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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    Fire usage and ancient hominin detoxification genes : Protective ancestral variants dominate while additional derived risk variants appear in modern humans
    Aarts, Jac M.M.J.G. ; Alink, Gerrit M. ; Scherjon, Fulco ; MacDonald, Katharine ; Smith, Alison C. ; Nijveen, Harm ; Roebroeks, Wil - \ 2016
    PLoS ONE 11 (2016)9. - ISSN 1932-6203

    Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions.

    Role of membrane disturbance and oxidative stress in the mode of action underlying the toxicity of differently charged polystyrene nanoparticles
    Bhattacharjee, S. ; Ershov, D.S. ; Islam, M.A. ; Kämpfer, A.M. ; Maslowska, K.A. ; Gucht, J. van der; Alink, G.M. ; Marcelis, A.T.M. ; Zuilhof, H. ; Rietjens, I.M.C.M. - \ 2014
    RSC Advances : An international journal to further the chemical sciences 4 (2014)37. - ISSN 2046-2069 - p. 19321 - 19330.
    in-vitro toxicity - cellular uptake - surface-charge - manufactured nanoparticles - gold nanoparticles - cytotoxicity - cells - mitochondria - silicon
    Surface charge is often hypothesized to influence toxicity of nanoparticles (NPs) including polymeric nanoparticles (PNPs) while oxidative stress is considered to be an important mode of action (MOA) for such toxicity. In order to investigate the role of membrane disturbance and oxidative stress in the MOA of PNPs, the cytotoxicity and a range of related cellular endpoints induced by monodisperse, fluorescent, cationic and anionic polystyrene nanoparticles (PSNPs) of 50 and 100 nm sizes were investigated in vitro in macrophage NR8383 cells. Only amine-terminated cationic PSNPs exhibited cytotoxicity which was accompanied by induction of intracellular reactive oxygen species (ROS), increased levels of cytoplasmic free calcium, a reduced phagocytic index, a reduced mitochondrial membrane potential (¿¿m) and a decreased intracellular ATP content with the effects being more pronounced for 50 nm than 100 nm PSNPs. Both cationic and anionic PSNPs were found to increase the roughness of the cell membrane with the effect being more profound for cationic PSNPs. The pattern of protection by cellular antioxidants against the effects induced by positive PSNPs was similar to the pattern of protection against effects induced by the mitochondrial electron transport disrupting agent 2,4-dinitrophenol (DNP) and dissimilar to that for protection against the model compound for oxidative stress, i.e. hydrogen peroxide (H2O2). Surface charge influences the cellular interaction for NPs. The results collectively indicated that membrane interaction, and disturbance of the mitochondrial electronic transport chain (ETC) may represent a principal mechanism of toxicity for cationic PSNPs resulting in ROS production and oxidative stress as secondary effects.
    Role of surface charge in bioavailability and biodistribution of tri-block copolymer nanoparticles in rats after oral exposure
    Bhattacharjee, S. ; Marcelis, A.T.M. ; Zuilhof, H. ; Woutersen, R.A. ; Rietjens, I.M.C.M. ; Alink, G.M. - \ 2013
    Toxicology Research 2 (2013)3. - ISSN 2045-452X - p. 187 - 192.
    silicon nanoparticles - gold nanoparticles - polystyrene particles - fischer-344 rats - cellular uptake - drug-delivery - in-vivo - cytotoxicity - toxicity - absorption
    Tri-block copolymer nanoparticles (TCNP) are increasingly utilized, especially in drug delivery and diagnostics platforms. From in vitro studies, surface charge was observed to influence the transport of TCNP across the Caco-2 monolayers grown on transwell inserts. The objective of this study was to investigate the influence of surface charge on bioavailability and biodistribution of TCNP after oral exposure in vivo and to compare with the in vitro data. To attain the set objectives, monodisperse (45 ± 5 nm), fluorescent and differently charged (positive and negative) TCNP were orally administered to inbred Fischer 344 rats. Blood samples were collected at t = 0, 1/2, 1, 2, 4 and 6 h followed by sacrifice of the animals and collection of the major organs (lungs, liver, kidney, spleen, brain, intestine, and tibia). Quantitative assessments of TCNP in blood and organs were performed by fluorescence measurements. TCNP of both surface charges got absorbed and appeared in the blood within 1/2 h of oral administration. No significant difference in bioavailability and biodistribution could be found between positive and negative TCNP. Both the TCNP, irrespective of charge, showed major accumulation in the liver, kidneys and spleen, were detected in the brain and did not cause any significant increase in the serum alkaline phosphatase levels. Contrary to the in vitro data, surface charge was not found to influence the in vivo bioavailability and biodistribution of TCNP after oral exposure. The obtained results encourage further development of such TCNP, especially for drug delivery purposes.
    Surface charge-specific interactions between polymer nanoparticles and ABC transporters in Caco-2 cells
    Bhattacharjee, S. ; Opstal, E.J. van; Alink, G.M. ; Marcelis, A.T.M. ; Zuilhof, H. ; Rietjens, I.M.C.M. - \ 2013
    Journal of Nanoparticle Research : an Interdisciplinary Forum for Nanoscale Science and Technology 15 (2013). - ISSN 1388-0764 - 14 p.
    follicle-associated epithelium - in-vitro - drug-delivery - silicon nanoparticles - cellular uptake - stem-cells - monolayers - cytotoxicity - chitosan - trafficking
    The surface charge-dependent transport of polymeric nanoparticles (PNPs) across Caco-2 monolayers grown on transwell culture systems as an in vitro model for intestinal transport was tested. The transport of well-characterized, monodisperse, and fluorescent tri-block copolymer nanoparticles (TCNPs/size ~45 nm) and polystyrene nanoparticles (PSNPs/size ~50 nm), with different surface charges (positive and negative), was quantified. The positive PNPs showed a higher intracellular uptake and flux across the Caco-2 monolayers than the negative PNPs. Multidrug resistance/P-glycoprotein (MDR1/P-gp), a specific ATP-binding cassette (ABC) transporter, was found to play a major role in the cellular efflux of positive PNPs, whereas the multidrug resistance protein 1 took part in the efflux of negative PNPs from Caco-2 cells. The positive PNPs also caused an increased cellular uptake and apical to basolateral transport of the carcinogen PhIP across the Caco-2 monolayer. The flavonoid quercetin, which is known to interact with ABC transporters, promoted the intracellular uptake of different PNPs and interfered with the normal distribution patterns of PNPs in the transwell system. These results indicate that PNPs display surface charge-specific interactions with ABC transporters and can even affect the bioavailability of toxic food-borne compounds (like pro-carcinogens).
    Cytotoxicity of surface-functionalized silicon and germanium nanoparticles: the dominant role of surface charges
    Bhattacharjee, S. ; Rietjens, I.M.C.M. ; Singh, M.P. ; Atkins, T.M. ; Purkait, T.K. ; Xu, Z. ; Regli, S. ; Shukaliak, A. ; Clark, R.J. ; Mitchell, B.S. ; Alink, G.M. ; Marcelis, A.T.M. ; Fink, M.J. ; Veinot, J.G.C. ; Kauzlarich, S.M. ; Zuilhof, H. - \ 2013
    Nanoscale 5 (2013). - ISSN 2040-3364 - p. 4870 - 4883.
    block copolymer nanoparticles - cerium oxide nanoparticles - quantum dots - in-vitro - oxidative stress - gold nanoparticles - cellular toxicity - dependent endocytosis - hemolytic-activity - epithelial-cells
    Although it is frequently hypothesized that surface (like surface charge) and physical characteristics (like particle size) play important roles in cellular interactions of nanoparticles (NPs), a systematic study probing this issue is missing. Hence, a comparative cytotoxicity study, quantifying nine different cellular endpoints, was performed with a broad series of monodisperse, well characterized silicon (Si) and germanium (Ge) NPs with various surface functionalizations. Human colonic adenocarcinoma Caco-2 and rat alveolar macrophage NR8383 cells were used to clarify the toxicity of this series of NPs. The surface coatings on the NPs appeared to dominate the cytotoxicity: the cationic NPs exhibited cytotoxicity, whereas the carboxylic acid-terminated and hydrophilic PEG- or dextran-terminated NPs did not. Within the cationic Si NPs, smaller Si NPs were more toxic than bigger ones. Manganese-doped (1% Mn) Si NPs did not show any added toxicity, which favors their further development for bioimaging. Iron-doped (1% Fe) Si NPs showed some added toxicity, which may be due to the leaching of Fe3+ ions from the core. A silica coating seemed to impart toxicity, in line with the reported toxicity of silica. Intracellular mitochondria seem to be the target for the toxic NPs since a dose-, surface charge- and size-dependent imbalance of the mitochondrial membrane potential was observed. Such an imbalance led to a series of other cellular events for cationic NPs, like decreased mitochondrial membrane potential (¿¿m) and ATP production, induction of ROS generation, increased cytoplasmic Ca2+ content, production of TNF-a and enhanced caspase-3 activity. Taken together, the results explain the toxicity of Si NPs/Ge NPs largely by their surface characteristics, provide insight into the mode of action underlying the observed cytotoxicity, and give directions on synthesizing biocompatible Si and Ge NPs, as this is crucial for bioimaging and other applications in for example the field of medicine.
    Surface charge-specific cytotoxicity and cellular uptake of tri-block copolymer nanoparticles
    Bhattacharjee, S. ; Ershov, D.S. ; Gucht, J. van der; Alink, G.M. ; Rietjens, I. ; Zuilhof, H. ; Marcelis, A.T.M. - \ 2013
    Nanotoxicology 7 (2013)1. - ISSN 1743-5390 - p. 71 - 84.
    supported lipid-bilayers - cerium oxide nanoparticles - gold nanoparticles - oxidative stress - gene-expression - in-vitro - manufactured nanoparticles - chitosan nanoparticles - silicon nanoparticles - mitochondrial damage
    A series of monodisperse (45 ± 5 nm) fluorescent nanoparticles from tri-block copolymers (polymeric nanoparticles (PNPs)) bearing different surface charges were synthesised and investigated for cytotoxicity in NR8383 and Caco-2 cells. The positive PNPs were more cytotoxic and induced a higher intracellular reactive oxygen species production than the neutral and negative ones. The cytotoxicity of positive PNPs with quaternary ammonium groups decreased with increasing steric bulk. The intracellular uptake and cellular interactions of these different PNPs were also tested in NR8383 cells by confocal laser scanning microscopy, which revealed higher uptake for positive than for negative PNPs. Also positive PNPs were found to interact much more with cell membranes, whereas the negative PNPs were internalised mainly by lysosomal endocytosis. Uptake of positive PNPs decreased with increasing steric bulk around the positive charge. A surface charge-specific interaction of clathrin for positive PNPs and caveolin receptors for negative PNPs was observed. These findings confirm that surface charge is important for the cytotoxicity of these PNPs, while they additionally point to considerable additional effects of the steric shielding around positive charges on PNP cytotoxicity.
    Genotoxicity testing of samples generated during UV/H2O2 treatment of surface water for the production of drinking water using the Ames test in vitro and the Comet assay and the SCE test in vivo
    Penders, E.J.M. ; Martijn, A.J. ; Spenkelink, A. ; Alink, G.M. ; Rietjens, I. ; Hoogenboezem, W. - \ 2012
    Journal of Water Services Research and Technology-Aqua 61 (2012)7. - ISSN 0003-7214 - p. 435 - 445.
    mudminnow umbra-pygmaea - rhine water - dna-damage - by-product - toxicity - exposure - disinfection - mutagenicity - l.
    UV/H2O2 treatment can be part of the process converting surface water to drinking water, but would pose a potential problem when resulting in genotoxicity. This study investigates the genotoxicity of samples collected from the water treatment plant Andijk, applying UV/H2O2 treatment with an electrical energy dose of 0.54 kWh/m(3) and a H2O2 dose of 6 mg/l. Genotoxicity was tested in vitro using the Ames and Comet assay. All samples showed negative results. Samples were also tested in in vivo genotoxicity tests in Eastern mudminnow fish (Umbra pygmaea) by a sister chromatid exchange (SCE) and a Comet assay. No significant increases in SCEs were observed, but gill cells isolated from fish exposed to water obtained immediately after UV/H2O2 treatment and to Lake IJsselmeer water showed significantly increased DNA damage in the Comet assay. All other samples tested negative in this Comet assay. This indicates that DNA damaging compounds may result from the UV/H2O2 treatment, but also that these can be efficiently eliminated upon granular activated carbon (GAC) treatment of the water. It is concluded that when combined with this subsequent GAC treatment, UV/H2O2 treatment for the production of drinking water from surface water is not of concern with respect to genotoxicity.
    Genotoxic effects in the Eastern mudminnow (Umbra pygmaea) after prolonged exposure to River Rhine water, as assessed by use of the in vivo SCE and Comet assays
    Penders, E.J.M. ; Spenkelink, A. ; Hoogenboezem, W. ; Rotteveel, S.G.P. ; Maas, J.L. ; Alink, G.M. - \ 2012
    Environmental and Molecular Mutagenesis 53 (2012)4. - ISSN 0893-6692 - p. 304 - 310.
    surface waters - fish - exchanges - vitro
    The production of drinking water from river water requires a certain minimal river water quality. The Association of River Rhine Water Works (RIWA), therefore, operates a monitoring network. In vitro mutagenicity studies have shown that the genotoxicity of the River Rhine water steadily decreased from 1981 until 2001. Compared to a study in 1978, a decrease in genotoxicity was also observed in an in vivo genotoxicity study in 2005, in which Eastern mudminnows (Umbra pygmaea) were exposed to River Rhine water, and gill cells were used for the Sister Chromatid Exchange (SCE) test and the Comet assay. In this 2005 study, the in vivo genotoxicity increased upon extending exposure of the fish from 3 to 11 days. Therefore, the objectives of this study were to investigate (i) whether new data corroborate that in vivo genotoxicity of River Rhine water is at present lower than in 1978, (ii) whether the Comet assay is a suitable alternative to the SCE assay, and (iii) whether further prolonged exposure results in a further increase in in vivo genotoxicity. The new data corroborate that in vivo genotoxicity of River Rhine water is at present lower than in 1978. The Comet assay is a useful addition but does not provide a substitute for the SCE endpoint in these in vivo genotoxicity studies. Prolonging the exposure time of Eastern mudminnows to River Rhine water from 11 to 42 days did not give a significant increase in SCEs and DNA damage (Comet assay) in gill cells. Mol. Mutagen. 2012. (c) 2012 Wiley Periodicals, Inc.
    In vivo validation of DNA adduct formation by estragole in rats predicted by physiologically based biodynamic modelling
    Paini, A. ; Punt, A. ; Scholz, G. ; Gremaud, E. ; Spenkelink, A. ; Alink, G.M. ; Schilter, B. ; Bladeren, P.J. van; Rietjens, I. - \ 2012
    Mutagenesis 27 (2012)6. - ISSN 0267-8357 - p. 653 - 663.
    post-labeling analysis - naturally-occurring alkenylbenzenes - tandem mass-spectrometry - species-differences - drug-metabolism - mouse-liver - 1'-hydroxyestragole - glucuronidation - bioactivation - safrole
    Estragole is a naturally occurring food-borne genotoxic compound found in a variety of food sources, including spices and herbs. This results in human exposure to estragole via the regular diet. The objective of this study was to quantify the dose-dependent estragoleDNA adduct formation in rat liver and the urinary excretion of 1'-hydroxyestragole glucuronide in order to validate our recently developed physiologically based biodynamic (PBBD) model. Groups of male outbred Sprague Dawley rats (n = 10, per group) were administered estragole once by oral gavage at dose levels of 0 (vehicle control), 5, 30, 75, 150, and 300mg estragole/kg bw and sacrificed after 48h. Liver, kidney and lungs were analysed for DNA adducts by LC-MS/MS. Results obtained revealed a dose-dependent increase in DNA adduct formation in the liver. In lungs and kidneys DNA adducts were detected at lower levels than in the liver confirming the occurrence of DNA adducts preferably in the target organ, the liver. The results obtained showed that the PBBD model predictions for both urinary excretion of 1'-hydroxyestragole glucuronide and the guanosine adduct formation in the liver were comparable within less than an order of magnitude to the values actually observed in vivo. The PBBD model was refined using liver zonation to investigate whether its predictive potential could be further improved. The results obtained provide the first data set available on estragoleDNA adduct formation in rats and confirm their occurrence in metabolically active tissues, i.e. liver, lung and kidney, while the significantly higher levels found in liver are in accordance with the liver as the target organ for carcinogenicity. This opens the way towards future modelling of dose-dependent estragole liver DNA adduct formation in human.
    Comparison of Micro- and Nanoscale Fe+3-Containing (Hematite) Particles for Their Toxicological Properties in Human Lung Cells In Vitro
    Bhattacharya, K. ; Hoffmann, E. ; Schins, R.F.P. ; Boertz, J. ; Prantl, E.M. ; Alink, G.M. ; Byrne, H.J. ; Kuhlbusch, T.A.J. ; Rahman, Q. ; Wiggers, H. ; Schulz, C. ; Dopp, E. - \ 2012
    Toxicological sciences 126 (2012)1. - ISSN 1096-6080 - p. 173 - 182.
    protein corona - ferric-oxide - nanoparticles - toxicity - rats
    The specific properties of nanoscale particles, large surface-to-mass ratios and highly reactive surfaces, have increased their commercial application in many fields. However, the same properties are also important for the interaction and bioaccumulation of the nonbiodegradable nanoscale particles in a biological system and are a cause for concern. Hematite (alpha-Fe2O3), being a mineral form of Fe(III) oxide, is one of the most used iron oxides besides magnetite. The aim of our study was the characterization and comparison of biophysical reactivity and toxicological effects of alpha-Fe2O3 nano- (d <100 nm) and microscale (d <5 mu m) particles in human lung cells. Our study demonstrates that the surface reactivity of nanoscale alpha-Fe2O3 differs from that of microscale particles with respect to the state of agglomeration, radical formation potential, and cellular toxicity. The presence of proteins in culture medium and agglomeration were found to affect the catalytic properties of the hematite nano- and microscale particles. Both the nano- and microscale alpha-Fe2O3 particles were actively taken up by human lung cells in vitro, although they were not found in the nuclei and mitochondria. Significant genotoxic effects were only found at very high particle concentrations (> 50 mu g/ml). The nanoscale particles were slightly more potent in causing cyto- and genotoxicity as compared with their microscale counterparts. Both types of particles induced intracellular generation of reactive oxygen species. This study underlines that alpha-Fe2O3 nanoscale particles trigger different toxicological reaction pathways than microscale particles. However, the immediate environment of the particles (biomolecules, physiological properties of medium) modulates their toxicity on the basis of agglomeration rather than their actual size.
    Cytotoxicity and cellular uptake of triblock copolymer nanoparticles with different size and surface characteristics
    Bhattacharjee, S. ; Ershov, D.S. ; Fytioanos, K. ; Gucht, J. van der; Alink, G.M. ; Rietjens, I.M.C.M. ; Marcelis, A.T.M. ; Zuilhof, H. - \ 2012
    Particle and Fibre Toxicology 9 (2012). - ISSN 1743-8977
    clathrin-mediated endocytosis - oxidative stress - in-vitro - silver nanoparticles - drug-delivery - manufactured nanoparticles - dependent internalization - silicon nanoparticles - gold nanoparticles - mannose receptor
    Background Polymer nanoparticles (PNP) are becoming increasingly important in nanomedicine and food-based applications. Size and surface characteristics are often considered to be important factors in the cellular interactions of these PNP, although systematic investigations on the role of surface properties on cellular interactions and toxicity of PNP are scarce. Results Fluorescent, monodisperse tri-block copolymer nanoparticles with different sizes (45 and 90 nm) and surface charges (positive and negative) were synthesized, characterized and studied for uptake and cytotoxicity in NR8383 and Caco-2 cells. All types of PNP were taken up by the cells. The positive smaller PNP45 (45 nm) showed a higher cytotoxicity compared to the positive bigger PNP90 (90 nm) particles including reduction in mitochondrial membrane potential (¿¿m), induction of reactive oxygen species (ROS) production, ATP depletion and TNF-a release. The negative PNP did not show any cytotoxic effect. Reduction in mitochondrial membrane potential (¿¿m), uncoupling of the electron transfer chain in mitochondria and the resulting ATP depletion, induction of ROS and oxidative stress may all play a role in the possible mode of action for the cytotoxicity of these PNP. The role of receptor-mediated endocytosis in the intracellular uptake of different PNP was studied by confocal laser scanning microscopy (CLSM). Involvement of size and charge in the cellular uptake of PNP by clathrin (for positive PNP), caveolin (for negative PNP) and mannose receptors (for hydroxylated PNP) were found with smaller PNP45 showing stronger interactions with the receptors than bigger PNP90. Conclusions The size and surface characteristics of polymer nanoparticles (PNP; 45 and 90 nm with different surface charges) play a crucial role in cellular uptake. Specific interactions with cell membrane-bound receptors (clathrin, caveolin and mannose) leading to cellular internalization were observed to depend on size and surface properties of the different PNP. These properties of the nanoparticles also dominate their cytotoxicity, which was analyzed for many factors. The effective reduction in the mitochondrial membrane potential (¿¿m), uncoupling of the electron transfer chain in mitochondria and resulting ATP depletion, induction of ROS and oxidative stress likely all play a role in the mechanisms behind the cytotoxicity of these PNP.
    Evaluation of agronomic practices for mitigation of natural toxins
    Speijers, G. ; Alink, G.M. ; Saeger, S. de; Hardy, A. ; Magan, N. ; Pilegaard, K. ; Battilani, P. ; Riemens, M.M. - \ 2010
    Brussel : ILSI Europe, International Life Sciences Institute (ILSI Europe report series ) - ISBN 9789078637226 - 48
    agronomie - natuurlijke toxinen - mitigatie - mycotoxinen - risicoschatting - agronomy - natural toxins - mitigation - mycotoxins - risk assessment
    Role of surface charge and oxidative stress in cytotoxicity of organic monolayer-coated silicon nanoparticles towards macrophage NR8383 cells
    Bhattacharjee, S. ; Haan, L.H.J. de; Evers, N.M. ; Jiang, X. ; Marcelis, A.T.M. ; Zuilhof, H. ; Rietjens, I.M.C.M. ; Alink, G.M. - \ 2010
    Particle and Fibre Toxicology 7 (2010). - ISSN 1743-8977 - p. 25 - 25.
    semiconductor quantum dots - in-vitro - gene-expression - mitochondrial damage - ultrafine particles - oxide nanoparticles - epithelial-cells - cellular uptake - cancer cells - low-toxicity
    Background - Surface charge and oxidative stress are often hypothesized to be important factors in cytotoxicity of nanoparticles. However, the role of these factors is not well understood. Hence, the aim of this study was to systematically investigate the role of surface charge, oxidative stress and possible involvement of mitochondria in the production of intracellular reactive oxygen species (ROS) upon exposure of rat macrophage NR8383 cells to silicon nanoparticles. For this aim highly monodisperse (size 1.6 ± 0.2 nm) and well-characterized Si core nanoparticles (Si NP) were used with a surface charge that depends on the specific covalently bound organic monolayers: positively charged Si NP-NH2, neutral Si NP-N3 and negatively charged Si NP-COOH. Results - Positively charged Si NP-NH2 proved to be more cytotoxic in terms of reducing mitochondrial metabolic activity and effects on phagocytosis than neutral Si NP-N3, while negatively charged Si NP-COOH showed very little or no cytotoxicity. Si NP-NH2 produced the highest level of intracellular ROS, followed by Si NP-N3 and Si NP-COOH; the latter did not induce any intracellular ROS production. A similar trend in ROS production was observed in incubations with an isolated mitochondrial fraction from rat liver tissue in the presence of Si NP. Finally, vitamin E and vitamin C induced protection against the cytotoxicity of the Si NP-NH2 and Si NP-N3, corroborating the role of oxidative stress in the mechanism underlying the cytotoxicity of these Si NP. Conclusion - Surface charge of Si-core nanoparticles plays an important role in determining their cytotoxicity. Production of intracellular ROS, with probable involvement of mitochondria, is an important mechanism for this cytotoxicity
    Synthesis and cytotoxicity of silicon nanoparticles with covalently attached organic monolayers
    Ruizendaal, L. ; Bhattacharjee, S. ; Pournazari, K. ; Rosso-Vasic, M. ; Haan, L.H.J. de; Alink, G.M. ; Marcelis, A.T.M. ; Zuilhof, H. - \ 2009
    Nanotoxicology 3 (2009)4. - ISSN 1743-5390 - p. 339 - 347.
    quantum dots - alkyl monolayers - in-vivo - terminated silicon - surface - toxicity - nanocrystals - functionalization - cells - assay
    A series of highly monodisperse silicon nanoparticles (Si NPs) with either positively (amine), neutral (azide) or negatively (carboxylic acid) charged covalently attached organic monolayers were synthesized and investigated for their cytotoxicity. Infrared data confirmed the presence of these covalently attached surface groups. The Si NPs were characterized by absorption and fluorescence spectroscopy. The cytotoxicity was investigated in Caco-2 cells by determining the cell viability and proliferation. The IC50 values for the Si NPs ranged from 20 µg/l for the amine-terminated Si NPs, via 550–850 µg/l for the azide-terminated Si NPs to non-toxic (no measureable IC50) for the carboxylic acid-terminated Si NPs. These results indicate a trend in cytotoxicity, depending on surface charge, i.e., that positively charged Si NPs are more cytotoxic than negatively charged Si NPs. Interestingly, it appeared that the cytotoxicity of the Si NP-NH2 depends strongly on the presence of fetal calf serum in the medium.
    Humane risicobeoordeling in zicht : een inventarisatie van de mogelijkheden voor het optimaliseren van het gebruik van humane data bij de risicobeoordeling van chemische stoffen in de voeding
    Karman, J. ; Geelen, A. ; Alink, G.M. ; Veer, P. van 't - \ 2009
    Wageningen : Wageningen Universiteit - 49
    risicoschatting - voedselveiligheid - toxicologie - epidemiologie - chemische verbindingen - risk assessment - food safety - toxicology - epidemiology - chemical compounds
    Het doel van deze studie was het identificeren van visies op het huidige risicobeoordelingsproces, het optimaliseren van het gebruik van humane data en de samenwerking tussen toxicologie en epidemiologie. Gegevens zijn verkregen middels 23 semigestructureerde interviews
    An n-3 PUFA-rich microalgal oil diet protects to a similar extent as a fish oil-rich diet against AOM-induced colonic aberrant crypt foci in male F344 rats
    Beelen, V.A. van; Spenkelink, A. ; Mooibroek, H. ; Sijtsma, L. ; Bosch, H.J. ; Rietjens, I.M.C.M. ; Alink, G.M. - \ 2009
    Food and Chemical Toxicology 47 (2009)2. - ISSN 0278-6915 - p. 316 - 320.
    polyunsaturated fatty-acids - tumor-incidence - chemopreventive agents - docosahexaenoic acid - oxidation-products - regulated genes - corn-oil - cancer - carcinogenesis - azoxymethane
    The chemopreventive effects of high fat microalgal oil diet on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were studied in male Fischer 344 rats following 8 weeks of dietary treatment. These effects were compared to the effects of high fat fish oil and high fat corn oil diets to determine whether microalgal oil is a good alternative for fish oil regarding protection against colorectal cancer. Despite the difference in fatty acid composition and total amount of n-3 polyunsaturated fatty acids (PUFAs) between microalgal oil and fish oil, both these oils gave the same 50% reduction of AOM-induced ACF when compared to corn oil. To determine whether oxidative stress could play a role in the chemoprevention of colorectal cancer by n-3 PUFAs, feces and caecal content were examined using the TBA assay. The results showed that lipid peroxidation does occur in the gastrointestinal tract. As several lipid peroxidation products of n-3 PUFAs can induce phase II detoxifying enzymes by an EpRE-mediated pathway, the in vivo results suggest that this route may contribute to n-3 PUFA-mediated chemoprevention. All in all, n-3 PUFA-rich oil from microalgae is as good as fish oil regarding chemoprevention in the colon of the rat.
    Quercetin increases the bioavailability of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats
    Schutte, M.E. ; Alink, G.M. ; Freidig, A.P. ; Spenkelink, A. ; Vaessen, J. ; Sandt, J.J.M. van de; Groten, J.P. ; Rietjens, I.M.C.M. - \ 2008
    Food and Chemical Toxicology 46 (2008)11. - ISSN 0278-6915 - p. 3422 - 3428.
    multidrug-resistance protein-1 - epithelial caco-2 cells - heterocyclic amines - dietary flavonoids - efflux proteins - drug absorption - transport - cancer - expression - carcinogen
    This study investigates whether the previous observation that quercetin increases the transport of PhIP through Caco-2 monolayers in vitro could be confirmed in an in vivo rat model. Co-administration of 1.45 micromol PhIP/kg bw and 30 micromol quercetin/kg bw significantly increased the blood AUC(0-8h) of PhIP in rats to 131+/-14% of the AUC(0-8h) for rats dosed with PhIP alone. Significantly increased blood PhIP levels were detected at 15, 30, 45 and 180 min. At 4 and 8h post-dosing a difference in the PhIP levels in the blood between the two treatment groups was no longer observed. In vitro and in silico modeling of PhIP transport using Caco-2 cells and a previously described kinetic model for PhIP transport revealed that the relative increase in PhIP transport caused by quercetin is dependent on the concentration of the two compounds. When substituting the PhIP and quercetin concentrations used in the in vivo experiment in the kinetic model, an effect of quercetin on PhIP transport was predicted that matches the actual effect of 131% observed in vivo. It is concluded that quercetin increases the bioavailability of the pro-carcinogen PhIP in rats pointing at a potential adverse effect of this supposed beneficial food ingredient.
    Transcriptome and proteonome profiling of colon mucosa from quercetin fed F344 rats point to tumor preventive mechanisms, increased mitochondrial fatty acid degradation and decreased glycolysis
    Dihal, A.A. ; Hendriksen, P.J.M. ; Charif, H. ; Dekker, L.J. ; IJsselstijn, L. ; Boer, V.C.J. de; Alink, G.M. ; Rietjens, I.M.C.M. ; Woutersen, R.A. ; Stierum, R.H. - \ 2008
    Proteomics 8 (2008)1. - ISSN 1615-9853 - p. 45 - 61.
    gene-expression - colorectal-cancer - suppresses growth - messenger-rna - cell-line - identification - antioxidant - enrichment - pathway - targets
    Quercetin has been shown to act as an anticarcinogen in experimental colorectal cancer (CRC). The aim of the present study was to characterize transcriptome and proteome changes occurring in the distal colon mucosa of rats supplemented with 10 g quercetin/kg diet for 11 wk. Transcriptome data analyzed with Gene Set Enrichment Analysis showed that quercetin significantly downregulated the potentially oncogenic mitogen-activated protein kinase (Mapk) pathway. In addition, quercetin enhanced expression of tumor suppressor genes, including Pten, Tp53, and Msh2, and of cell cycle inhibitors, including Mutyh. Furthermore, dietary quercetin enhanced genes involved in phase I and II metabolism, including Fmo5, Ephx1, Ephx2, and Gpx2. Quercetin increased PPAR target genes, and concomitantly enhanced expression of genes involved in mitochondrial fatty acid (FA) degradation. Proteomics performed in the same samples revealed 33 affected proteins, of which four glycolysis enzymes and three heat shock proteins were decreased. A proteome-transcriptome comparison showed a low correlation, but both pointed out toward altered energy metabolism. In conclusion, transcriptomics combined with proteomics showed that dietary quercetin evoked changes contrary to those found in colorectal carcinogenesis. These tumor-protective mechanisms were associated with a shift in energy production pathways, pointing at decreased cytoplasmic glycolysis and toward increased mitochondrial FA degradation.
    Safety and nutritional assessment of GM plants and derived food and feed: The role of animal feeding trials
    Haver, E. van; Alink, G.M. ; Cockburn, A. ; Kuiper, H.A. ; Peijnenburg, A.A.C.M. - \ 2008
    Food and Chemical Toxicology 46 (2008)Sup. 1. - ISSN 0278-6915 - p. s2 - s70.
    genetically-modified plants - glyphosate-tolerant corn - gamma-linolenic acid - sprague-dawley rats - commercial reference corn - das-59122-7 maize grain - lupinus-angustifolius-l - growing-finishing pigs - lactating dairy-cows - term test systems
    In this report the various elements of the safety and nutritional assessment procedure for genetically modified (GM) plant derived food and feed are discussed, in particular the potential and limitations of animal feeding trials for the safety and nutritional testing of whole GM food and feed. The general principles for the risk assessment of GM plants and derived food and feed are followed, as described in the EFSA guidance document of the EFSA Scientific Panel on Genetically Modified Organisms
    The role of oxidative stress in the differential effects between n - 3 and n - 6 polyunsaturated fatty acids and the protective effects of algal and fish oil in colon carcinogenesis
    Alink, G.M. ; Beelen, V.A. van; Aarts, J.M.M.J.G. ; Bino, R.J. ; Bosch, H.J. ; Hooiveld, G.J.E.J. ; Mooibroek, H. ; Muller, M.R. ; Reus, A. ; Roeleveld, J. ; Sijtsma, L. ; Spenkelink, A. ; Rietjens, I.M.C.M. - \ 2007
    In: 44th Congress of the European Societies of Toxicology. - - p. S60 - S61.
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