeld, paragraaf 3 bevat de resultaten en de conclusie.
    Ontwikkeling van de ammoniakdepositie op de Overijsselse Natura 2000-gebieden : analyse van de ammoniak-depositie als gevolg van Overijsselse stal- en opslagemissies in de periode van 1994, 1995, 2000 of 2004 tot 2009
    Gies, T.J.A. ; Kros, J. ; Jeurissen, L.J.J. ; Voogd, J.C.H. - \ 2014
    Wageningen : Alterra, Wageningen-UR (Alterra-rapport 2495) - 33
    natura 2000 - ammoniakemissie - emissiereductie - intensieve veehouderij - stikstof - milieubeleid - natura 2000 - ammonia emission - emission reduction - intensive livestock farming - nitrogen - environmental policy
    In dit rapport wordt de ontwikkeling van de netto toe- of afname van de ammoniakdepositie als gevolg van de stal- en opslagemissies tussen verschillende peiljaren vanaf 1994 en 1 februari 2009 op de verschillende habitattypen in de Natura 2000-gebieden in de provincie Overijsel in beeld gebracht. Dit inzicht is nodig om in het kader van de Programmatische Aanpak Stikstof (PAS) de niet-Nb-wet vergunde economische ontwikkelingen uit het verleden (interim-uitbreiders) te vereffenen.
    Spatial relationships in the Q fever outbreaks 2007–2010 in the Netherlands
    Commandeur, M.A.M. ; Jeurissen, L.J.J. ; Hoek, W. van der; Roest, H.I.J. ; Hermans, C.M.L. - \ 2014
    International Journal of Environmental Health Research 24 (2014)2. - ISSN 0960-3123 - p. 137 - 157.
    epidemic
    We analyzed the Q fever epidemic in the Netherlands on a national scale from a spatial point of view. Data on dairy goat farms and Dutch population, whether or not infected, were geo-referenced. Human cases were counted in GIS at different distance classes for all dairy goat farms, farms with Q fever based on BTM analysis, and farms with clinical symptoms. In all selections, human incidence decreased with increasing distances from dairy goat farms. Incidence was highest around farms with clinical symptoms. Depending on the acceptable incidence value, a dairy goat-free zone around residential areas could be defined. Cluster analyses were performed to identify local clusters of both infected farms and human cases and to identify focused clusters of human cases. Focused clusters were detected for only 14 out of 29 farms with clinical symptoms, giving rise to a new hypothesis on the transmission of Q fever
    Macrophage Specific Caspase-1/11 Deficiency Protects against Cholesterol Crystallization and Hepatic Inflammation in Hyperlipidemic Mice
    Hendrikx, T. ; Bieghs, V. ; Walenbergh, S.M.A. ; Gorp, P.J. van; Verheyen, F. ; Jeurissen, M.L.J. ; Steinbusch, M.M.F. ; Vaes, N. ; Binder, C.J. ; Koek, G.H. ; Stienstra, R. ; Netea, M.G. ; Hofker, M.H. ; Shiri-Sverdlov, R. - \ 2013
    PLoS ONE 8 (2013)12. - ISSN 1932-6203 - 10 p.
    nonalcoholic steatohepatitis - il-1-beta production - nlrp3 inflammasomes - nalp3 inflammasome - gut microbiota - autophagy - activation - atherosclerosis - crystals - disease
    Background & Aims: While non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis combined with inflammation, the mechanisms triggering hepatic inflammation are unknown. In Ldlr(-/-) mice, we have previously shown that lysosomal cholesterol accumulation in Kupffer cells (KCs) correlates with hepatic inflammation and cholesterol crystallization. Previously, cholesterol crystals have been shown to induce the activation of inflammasomes. Inflammasomes are protein complexes that induce the processing and release of pro-inflammatory cytokines IL-1b and IL-18 via caspase-1 activation. Whereas caspase-1 activation is independent of caspase-11 in the canonical pathway of inflammasome activation, caspase-11 was found to trigger caspase-1-dependent IL-1b and IL-18 in response to non-canonical inflammasome activators. So far, it has not been investigated whether inflammasome activation stimulates the formation of cholesterol crystals. We hypothesized that inflammasome activation in KCs stimulates cholesterol crystallization, thereby leading to hepatic inflammation. Methods: Ldlr(-/-) mice were transplanted (tp) with wild-type (Wt) or caspase-1/11(-/-) (dKO) bone marrow and fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks. In vitro, bone marrow derived macrophages (BMDM) from wt or caspase-1/11(-/-) mice were incubated with oxLDL for 24h and autophagy was assessed. Results: In line with our hypothesis, caspase-1/11(-/-)-tp mice had less severe hepatic inflammation than Wt-tp animals, as evident from liver histology and gene expression analysis in isolated KCs. Mechanistically, KCs from caspase-1/11(-/-)-tp mice showed less cholesterol crystals, enhanced cholesterol efflux and increased autophagy. In wt BMDM, oxLDL incubation led to disturbed autophagy activity whereas BMDM from caspase-1/11(-/-) mice had normal autophagy activity. Conclusion: Altogether, these data suggest a vicious cycle whereby disturbed autophagy and decreased cholesterol efflux leads to newly formed cholesterol crystals and thereby maintain hepatic inflammation during NASH by further activating the inflammasome.
    Matrix modulation of the toxicity of alkenylbenzenes, studied by an integrated approach using in vitro, in vivo, and physiologically based biokinetic models
    Al-Husainy, W.A.A.M. - \ 2013
    Wageningen University. Promotor(en): Ivonne Rietjens; Peter van Bladeren, co-promotor(en): Ans Punt. - Wageningen : Wageningen UR - ISBN 9789461738066 - 199
    methyleugenol - toxiciteit - keukenkruiden - flavonoïden - methyl eugenol - toxicity - culinary herbs - flavonoids

    Alkenylbenzenes such as estragole and methyleugenol are common components of spices and herbs such as tarragon, basil, fennel, mace, allspice, star anise and anise and their essential oils (Smithet al., 2002). There is an interest in the safety evaluation of alkenylbenzenes because these compounds can induce hepatic tumours in rodents when dosed orally at high dose levels (Milleret al., 1983; NTP, 2000). Based on the rodent studies with estragole, methyleugenoland structurally related alkenylbenzenes like safrole the hepatocarcinogenicity of alkenylbenzenes is ascribed to their bioactivation by cytochrome P450 enzymes leading to the formation of the proximate carcinogenen, the 1′-hydroxy metabolite, which is further bioactivated to the ultimate carcinogenen, the 1′-sulfooxy metabolite (Milleret al., 1983; Phillipset al., 1984; Randerathet al., 1984; Smithet al., 2010). The 1′-sulfooxy metabolite is unstable and binds via a presumed reactive carbocation intermediate covalently to different endogenous nucleophiles including DNA (Phillipset al., 1981; Boberget al., 1983; Milleret al., 1983; Phillipset al., 1984; Randerathet al., 1984; Fennellet al., 1985; Wisemanet al., 1987; Smithet al., 2002).

    Because of their genotoxicity and carcinogenicity, the addition of estragole and methyleugenolas pure substances to foodstuffs has been prohibited within the European Union since September 2008 (European Commission, 2008). In 2008, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) re-evaluated the safety of alkenylbenzenes and indicated that although evidence of carcinogenicity to rodents given high doses of alkenylbenzenes exists, further research is needed to assess the potential risk to human health at relevant dietary exposure levels (JECFA, 2008).

    A significant difficulty in evaluating the toxicological data for alkenylbenzenes is that human exposure to these substances results from exposure to a complex mixture of food, spice, and spice oil constituents which may influence the biochemical fate and toxicological risk of the alkenylbenzenes. In this regard, it was shown that a methanolic extract of basil inhibited the formation of estragole DNA adducts in human HepG2 cells exposed to the proximate carcinogen 1′-hydroxyestragole (Jeurissenet al., 2008). This inhibition occurred at the level of sulfotransferase (SULT)-mediated bioactivation of 1′-hydroxyestragole into 1′-sulfooxyestragole (Jeurissenet al., 2008).

    The objective of this PhD research was to study the inhibitory action of components in alkenylbenzene-containing herbs and spices on SULT-mediated alkenylbenzene DNA adduct formation and the consequences of this combination effect for risk assessment using estragole and methyleugenol as the model alkenylbenzenes. To achieve this objective, an integrated approach of in vitro, in vivo and physiologically based biokinetic (PBBK) models was applied to investigate how the SULT inhibition influences the bioactivation and thus potentially also the toxicity and risk assessment of estragole and methyleugenol.

    Chapter 1of the thesis presents an introduction to the bioactivation, detoxification, genotoxicity and carcinogenicity of the alkenylbenzenes estragole and methyleugenol as well as a short introduction to PBBK modeling and the state-of-the-art knowledge on risk assessment strategies and regulatory status for alkenylbenzenes.

    Chapter 2of the thesis identifies nevadensin as a basil constituent able to inhibit SULT-mediated DNA adduct formation in rat hepatocytes exposed to the proximate carcinogen 1′-hydroxyestragole and nevadensin. The type of inhibition by nevadensin was shown to be non-competitive with an inhibition constant (Ki) of 4 nM. Furthermore, nevadensin up to 20 μM did not inhibit 1′-hydroxyestragole detoxification by glucuronidation and oxidation. The inhibition of SULT by nevadensin was incorporated into the PBBK models describing bioactivation and detoxification of estragole in male rat and human. The models thus obtained predict that co-administration of estragole at a level inducing hepatic tumours in vivo (50 mg/kg bw) with nevadensin at a molar ratio to estragole representing the molar ratio of their occurrence in basil, results in more than 83% inhibition of the formation of the carcinogenic metabolite, 1ʹ-sulfooxyestragole, inthe liver of male rat and human even at 1% uptake of nevadensin.

    To extend the work to other alkenylbenzene-containing herbs and spices than basil chapter 3 presents data showing that methanolic extracts from different alkenylbenzene-containing herbs and spices such as nutmeg, mace, anise and others are able to inhibit the SULT enzyme activity. Flavonoids including nevadensin, quercetin, kaempferol, myricetin, luteolin and apigenin were the major constituents responsible for this inhibition of SULT activity with Kivalues in the nano to sub-micromolar range. Also, the various flavonoids individually or in mixtures were able to inhibit estragole DNA adduct formation in human HepG2 cells exposed to the proximate carcinogen 1ʹ-hydroxyestragole, and to shift metabolism in favour of detoxification (e.g. glucuronidation) at the cost of bioactivation (e.g. sulfonation).

    In a next step, the kinetics for SULT inhibition were incorporated in PBBK models for estragole in rat and human to predict the effect of co-exposure to estragole and (mixtures of) the different flavonoids on the bioactivation in vivo. The PBBK-model-based predictions indicate that the reduction of estragole bioactivation in rat and human by co-administration of the flavonoids is dependent on whether the intracellular liver concentrations of the flavonoids can reach their Ki values. Finally, we concluded that it is expected that this is most easily achieved for nevadensin which has a Kivalue in the nanomolar range and is, due to its methylation, more metabolically stable and bioavailable than the other flavonoids.

    Chapter 4of the thesis investigates whether the previous observation that nevadensin is able to inhibit SULT-mediated estragole DNA adduct formation in primary rat hepatocytes could be validated in vivo. Moreover, the previously developed PBBK models to study this inhibition in rat and in human liver was refined by including a sub-model describing nevadensin kinetics. Nevadensin resulted in a significant reduction in the levels of estragole DNA adducts formed in the liver of Sprague–Dawley rats orally dosed with estragole and nevadensin simultaneously at a ratio reflecting their presence in basil. Moreover, the refined PBBK model predicted the formation of estragole DNA adducts in the liver of rat with less than 2-fold difference compared to in vivo data and suggests more potent inhibition in the liver of human compared to rat due to less efficient metabolism of nevadensin in human liver and intestine.

    Also, an updated risk assessment for estragole was presented taking into account the matrix effect and this revealed that the BMDL10 and the resulting MOE for estragole increase substantially when they would be derived from rodent bioassays in which the animals would be exposed to estragole in the presence of nevadensin instead of to pure estragole.

    To extend the work to other alkenylbenzenes than estragole chapter 5 of the thesis investigates the potential of nevadensin to inhibit the SULT-mediated bioactivation and subsequent DNA adduct formation of methyleugenolusing human HepG2 cells as an in vitro model. Nevadensin was able to inhibit SULT-mediated DNA adduct formation in HepG2 cells exposed to the proximate carcinogen 1′-hydroxymethyleugenol in the presence of nevadensin.To investigate possible in vivo implications for SULT inhibition by nevadensin on methyleugenolbioactivation, the rat PBBK model developed in our previous work to describe the dose-dependent bioactivation and detoxification of methyleugenolin male rat was combined with the recently developed PBBK model describing the dose-dependent kinetics of nevadensin in male rat. Similar to what was presented for estragole in chapter 4, chapter 5 presents an updated risk assessment for methyleugenoltaking the matrix effect into account. This revealed that the BMDL10 and the resulting MOE for methyleugenolincrease substantially when they would be derived from rodent bioassays in which the animals would be exposed to methyleugenolin the presence of nevadensin instead of to pure methyleugenol.

    In a next step, we aimed at moving one step forward towards endpoints that are closer to initiation of carcinogenesis than DNA adduct formation, namely, formation of hepatocellular altered foci (HAF). Chapter 6 presents data showing that the potent in vivo inhibitory activity of nevadensin on SULT enzyme activity and on alkenylbenzene DNA adduct formation is accompanied by a potent in vivo reduction in early markers of carcinogenesis such as HAF. This also suggests that a reduction in the incidence of hepatocarcinogenicity is expected in liver of rodents when alkenylbenzenes would be dosed simultaneously with nevadensin.

    Chapter 7presents a discussion on the in vitro and in vivo activity of dietary SULT inhibitors and their potential in reducing the cancer risk associated with alkenylbenzene consumption. This chapter also presents some future perspectives based on the major issues raised by our research.

    Altogether, the results of the present thesis indicate that the likelihood of bioactivation and subsequent adverse effects may be lower when alkenylbenzenes are consumed in a matrix containing SULT inhibitors such as nevadensincompared to experiments using pure alkenylbenzenes as single compounds. Also,the consequences of the in vivo matrix effect were shown to be significant when estragole or methyleugenolwas tested in rodent bioassays in the presence of nevadensin at ratios detected in basil, thereby likely increasing BMDL10 and resulting MOE values substantially in a subsequent risk assessment. However, the results also indicate that matrix effects may be lower at daily human dietary exposure levels of estragole or methyleugenoland nevadensin resulting from basil consumption. Also, matrix effects seem to be limited in the presence of other SULT inhibiting dietary flavonoids even at high exposure levels of these flavonoids coming from supplements. This indicates that the importance of a matrix effect for risk assessment of individual compounds requires analysis of dose dependent effects on the interactions detected, an objective that can be achieved by using PBBK modeling.

    Overall, the present study provides an example of an approach that can be used to characterise dose- species- and inter-individual differences as well as matrix effects in the risk assessment of food-borne toxicants present (e.g. alkenylbenzenes). In this approach the most important toxicokinetic interactions are addressed using an integrated strategy of in vitro, in vivo and PBBK modeling approaches.

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