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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    Whole Grain Wheat Consumption Affects Postprandial Inflammatory Response in a Randomized Controlled Trial in Overweight and Obese Adults with Mild Hypercholesterolemia in the Graandioos Study
    Hoevenaars, Femke P.M. ; Esser, Diederik ; Schutte, Sophie ; Priebe, Marion G. ; Vonk, Roel J. ; Brink, Willem J. van den; Kamp, Jan Willem van der; Stroeve, Johanna H.M. ; Afman, Lydia A. ; Wopereis, Suzan - \ 2019
    The Journal of Nutrition 149 (2019)12. - ISSN 0022-3166 - p. 2133 - 2144.
    (compromised) healthy subjects - challenge test - composite biomarkers - inflammation - liver - metabolic health - phenotypic flexibility - resilience - whole grain wheat

    BACKGROUND: Whole grain wheat (WGW) consumption is associated with health benefits in observational studies. However, WGW randomized controlled trial (RCT) studies show mixed effects. OBJECTIVES: The health impact of WGW consumption was investigated by quantification of the body's resilience, which was defined as the "ability to adapt to a standardized challenge." METHODS: A double-blind RCT was performed with overweight and obese (BMI: 25-35 kg/m2) men (n = 19) and postmenopausal women (n = 31) aged 45-70 y, with mildly elevated plasma total cholesterol (>5 mmol/L), who were randomly assigned to either 12-wk WGW (98 g/d) or refined wheat (RW). Before and after the intervention a standardized mixed-meal challenge was performed. Plasma samples were taken after overnight fasting and postprandially (30, 60, 120, and 240 min). Thirty-one biomarkers were quantified focusing on metabolism, liver, cardiovascular health, and inflammation. Linear mixed-models evaluated fasting compared with postprandial intervention effects. Health space models were used to evaluate intervention effects as composite markers representing resilience of inflammation, liver, and metabolism. RESULTS: Postprandial biomarker changes related to liver showed decreased alanine aminotransferase by WGW (P = 0.03) and increased β-hydroxybutyrate (P = 0.001) response in RW. Postprandial changes related to inflammation showed increased C-reactive protein (P = 0.001), IL-6 (P = 0.02), IL-8 (P = 0.007), and decreased IL-1B (P = 0.0002) in RW and decreased C-reactive protein (P < 0.0001), serum amyloid A (P < 0.0001), IL-8 (P = 0.02), and IL-10 (P < 0.0001) in WGW. Health space visualization demonstrated diminished inflammatory (P < 0.01) and liver resilience (P < 0.01) by RW, whereas liver resilience was rejuvenated by WGW (P < 0.05). CONCLUSIONS: Twelve-week 98 g/d WGW consumption can promote liver and inflammatory resilience in overweight and obese subjects with mildly elevated plasma cholesterol. The health space approach appeared appropriate to evaluate intervention effects as composite markers. This trial was registered at www.clinicaltrials.gov as NCT02385149.

    Dietary supplementation of 11 different plant extracts on the antioxidant capacity of blood and selected tissues in lightweight lambs
    Leal, Leonel N. ; Jordán, María J. ; Bello, José M. ; Otal, Julio ; Hartog, Leo A. den; Hendriks, Wouter H. ; Martín-Tereso, Javier - \ 2019
    Journal of the Science of Food and Agriculture 99 (2019)9. - ISSN 0022-5142 - p. 4296 - 4303.
    kidney - lambs - liver - muscle - plant extracts - plasma

    BACKGROUND: Due to the growing public concern regarding the addition of chemical antioxidants to foods, focus has shifted towards natural alternatives. Because of their antioxidant potential, culinary herbs and spices have long been used to extend the shelf-life of foods. However, a better understanding of the fate of these products following intake is required to assess their use in lamb diets. RESULTS: Two hundred and eighty-eight Rasa Aragonesa male lambs (70 days old) were supplemented (5.0 g kg −1 compound feed) with bay, marjoram, oregano, rosemary, thyme, turmeric, cumin, caraway, dill, cinnamon and nutmeg extracts for 14 days before slaughter. Dietary supplementation with plant extracts had no effect on intake, growth performance or antioxidant activity in blood (TEAC values). In muscle, nutmeg supplementation increased (P < 0.05) the radical-scavenging capacity (TEAC), whereas a decrease in the radical-scavenging capacity was found for lambs supplemented with oregano, dill, cinnamon and nutmeg (ORAC values). In liver, nutmeg supplementation increased (P < 0.05) the antioxidant capacity (TEAC), whereas bay (ORAC), turmeric, cinnamon and nutmeg (DPPH values) decreased (P < 0.05) the radical-scavenging capacity of the tissue. In kidney, a lower (P < 0.05) radical-scavenging capacity (TEAC values) was found in lambs supplemented with oregano, cumin and caraway, whereas, turmeric, cumin, caraway, cinnamon and nutmeg increased (P < 0.05) the antioxidant capacity (ORAC values) in kidney. CONCLUSION: Supplementation of lamb diets with plant extracts affected radical-scavenging activity in muscle, liver and kidney. However, due to the divergent results of the different assays for the same tissue, it is not advisable to discriminate plant extracts using this approach.

    Biological mechanisms discriminating growth rate and adult body weight phenotypes in two Chinese indigenous chicken breeds
    Dou, Tengfei ; Zhao, Sumei ; Rong, Hua ; Gu, Dahai ; Li, Qihua ; Huang, Ying ; Xu, Zhiqiang ; Chu, Xiaohui ; Tao, Linli ; Liu, Lixian ; Ge, Changrong ; Pas, M.F.W. te; Jia, Junjing - \ 2017
    Yunnan Agriculture University
    growth rate - chicken breeds - Gallus gallus - breast muscle - liver - microarray - metabolic differences - biological mechanisms
    Background Intensive selection has resulted in increased growth rates and muscularity in broiler chickens, in addition to adverse effects, including delayed organ development, sudden death syndrome, and altered metabolic rates. The biological mechanisms underlying selection responses remain largely unknown. Non-artificially-selected indigenous Chinese chicken breeds display a wide variety of phenotypes, including differential growth rate, body weight, and muscularity. The Wuding chicken breed is a fast growing large chicken breed, and the Daweishan mini chicken breed is a slow growing small chicken breed. Together they form an ideal model system to study the biological mechanisms underlying broiler chicken selection responses in a natural system. The objective of this study was to study the biological mechanisms underlying differential phenotypes between the two breeds in muscle and liver tissues, and relate these to the growth rate and body development phenotypes of the two breeds. Results The muscle tissue in the Wuding breed showed higher expression of muscle development genes than muscle tissue in the Daweishan chicken breed. This expression was accompanied by higher expression of acute inflammatory response genes in Wuding chicken than in Daweishan chicken. The muscle tissue of the Daweishan mini chicken breed showed higher expression of genes involved in several metabolic mechanisms including endoplasmic reticulum, protein and lipid metabolism, energy metabolism, as well as specific immune traits than in the Wuding chicken. The liver tissue showed fewer differences between the two breeds. Genes displaying higher expression in the Wuding breed than in the Daweishan breed were not associated with a specific gene network or biological mechanism. Genes highly expressed in the Daweishan mini chicken breed compared to the Wuding breed were enriched for protein metabolism, ABC receptors, signal transduction, and IL6-related mechanisms. Conclusions We conclude that faster growth rates and larger body size are related to increased expression of genes involved in muscle development and immune response in muscle, while slower growth rates and smaller body size are related to increased general cellular metabolism. The liver of the Daweishan breed displayed increased expression of metabolic genes.
    Transfer of pyrrolizidine alkaloids from various herbs to eggs and meat in laying hens
    Mulder, Patrick P.J. ; Witte, Susannah L. de; Stoopen, Geert M. ; Meulen, Jan van der; Wikselaar, Piet G. van; Gruys, Erik ; Groot, Maria J. ; Hoogenboom, Ron L.A.P. - \ 2016
    Food Additives & Contaminants. Pt. A, Chemistry, Analysis, Control, Exposure & Risk Assessment 33 (2016)12. - ISSN 1944-0049 - p. 1826 - 1893.
    eggs - laying hens - liver - meat - Pyrrolizidine alkaloids - transfer

    To investigate the potential transfer of pyrrolizidine alkaloids (PAs), laying hens were fed for 14 days with diets containing 0.5% of dried common ragwort, common groundsel, narrow-leaved ragwort or viper’s bugloss, or 0.1% of common heliotrope. This resulted in total PA levels in feed of respectively 5.5, 11.1, 53.1, 5.9 and 21.7 mg kg 1, with varying composition. PAs were transferred to eggs, in particular yolk, with steady-state levels of respectively 12, 21, 216, 2 and 36 µg kg 1. Overall transfer rates for the sum of PAs were estimated between 0.02% and 0.23%, depending on the type of PAs in the feed. In animals slaughtered shortly after the last exposure, levels in meat were slightly lower than those in eggs, levels in livers somewhat higher. When switched to clean feed, levels in eggs gradually decreased, but after 14 days were still above detection limits in the hens exposed to higher PA levels. Similar was the case for meat and especially kidneys and livers. It is concluded that the intake of PA containing herbs by laying hens may result in levels in eggs and meat that could be of concern for consumers, and as such should be avoided.

    Substitution of starch for palm oil during gestation: Impact on offspring survival and hepatic gene expression in the pig
    Almond, K.L. ; Fainberg, H.P. ; Lomax, M.A. ; Bikker, P. ; Symonds, M.E. ; Mostyn, A. - \ 2015
    Reproduction Fertility and Development 27 (2015)7. - ISSN 1031-3613 - p. 1057 - 1064.
    development - liver - nutrition - pregnancy

    Piglet neonatal mortality rates are high (∼20%), so nutritional strategies to reduce this are highly desirable. Maternal fat substitution (FS) may promote the preweaning survival of piglets by improving their energy status. Therefore, the aim of the present study was to investigate the effects of FS throughout pregnancy on offspring viability, together with the gene expression of stress-related markers in the liver. Sixteen pregnant sows were randomly allocated to one of two isocaloric diets, control (C) or FS in the form of palm oil, fed from 0 to 110 days gestation. Glucose tolerance was examined on Day 108. Median and low birthweight offspring were allocated to tissue sampling at either 7 days or 6 months postnatal age. In response to a glucose tolerance test, FS sows exhibited a raised glucose area under the curve with no change in basal glucose. Average piglet mortality (up to Day 28) was increased fourfold in the FS group, with surviving median-sized piglets exhibiting significantly lower fatty acid binding protein 1 (FABP1) expression at 7 days. There were no effects on the abundance of any other stress- or metabolic-related genes examined. Thus, this study demonstrates that maternal FS throughout gestation causes maternal glucose intolerance that may be linked to the observed increase in piglet mortality. However, the surviving offspring do not exhibit any detectable differences in postnatal growth or hepatic gene profile in later life.

    Unravelling mechanisms of dietary flavonoid-mediated health effects: effects on lipid metabolism and genotoxicity
    Hoek-van den Hil, E.F. - \ 2015
    Wageningen University. Promotor(en): Ivonne Rietjens; Jaap Keijer, co-promotor(en): Peter Hollman. - Wageningen : Wageningen University - ISBN 9789462573031 - 157
    flavanoïden - flavonoïden - vetzuren - quercetine - flavonolen - lichaamsgewicht - lipidenmetabolisme - hart- en vaatziekten - lever - vetweefsel - gezondheid - genotoxiciteit - voeding - muizen - flavanoids - flavonoids - fatty acids - quercetin - flavonols - body weight - lipid metabolism - cardiovascular diseases - liver - adipose tissue - health - genotoxicity - nutrition - mice

    Summary

    Consumption of foods containing flavonoids is associated with a reduced risk of cardiovascular diseases (CVD), possibly by lipid-lowering effects. On the other hand, for one of these flavonoids, quercetin, also genotoxicity was shown especially in in vitro bioassays. Therefore, the first aim of this thesis was to identify mechanisms underlying potential beneficial health effects of flavonoids. The focus was on hepatic lipid metabolism and circulating lipids and a molecular and physiological approach was used. Secondly, we aimed to study the potential in vivo genotoxic effects of quercetin by transcriptome analyses in liver and small intestine, since these represent the tissues of first contact exposed to relatively high levels upon oral intake of flavonoids.

    Circulating lipids are important CVD-related risk markers, which are in general determined with commercially available enzyme-based assays. However, the usual enzyme in these assays, peroxidase, has previously been reported to be inhibited by flavonoids. Therefore, we have studied in chapter 2 whether these assays can adequately be used in flavonoid research. We observed that various flavonoid aglycones interfere with peroxidase used in triglycerides (TG) and free fatty acids (FFA) enzymatic assays, reporting incorrect lower TG and FFA levels than actually present. Furthermore, addition of metabolites such as isorhamnetin or quercetin-3-O-glucuronide, the major metabolite of quercetin in human and rat plasma, to murine serum also resulted in a significant reduction of the detected TG levels, while a trend was seen towards reduced FFA levels. It can be concluded that when applying these biochemical assays, vigilance is needed and alternative analytical methods assessing FFA or TG levels should preferably be applied for studying the biological effects of flavonoids on TG and FFA levels.

    In chapter 3 mechanistic and physiological effects of quercetin on hepatic lipid metabolism were studied. C57BL/6JOlaHsd male adult mice received a mild high-fat (30 en%) diet without or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H-NMR were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify potential mechanisms underlying altered circulating lipid levels by quercetin supplementation. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, TG levels were decreased by 14% (p<0.001) and total poly unsaturated fatty acids (PUFA) levels were increased by 13% (p<0.01). Levels of palmitic acid, oleic acid, and linoleic acid were all decreased by 9-15% (p<0.05) in quercetin-fed mice. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Gene expression profiling showed indeed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up-regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450 activities) and the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3) were also up- regulated in the quercetin-fed mice. We concluded that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects of quercetin on CVD.

    Subsequently, in chapter 4 effects of quercetin supplementation were studied in mice given a high-fat (40 en%) background diet. The set-up of the experiment was the same as in chapter 3, with the exception of the background diet that was used, which was different in fat content and composition. This high-fat diet-induced body weight gain, and serum and hepatic lipid accumulation, which are all known risk factors for CVD. The aim of this study was to investigate the effects and underlying molecular mechanisms of the effects of the flavonoid quercetin on hepatic lipid metabolism in mice given this high-fat diet background. C57BL/6JOlaHsd male adult mice received the high-fat diet without or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Body weight gain was 29% lower in quercetin fed mice versus control mice (p<0.01), while the energy intake was not significantly different. Quercetin supplementation lowered high-fat diet-induced hepatic lipid accumulation to 29% of the amount present in the control mice (p<0.01). 1H-NMR serum lipid profiling revealed that the supplementation also significantly lowered high-fat diet-induced increases in serum lipid levels. Global gene expression profiling of liver showed that cytochrome P450 2b (Cyp2b) genes, key target genes of the transcription factor Car, were down-regulated. However, the induction of omega-oxidation observed by quercetin supplementation to a mild high-fat (30en%) diet (chapter 3), was not observed this time with the high-fat (40en%) diet. Cumulatively, quercetin decreased high-fat diet-induced body weight gain, hepatic lipid accumulation and serum lipid levels. This was accompanied by regulation of cytochrome P450 2b genes in liver, which are considered to be under transcriptional control of CAR. The quercetin effects are likely dependent on the fat content and composition of the diet.

    In chapter 5 we investigated whether flavonoids from other flavonoid subclasses can exert the same effects as we observed for quercetin. Effects of quercetin, hesperetin, epicatechin, apigenin and anthocyanins, in C57BL/6JOlaHsd male adult mice fed a high-fat diet for 12 weeks were compared, relative to a normal-fat diet. High-fat diet-induced body weight gain was significantly lowered by all flavonoids (17-29%), but most by quercetin. Quercetin significantly lowered high-fat diet-induced hepatic lipid accumulation (by 71%). High-fat diet-induced increases of mesenteric adipose tissue weight and serum leptin levels were significantly lowered by quercetin, hesperetin, and anthocyanins. Adipocyte cell size and adipose tissue inflammation were not affected.

    The effects on body weight and adiposity could not be explained by individual significant differences in energy intake, energy expenditure, nor by differences in activity. Lipid metabolism was not changed as measured by indirect calorimetry or expression of known lipid metabolic genes in liver and white adipose tissue. Hepatic expression of Cyp2b9 was strongly down-regulated by all flavonoids. Overall, all five flavonoids lowered parameters of high-fat diet-induced adiposity, with quercetin being most effective.

    Next to the beneficial health effects of flavonoids, the safety of flavonoids is under discussion, mainly because of potential genotoxic effects found for quercetin in vitro. Therefore, in chapter 6 the in vivo genotoxicity of this flavonoid was studied by transcriptome analyses in two tissues, small intestine and liver, where the highest exposure to quercetin is expected. This is especially of interest in view of high intake by widely available food supplements. Quercetin (0.33%) supplemented to a high-fat diet was administered to C57BL/6JOlaHsd male adult mice during 12 weeks. Serum alanine aminotransferase and aspartate aminotransferase levels revealed no indications for hepatotoxicity. General microarray pathway analysis of liver and small intestinal tissue samples showed no regulation of genotoxicity related pathways. In addition, analysis of DNA damage pathways in these tissues did also not point at genotoxicity. Furthermore, comparison with a published classifier set of transcripts for identifying genotoxic compounds did not reveal any similarities in the regulation of these classifier set by quercetin. Available microarray datasets of known genotoxic liver carcinogens, 2-acetylaminofluorene and aflatoxin B1 in mice were taken along as positive controls for comparison, and indeed showed genotoxic properties (regulation of genotoxic related genes) in the analyses. This transcriptomic analysis showed that supplementation with quercetin at ~350 mg/kg bw/day for 12 weeks did not induce genotoxicity in liver and small intestine.

    In conclusion, we have shown in vivo efficacy of flavonoids reflected by effects on metabolic health parameters, including hepatic lipid metabolism. These effects on hepatic lipid metabolism seemed to be related or influenced by the transcription factor CAR. The dietary contexts appeared to modify the health effects. The five studied flavonoids in general showed the same effects, with quercetin being the most effective. No genotoxicity of quercetin was found by transcriptome analyses in liver and small intestine. Overall, we have obtained indications for beneficial health effects of flavonoids in mice, which makes it interesting to study if these effects can be extrapolated to humans to further explore their potential as functional compounds of dietary flavonoid intake.

    Effects of dry period length and dietary energy source on metabolic status and hepatic gene expression of dairy cows in early lactation
    Chen, J.C. ; Gross, J.J. ; Dorland, H.A. van; Remmelink, G.J. ; Bruckmaier, R.M. ; Kemp, B. ; Knegsel, A.T.M. van - \ 2015
    Journal of Dairy Science 98 (2015)2. - ISSN 0022-0302 - p. 1033 - 1045.
    organic nutrient metabolism - messenger-rna - transition period - somatotropic axis - milk-production - fatty-acids - liver - balance - system - performance
    In a prior study, we observed that cows with a 0-d dry period had greater energy balance and lower milk production compared with cows with a 30- or 60-d dry period in early lactation. The objective of the current study was to evaluate the influence of dry period length on metabolic status and hepatic gene expression in cows fed a lipogenic or glucogenic diet in early lactation. Holstein-Friesian dairy cows (n = 167) were assigned randomly to 3 × 2 factorial design with 3 dry period lengths (n = 56, 55, and 56 for 0-, 30-, and 60-d dry, respectively) and 2 early lactation diets (n = 84 and 83 for glucogenic and lipogenic diet, respectively). Cows were fed a glucogenic or lipogenic diet from 10 d before the expected calving date and onward. The main ingredient for a glucogenic concentrate was corn, and the main ingredients for a lipogenic concentrate were sugar beet pulp, palm kernel, and rumen-protected palm oil. Blood was sampled weekly from 95 cows from wk 3 precalving to wk 8 postcalving. Liver samples were collected from 76 cows in wk -2, 2, and 4 relative to calving. Liver samples were analyzed for triacylglycerol concentrations and mRNA expression of 12 candidate genes. Precalving, cows with a 0-d dry period had greater plasma ß-hydroxybutyrate, urea, and insulin concentrations compared with cows with a 30- or 60-d dry period. Postcalving, cows with a 0-d dry period had lower liver triacylglycerol and plasma nonesterified fatty acids concentrations (0.20, 0.32, and 0.36 mmol/L for 0-, 30-, and 60-d dry period, respectively), greater plasma glucose, insulin-like growth factor-I, and insulin (24.38, 14.02, and 11.08 µIU/mL for 0-, 30-, and 60-d dry period, respectively) concentrations, and lower hepatic mRNA expression of pyruvate carboxylase, compared with cows with a 30- or 60-d dry period. Plasma urea and ß-hydroxybutyrate concentrations were greater in cows fed a lipogenic diet compared with cows fed a glucogenic diet. In conclusion, cows with a 0-d dry period had an improved metabolic status in early lactation, indicated by lower plasma concentrations of nonesterified fatty acids, greater plasma concentrations of glucose, insulin-like growth factor-I, and insulin, and lower mRNA expression of pyruvate carboxylase in the liver, compared with cows with a 30- or 60-d dry period. Independent of dry period length, the glucogenic diet also improved the metabolic status compared with the lipogenic diet.
    The ER-Associated Degradation Adaptor Protein Sel1L Regulates LPL Secretion and Lipid Metabolism
    Sha, H. ; Sun, S. ; Francisco, A. ; Ehrhardt, N. ; Xue, Z.Q. ; Liu, L. ; Mattijssen, F.B.J. ; Kersten, A.H. - \ 2014
    Cell Metabolism 20 (2014)3. - ISSN 1550-4131 - p. 458 - 470.
    reticulum-associated-degradation - endoplasmic-reticulum - lipoprotein-lipase - caenorhabditis-elegans - membrane-protein - stress - deficiency - maturation - disease - liver
    Sel1L is an essential adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum (ER)-associated degradation (ERAD), a universal quality-control system in the cell; but its physiological role remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Further analyses reveal that Sel1L is indispensable for the secretion of lipoprotein lipase (LPL), independent of its role in Hrd1-mediated ERAD and ER homeostasis. Sel1L physically interacts with and stabilizes the LPL maturation complex consisting of LPL and lipase maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and forms protein aggregates, which are degraded primarily by autophagy. The Sel1L-mediated control of LPL secretion is also seen in other LPL-expressing cell types including cardiac myocytes and macrophages. Thus, our study reports a role of Sel1L in LPL secretion and systemic lipid metabolism.
    PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism
    Diepen, J.A. van; Jansen, P.A. ; Ballak, D.B. ; Hijmans, A. ; Hooiveld, G.J.E.J. ; Rommelaere, S. ; Kersten, A.H. ; Stienstra, R. - \ 2014
    Journal of Hepatology 61 (2014)2. - ISSN 0168-8278 - p. 366 - 372.
    high-fat diet - gene-expression - insulin-resistance - null mice - liver - cysteamine - tissue - acids - hepatocytes - fenofibrate
    Background & Aims Peroxisome proliferator-activated receptor alpha (PPARa) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARa target gene in liver, but its function in hepatic lipid metabolism is unknown. Methods We investigated the regulation of vanin-1, and total vanin activity, by PPARa in mice and humans. Furthermore, the function of vanin-1 in the development of hepatic steatosis in response to starvation was examined in Vnn1 deficient mice, and in rats treated with an inhibitor of vanin activity. Results Liver microarray analyses reveals that Vnn1 is the most prominently regulated gene after modulation of PPARa activity. In addition, activation of mouse PPARa regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPARa, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPARa agonist fenofibrate. In mice, absence of vanin-1 exacerbates the fasting-induced increase in hepatic triglyceride levels. Similarly, inhibition of vanin activity in rats induces accumulation of hepatic triglycerides upon fasting. Microarray analysis reveal that the absence of vanin-1 associates with gene sets involved in liver steatosis, and reduces pathways involved in oxidative stress and inflammation. Conclusions We show that hepatic vanin-1 is under extremely sensitive regulation by PPARa and that plasma vanin activity could serve as a readout of changes in PPARa activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting. Abbreviations PPAR, Peroxisome proliferator-activated receptor; RXR, Retinoid X Receptor; VNN1, vanin-1; VNN2, vanin-2; VNN3, vanin-3; WT, wild-type; BMI, body mass index; Pan-AMC, pantothenate-7-amino-4-methylcoumarin; TG, Triglycerides; TC, total cholesterol; FFA, free fatty acids; KLF15, Kruppel-like factor 15; STAT3, signal transducer and activator of transcription 3; SP1, trans-acting transcription factor 1; CBFB, core binding factor beta; XBP1, x-box binding protein 1; NAFLD, non-alcoholic fatty liver disease; Pan-PNa, pantothenate-4-nitroanilide; Abcd2, chemokine (C-C motif) ligand 17; Acadm, acyl-CoA dehydrogenase, medium chain; Acot1, acyl-CoA thioesterase 1; Acot2, acyl-CoA thioesterase 2; Acsl5, acyl-CoA synthetase long-chain family member 5; Ehhadh, enoyl-CoA hydratase/3-hydroxylacyl CoA dehydrogenase; NASH, non-alcoholic steatohepatitis (NASH)
    Metabolic and transcriptional responses of gilthead sea bream (Sparus aurata L.) to environmental stress: New insights in fish mitochondrial phenotyping
    Bermejo-Nogales, A. ; Nederlof, M.A.J. ; Benedito-Palos, L. ; Ballester-Lozano, G.F. ; Folkedal, O. ; Olsen, R.E. ; Sitjà-Bobadilla, A. ; Pérez-Sánchez, J. - \ 2014
    General and Comparative Endocrinology 205 (2014). - ISSN 0016-6480 - p. 305 - 315.
    skeletal-muscle - confinement exposure - compensatory growth - protein import - marine fish - factor-a - biogenesis - liver - exercise - acclimation
    The aim of the current study was to phenotype fish metabolism and the transcriptionally-mediated response of hepatic mitochondria of gilthead sea bream to intermittent and repetitive environmental stressors: (i) changes in water temperature (T-ST), (ii) changes in water level and chasing (C-ST) and (iii) multiple sensory perception stressors (M-ST). Gene expression profiling was done using a quantitative PCR array of 60 mitochondria-related genes, selected as markers of transcriptional regulation, oxidative metabolism, respiration uncoupling, antioxidant defense, protein import/folding/assembly, and mitochondrial dynamics and apoptosis. The mitochondrial phenotype mirrored changes in fish performance, haematology and lactate production. T-ST especially up-regulated transcriptional factors (PGC1a, NRF1, NRF2), rate limiting enzymes of fatty acid ß-oxidation (CPT1A) and tricarboxylic acid cycle (CS), membrane translocases (Tim/TOM complex) and molecular chaperones (mtHsp10, mtHsp60, mtHsp70) to improve the oxidative capacity in a milieu of a reduced feed intake and impaired haematology. The lack of mitochondrial response, increased production of lactate and negligible effects on growth performance in C-ST fish were mostly considered as a switch from aerobic to anaerobic metabolism. A strong down-regulation of PGC1a, NRF1, NRF2, CPT1A, CS and markers of mitochondrial dynamics and apoptosis (BAX, BCLX, MFN2, MIRO2) occurred in M-ST fish in association with the greatest circulating cortisol concentration and a reduced lactate production and feed efficiency, which represents a metabolic condition with the highest allostatic load score. These findings evidence a high mitochondrial plasticity against stress stimuli, providing new insights to define the threshold level of stress condition in fish.
    Molecular characterization of LEAP-2 cDNA in common carp (cyprinus carpio L.) and the differential expression upon a vibrio anguillarum stimulus; indications for a significant immune role in skin
    Yang Guiwen, ; Guo, H. ; Li, H. ; Shan, S. ; Zhang, X. ; Rombout, J.H.W.M. ; An, L. - \ 2014
    Fish and Shellfish Immunology 37 (2014)1. - ISSN 1050-4648 - p. 22 - 29.
    antimicrobial peptide gene - rainbow-trout - oncorhynchus-mykiss - channel catfish - bacterial challenge - hepcidin gene - nk-lysin - liver - fish - identification
    LEAP-2 is a cysteine-rich cationic antimicrobial peptide (AMP) playing an important role in host innate immune system. LEAP-2 genes have been identified from higher vertebrates and several fish species. Here we report the cloning and identification of two LEAP-2 cDNA sequences from the liver of common carp (Cyprinus carpio L.). The LEAP-2A cDNA was 1325 bp long and contained an ORF of 279 bp encoding a protein of 92 amino acids. The LEAP-2B cDNA was 608 bp long and contained an ORF of 276 bp encoding a protein of 91 amino acids. Both LEAP-2 proteins consisted of 41 amino acid residues and shared four cysteines at the conserved positions in the predicted mature peptides, highly similar to LEAP-2 of other species. Sequence alignment showed that LEAP-2 amino acid sequences were well conserved in different species, and the phylogenetic relation of LEAP-2 was coincident with evolution of biological species. Expression analysis data revealed that LEAP-2A and LEAP-2B mRNAs were expressed in a wide range of common carp tissues including liver, spleen, head kidney, skin, gills, hindgut and foregut. When injected intraperitoneally with Vibrio anguillarum, the expression level of common carp LEAP-2A was quickly up-regulated in liver, spleen, head kidney, skin, gills, foregut and hindgut, however, the expression level of LEAP-2B was similarly up-regulated in spleen, skin, gills and hindgut but not in liver, head kidney and foregut. Our results showed that the LEAP-2A had a markedly high constitutive expression in skin, and the LEAP-2A and the LEAP-2B had a significantly high up-regulated expression after stimulus in skin. This differential expression of LEAP-2 in common carp suggests that it may play a key role in immune responses against invading pathogens and both LEAP-2 molecules may be involved in mucosal immunity.
    Investigation of the presence of prednisolone in bovine urine
    Rijke, E. de; Zoontjes, P.W. ; Samson, D. ; Oostra, S. ; Sterk, S.S. ; Ginkel, L.A. van - \ 2014
    Food Additives & Contaminants. Pt. A, Chemistry, Analysis, Control, Exposure & Risk Assessment 31 (2014)4. - ISSN 1944-0049 - p. 605 - 613.
    performance liquid-chromatography - synthetic corticosteroids - domestic livestock - mass-spectrometry - feces - metabolites - liver
    Over the past 2 years low levels of prednisolone have been reported in bovine urine by a number of laboratories in EU member states. Concentrations vary, but are reported to be below approximately 3 g/l. In 40% of bovine urine samples from the Dutch national control plan had concentrations of prednisolone between 0.112.04 g/l. In this study the mechanism of formation of prednisolone was investigated. In-vitro conversion of cortisol by bacteria from faeces and soil, bovine liver enzymes and stability at elevated temperatures were studied. In-vitro bovine liver S9 incubation experiments showed a significant 20% decrease of cortisol within 6 hours, and formation of prednisolone was observed from 0.2 g/l at t = 0 to 0.5 g/l at t = 6. Under the influence of faeces, the stability of cortisol in urine is reduced and cortisol breaks down within 50 h. Prednisolone is formed up to 4 g/l at 70C after 15 h. However, this decreases again to 0 after 50 h. With soil bacteria, a slower decrease of cortisol was observed, but slightly higher overall formation of prednisolone, up to 7 g/l at 20C. As opposed to incurred urine, in fortified urine incubated with faeces or soil bacteria no prednisolone was detected. This difference may be explained by the presence of natural corticosteroids in the incurred sample. With UPLC-QToF-MS experiments, in urine and water samples incubated with faeces, metabolites known from the literature could be (tentatively) identified as 20ß-hydroxy-prednisolone, cortisol-21-sulfate, oxydianiline, tetrahydrocortisone-3-glucuronide and cortexolone, but for all compounds except 20ß-hydroxy-prednisolone no standards were available for confirmation. Based on the results of this study and literature data, for regulatory purposes a threshold of 5 g/l for prednisolone in bovine urine is proposed. Findings of prednisolone in concentrations up to 5 g/l in bovine urine can, most likely, originate from other sources than illegal treatment with growth promoters.
    Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis
    Kienhuis, A.S. ; Vitins, A.P. ; Pennings, J.L.A. ; Pronk, T.E. ; Speksnijder, E.N. ; Roodbergen, M. ; Delft, J.H.M. van; Luijten, M. ; Ven, L.T.M. van der - \ 2013
    Toxicology Letters 221 (2013)3. - ISSN 0378-4274 - p. 225 - 236.
    proliferator-activated receptor - phospholipid transfer protein - nuclear receptors - bile-acids - liver - hepatotoxicity - transporters - mechanisms - mice - drugs
    In vitro models for hepatotoxicity testing are a necessity for advancement of toxicological research. Assessing the in vitro response requires in vivo validated gene sets reflective of the hepatotoxic phenotype. Cholestasis, the impairment of bile flow, is induced in C57BL/6J mice treated with cyclosporine A (CsA) to identify phenotype reflective gene sets. CsA treatment through oral gavage for 25 days induced cholestasis, as confirmed by histopathology and serum chemistry. Over 1, 4, and 11 days of CsA exposure gradual increases in serum markers were correlated to gene expression. This phenotype-directed analysis identified gene sets specific to the onset and progression of cholestasis, such as PPAR related processes and drug metabolism, by circumventing other effects of CsA, such as immunosuppression, found in dose*time group analysis. In vivo gene sets are enriched in publicly available data sets of CsA-treated HepaRG and primary mouse hepatocytes. However, genes identified within these gene sets did not overlap between in vivo and in vitro. In vitro regulated genes represent the initial response to cholestasis, whereas in vivo genes represent the later adaptive response. We conclude that the applicability of in vitro models for hepatotoxicity testing fully depends on a solid in vivo phenotype anchored analysis. (c) 2013 Elsevier Ireland Ltd. All rights reserved.
    Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion
    Diepen, J.A. van; Stienstra, R. ; Vroegrijk, I.O.C.M. ; Berg, S.A.A. van den; Salvatori, D. ; Hooiveld, G.J.E.J. ; Kersten, A.H. ; Tack, C.J. ; Netea, M.G. ; Smit, J.W.A. ; Joosten, L.A.B. ; Havekes, L.M. ; Dijk, K.W. van; Rensen, P.C.N. - \ 2013
    Journal of Lipid Research 54 (2013)2. - ISSN 0022-2275 - p. 448 - 456.
    lipid-metabolism - adipose-tissue - fatty-acids - lipoprotein metabolism - insulin-resistance - immune-responses - inflammation - liver - inflammasomes - interleukin-1
    Caspase-1 is known to activate the proinflammatory cytokines IL-1 beta and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 deficiency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-deficient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-deficient and wild-type mice. Caspase-1 deficiency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [H-3] TG-labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [H-3] TG-containing olive oil revealed that caspase-1 deficiency reduced TG absorption and subsequent uptake of TG-derived FA in liver, muscle, and adipose tissue. Similarly, despite an elevated hepatic TG content, caspase-1 deficiency reduced hepatic VLDL-TG production. Intestinal and hepatic gene expression analysis revealed that caspase-1 deficiency did not affect FA oxidation or FA uptake but rather reduced intracellular FA transport, thereby limiting lipid availability for the assembly and secretion of TG-rich lipoproteins.(jlr) The current study reveals a novel function for caspase-1, or caspase-1-cleaved substrates, in controlling intestinal TG absorption and hepatic TG secretion.-van Diepen, J. A., R. Stienstra, I. O. C. M. Vroegrijk, S. A. A. van den Berg, D. Salvatori, G. J. Hooiveld, S. Kersten, C. J. Tack, M. G. Netea, J. W. A. Smit, L. A. B. Joosten, L. M. Havekes, K. W. van Dijk, and P. C. N. Rensen. Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion. J. Lipid Res. 2013. 54: 448-456.
    Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome
    Sailer, M. ; Dahlhoff, C. ; Giesbertz, P. ; Eidens, M.K. ; Wit, N.J.W. de; Rubio-Aliaga, I. ; Boekschoten, M.V. ; Müller, M.R. ; Daniel, H. - \ 2013
    PLoS ONE 8 (2013)5. - ISSN 1932-6203
    amino-acid transporter - skeletal-muscle cells - arginine bioavailability ratios - high-fat diet - insulin-resistance - l-alanine - protein - liver - secretion - mechanism
    Article About the Authors Metrics Comments Related Content Abstract Introduction Results Discussion Materials and Methods Supporting Information Acknowledgments Author Contributions References Reader Comments (0) Figures Abstract In humans, plasma amino acid concentrations of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) increase in states of obesity, insulin resistance and diabetes. We here assessed whether these putative biomarkers can also be identified in two different obesity and diabetic mouse models. C57BL/6 mice with diet-induced obesity (DIO) mimic the metabolic impairments of obesity in humans characterized by hyperglycemia, hyperinsulinemia and hepatic triglyceride accumulation. Mice treated with streptozotocin (STZ) to induce insulin deficiency were used as a type 1 diabetes model. Plasma amino acid profiling of two high fat (HF) feeding trials revealed that citrulline and ornithine concentrations are elevated in obese mice, while systemic arginine bioavailability (ratio of plasma arginine to ornithine + citrulline) is reduced. In skeletal muscle, HF feeding induced a reduction of arginine levels while citrulline levels were elevated. However, arginine or citrulline remained unchanged in their key metabolic organs, intestine and kidney. Moreover, the intestinal conversion of labeled arginine to ornithine and citrulline in vitro remained unaffected by HF feeding excluding the intestine as prime site of these alterations. In liver, citrulline is mainly derived from ornithine in the urea cycle and DIO mice displayed reduced hepatic ornithine levels. Since both amino acids share an antiport mechanism for mitochondrial import and export, elevated plasma citrulline may indicate impaired hepatic amino acid handling in DIO mice. In the insulin deficient mice, plasma citrulline and ornithine levels also increased and additionally these animals displayed elevated BCAA and AAA levels like insulin resistant and diabetic patients. Therefore, type 1 diabetic mice but not DIO mice show the “
    Changes in milk proteome and metabolome associated with dry period length, energy balance and lactation stage in post parturient dairy cows
    Lu, J. ; Antunes Fernandes, E.C. ; Páez Cano, A.E. ; Vinitwatanakhun, J. ; Boeren, S. ; Hooijdonk, A.C.M. van; Knegsel, A.T.M. van; Vervoort, J. ; Hettinga, K.A. - \ 2013
    Journal of Proteome Research 12 (2013)7. - ISSN 1535-3893 - p. 3288 - 3296.
    mouse mammary-gland - epithelial-cells - fatty-acids - inflammatory response - beta-hydroxybutyrate - ketone-bodies - liver - apoptosis - stomatin - health
    The early lactation period of dairy cows, which produce high quantities of milk, is normally characterized by an insufficient energy intake to cover milk production and maintenance requirements. Mobilization of body reserves occurs to compensate this negative energy balance (NEB), and probably as a consequence there is a higher susceptibility to diseases and metabolic disorders. There are several diagnostic methods to detect NEB, usually involving ketosis related parameters. Due to the easy availability of milk this is a preferred matrix, but simple and robust predictors of NEB level are missing. To better understand the physiological mechanism of NEB, milk of cows subjected to different dry period lengths, in different energy balance status and lactation stage, were analyzed by untargeted metabolomics and proteomics techniques. Milk of cows in severe NEB showed higher concentrations of acute phase response proteins, unsaturated fatty acids, and galactose-1-phosphate. Improved energy balance (EB) resulted in higher concentration of cholesterol, cholesterol synthesis related proteins, and stomatin. The presence of stomatin and galactose-1-phosphate in milk was strongly dependent on the EB of the cows. These novel and interesting findings warrant more in-depth research to assess their applicability as robust indicators of NEB in milk and to clarify the role of stomatin and galactose-1-phophate in milk of dairy cows in NEB.
    High Environmental Temperature Increases Glucose Requirement in the Developing Chicken Embryo
    Molenaar, R. ; Borne, J.J.G.C. van den; Hazejager, E. ; Kristensen, N.B. ; Heetkamp, M.J.W. ; Meijerhof, R. ; Kemp, B. ; Brand, H. van den - \ 2013
    PLoS ONE 8 (2013)4. - ISSN 1932-6203 - 12 p.
    eggshell temperature - oxygen concentration - broiler embryos - domestic-fowl - carbohydrate metabolism - gallus domesticus - tissue glycogen - late incubation - turkey embryos - liver
    Environmental conditions during the perinatal period influence metabolic and developmental processes in mammals and avian species, which could impact pre- and postnatal survival and development. The current study investigated the effect of eggshell temperature (EST) on glucose metabolism in broiler chicken embryos. Broiler eggs were incubated at a high (38.9°C) or normal (37.8°C) EST from day 10.5 of incubation onward and were injected with a bolus of [U-13C]glucose in the chorio-allantoic fluid at day 17.5 of incubation. After [U-13C]glucose administration, 13C enrichment was determined in intermediate pools and end-products of glucose metabolism. Oxidation of labeled glucose occurred for approximately 3 days after injection. Glucose oxidation was higher in the high than in the normal EST treatment from day 17.6 until 17.8 of incubation. The overall recovery of 13CO2 tended to be 4.7% higher in the high than in the normal EST treatment. An increase in EST (38.9°C vs 37.8°C) increased 13C enrichment in plasma lactate at day 17.8 of incubation and 13C in hepatic glycogen at day 18.8 of incubation. Furthermore, high compared to normal EST resulted in a lower yolk-free body mass at day 20.9 (-2.74 g) and 21.7 (-3.81 g) of incubation, a lower hepatic glycogen concentration at day 18.2 (-4.37 mg/g) and 18.8 (-4.59 mg/g) of incubation, and a higher plasma uric acid concentration (+2.8 mg/mL/+43%) at day 21.6 of incubation. These results indicate that the glucose oxidation pattern is relatively slow, but the intensity increased consistently with an increase in developmental stage of the embryo. High environmental temperatures in the perinatal period of chicken embryos increased glucose oxidation and decreased hepatic glycogen prior to the hatching process. This may limit glucose availability for successful hatching and could impact body development, probably by increased gluconeogenesis from glucogenic amino acids to allow anaerobic glycolysis
    Detection of bacterial DNA in bile of cats with lymphocytic cholangitis
    Otte, C.M.A. ; Pérez, O.N. ; Favier, R.P. ; Rothuizen, J. ; Penning, L.C. - \ 2012
    Veterinary Microbiology 156 (2012)1-2. - ISSN 0378-1135 - p. 217 - 221.
    16s ribosomal-rna - gradient gel-electrophoresis - polymerase-chain-reaction - helicobacter-pylori - pcr amplification - sp-nov. - jeotgalicoccus - disease - liver - populations
    In this study, we have successfully used molecular methods based on the amplification of the 16S ribosomal RNA gene on feline bile samples to show that bile of cats with LC is not sterile. This is probably due to the fact that the inflammatory process in the biliary tree causes dilatations. As a result, bacteria can easily migrate from the intestines via the common bile duct. The diversity of species identified and the presence of Helicobacter spp. DNA in both patients and controls suggests that bacteriobilia is secondary to the disease and is not the cause of LC.
    Fish oil and inflammatory status alter the n-3 to n-6 balance of the endocannabinoid and oxylipin metabolomes in mouse plasma and tissues
    Balvers, M.G.J. ; Verhoeckx, K.C.M. ; Bijlsma, S. ; Rubingh, C.M. ; Meijerink, J. ; Wortelboer, H.M. ; Witkamp, R.F. - \ 2012
    Metabolomics 8 (2012)6. - ISSN 1573-3882 - p. 1130 - 1147.
    polyunsaturated fatty-acids - n-acylethanolamines - eicosapentaenoic acid - lipid mediators - endogenous cannabinoids - docosahexaenoic acid - amide hydrolase - anandamide - liver - docosatrienes
    It is well established that dietary intake of n-3 fatty acids is associated with anti-inflammatory effects, and this has been linked to modulation of the oxylipin and endocannabinoid metabolomes. However, the amount of data on specific tissue effects is limited, and it is not known how inflammation affects this relation. In the present study we systematically explored the combined effects of n-3 fatty acid diets and inflammation on the in vivo endocannabinoid and oxylipin metabolomes using a multicompartment, detailed targeted lipidomics approach. Male C57BL/6 mice received diets containing 0, 1, or 3 % w/w fish oil (FO) for 6 weeks, after which 2 mg/kg LPS or saline was administered i.p. Levels of endocannabinoids/N-acylethanolamines (NAEs) and oxylipins, covering n-3 and n-6 fatty acid derived compounds, were determined in plasma, liver, ileum and adipose tissue using LC–MS/MS. FO generally increased ‘n-3’ NAEs and oxylipins at the expense of compounds derived from other fatty acids, affecting all branches of the oxylipin metabolome. LPS generally increased levels of endocannabinoids/NAEs and oxylipins, with opposing effects across plasma and tissues. Multivariate data analysis revealed that separation between diet groups in the saline treated groups was primarily explained by decreases in other than n-3 derived compounds. In the LPS treated groups, the separation was primarily explained by increases in n-3 derived compounds. In conclusion, FO caused marked changes in the n-3 to n-6 balance of the endocannabinoid and oxylipin metabolomes, with specific effects depending on inflammatory status.
    NanoSIMS50 - a powerful tool to elucidate cellular localization of halogenated organic compounds
    Gutleb, A.C. ; Freitas, J. de; Murk, A.J. ; Verhaegen, S. ; Ropstad, E. ; Udelhoven, T. ; Hoffmann, L. ; Audinot, J.N. - \ 2012
    Analytical and Bioanalytical Chemistry 404 (2012)9. - ISSN 1618-2642 - p. 2693 - 2698.
    in-vitro - perfluorinated compounds - h295r steroidogenesis - t-screen - assay - visualization - metabolites - transport - exposure - liver
    Persistent organic pollutants are widely distributed in the environment and lots of toxicological data are available. However, little is known on the intracellular fate of such compounds. Here a method applying secondary ion mass spectrometry is described that can be used to visualize cellular localization of halogenated compounds and to semi-quantitatively calculate concentrations of such compounds. Of the model compounds tested, TBBPA was homogenously distributed in the cell membrane of the H295R cells while PFOS accumulated in very distinct locations in the cell membrane. Relative intracellular concentrations of 4-OH-BDE69 and 4-OH-BDE121 in GH3.TRE were 61 % and 18 %, respectively, compared to the parent compounds. These differences may partly explain that observed effect concentrations for 4-OH-BDEs in in vitro experiments are usually lower than what would be expected based on receptor binding studies. NanoSIMS50 proved to be a powerful tool to describe the cellular distribution of halogenated compounds. The semi-quantitative data that can be obtained may help to further explain results from in vitro or in vivo experiments
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