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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Omics analyses of potato plant materials using an improved one-class classification tool to identify aberrant compositional profiles in risk assessment procedures
Kok, Esther ; Dijk, Jeroen van; Voorhuijzen, Marleen ; Staats, Martijn ; Slot, Martijn ; Lommen, Arjen ; Venema, Dini ; Pla, Maria ; Corujo, Maria ; Barros, Eugenia ; Hutten, Ronald ; Jansen, Jeroen ; Voet, Hilko van der - \ 2019
Food Chemistry 292 (2019). - ISSN 0308-8146 - p. 350 - 358.
Compositional analysis - Genetically modified organism - GMO - Omics profiling - Risk assessment

The objective of this study was to quantitatively assess potato omics profiles of new varieties for meaningful differences from analogous profiles of commercial varieties through the SIMCA one-class classification model. Analytical profiles of nine commercial potato varieties, eleven experimental potato varieties, one GM potato variety that had acquired Phytophtora resistance based on a single insert with potato-derived DNA sequences, and its non-GM commercial counterpart were generated. The ten conventional varieties were used to construct the one-class model. Omics profiles from experimental non-GM and GM varieties were assessed using the one-class SIMCA models. No potential unintended effects were identified in the case of the GM variety. The model showed that varieties that were genetically more distant from the commercial varieties were recognized as aberrant, highlighting its potential in determining whether additional evaluation is required for the risk assessment of materials produced from any breeding technique, including genetic modification.

Use of omics analytical methods in the study of genetically modified maize varieties tested in 90 days feeding trials
Corujo, Maria ; Pla, Maria ; Dijk, Jeroen van; Voorhuijzen, Marleen ; Staats, Martijn ; Slot, Martijn ; Lommen, Arjen ; Barros, Eugenia ; Nadal, Anna ; Puigdomènech, Pere ; Paz, José Luís La ; Voet, Hilko van der; Kok, Esther - \ 2019
Food Chemistry 292 (2019). - ISSN 0308-8146 - p. 359 - 371.
GMO (genetically modified organism) - Metabolomics - One-class model - Proteomics - Risk assessment - Transcriptomics

Genetically modified (GM) maize and their non-modified counterparts were compared using MON810 varieties, the only GMO event cultivated in Europe. The differences in grain samples were analysed by omics profiles, including transcriptomics, proteomics and metabolomics. Other cultivated maize varieties were analysed as a reference for the variability that will exist between cultivated varieties. The observed differences between modified and non-modified maize varieties do not exceed typical differences between non-modified varieties. The use of these advanced analytical approaches to analyse novel plant materials as compared to the results from animal feeding trials with whole foods is assessed. No indications were observed for changes in the GM varieties that warrant further investigations. Furthermore, it was shown that such indications will be obtained if maize samples of inferior quality are analysed similarly. Omics data provide detailed analytical information of the plant material, which facilitates a risk assessment procedure of new (GM) plant varieties.

Comparison of gas chromatography/quadrupole time-of-flight and quadrupole Orbitrap mass spectrometry in anti-doping analysis : I. Detection of anabolic-androgenic steroids
Abushareeda, Wadha ; Tienstra, Marc ; Lommen, Arjen ; Blokland, Marco ; Sterk, Saskia ; Kraiem, Suhail ; Horvatovich, Peter ; Nielen, Michel ; Al-Maadheed, Muhammad ; Georgakopoulos, Costas - \ 2018
Rapid Communications in Mass Spectrometry 32 (2018)23. - ISSN 0951-4198 - p. 2055 - 2064.

Rationale: The World Anti-Doping Agency (WADA) encourages drug-testing laboratories to develop screening methods that can detect as many doping substances as possible in urine. The use of full-scan high-resolution acquisition (FS/HR) with gas chromatography/mass spectrometry (GC/MS) for the detection of known and unknown trimethylsilyl (TMS) derivatives of anabolic-androgenic steroids (AAS) provides anti-doping testing bodies with a new analytical tool. Methods: The AAS were extracted from urine samples by generic liquid–liquid extraction, after enzymatic hydrolysis, and TMS derivatization. The extracted urine was analyzed by GC/Q-TOF and GC/Q-Orbitrap to compare the performance of the two instrument types for the detection of 46 AAS in human urine. The quantitation of endogenous anabolic steroids and the ability of the two analytical platforms to comply with the requirements for testing as part of the WADA Athlete Biological Passport (ABP) were also assessed. Results: The data presented show that the analytical performance for both instruments complies with the WADA specifications. The limits of detection (LODs) for both instruments are well below the WADA 50% Minimum Required Performance Levels. The mass errors in the current study for the GC/Q-Orbitrap platform are lower than those obtained for the GC/Q-TOF instrument. Conclusions: The data presented herein proved that both molecular profiling platforms can be used for antidoping screening. The mass accuracies are excellent in both instruments; however, the GC/Q-Orbitrap performs better as it provides higher resolution than the GC/Q-TOF platform.

High resolution full scan liquid chromatography mass spectrometry comprehensive screening in sports antidoping urine analysis
Abushareeda, Wadha ; Vonaparti, Ariadni ; Saad, Khadija Al ; Almansoori, Moneera ; Meloug, Mbarka ; Saleh, Amal ; Aguilera, Rodrigo ; Angelis, Yiannis ; Horvatovich, Peter L. ; Lommen, Arjen ; Alsayrafi, Mohammed ; Georgakopoulos, Costas - \ 2018
Journal of Pharmaceutical and Biomedical Analysis 151 (2018). - ISSN 0731-7085 - p. 10 - 24.
Full scan high-resolution - Human urine - Liquid chromatography - Mass spectrometry - Small molecule prohibited substances - Sulfo-conjugate steroids
The aim of this paper is to present the development and validation of a high-resolution full scan (HR-FS) electrospray ionization (ESI) liquid chromatography coupled to quadrupole Orbitrap mass spectrometer (LC/Q/Orbitrap MS) platform for the screening of prohibited substances in human urine according to World Antidoping Agency (WADA) requirements. The method was also validated for quantitative analysis of six endogenous steroids (epitestosterone, testosterone, 5α-dihydrotestosterone, dehydroepiandrosterone, androsterone and etiocholanolone) in their intact sulfates form. The sample preparation comprised a combination of a hydrolyzed urine liquid–liquid extraction and the dilute & shoot addition of original urine in the extracted aliquot. The HR-FS MS acquisition mode with Polarity Switching was applied in combination of the Quadrupole-Orbitrap mass filter. The HR-FS acquisition of analytical signal, for known and unknown small molecules, allows the inclusion of all analytes detectable with LC–MS for antidoping investigations to identify the use of known or novel prohibited substances and metabolites after electronic data files’ reprocessing. The method has been validated to be fit-for-purpose for the antidoping analysis.
Gas chromatographic quadrupole time-of-flight full scan high resolution mass spectrometric screening of human urine in antidoping analysis
Abushareeda, Wadha ; Lyris, Emmanouil ; Kraiem, Suhail ; Wahaibi, Aisha Al ; Alyazidi, Sameera ; Dbes, Najib ; Lommen, Arjen ; Nielen, Michel ; Horvatovich, Peter L. ; Alsayrafi, Mohammed ; Georgakopoulos, Costas - \ 2017
Journal of Chromatography. B, Analytical technologies in the biomedical and life sciences 1063 (2017). - ISSN 1570-0232 - p. 74 - 83.
Anabolic steroids - Full scan high resolution - Gas chromatography - Human urine - Mass spectrometry

This paper presents the development and validation of a high-resolution full scan (FS) electron impact ionization (EI) gas chromatography coupled to quadrupole Time-of-Flight mass spectrometry (GC/QTOF) platform for screening anabolic androgenic steroids (AAS) in human urine samples. The World Antidoping Agency (WADA) enlists AAS as prohibited doping agents in sports, and our method has been developed to comply with the qualitative specifications of WADA to be applied for the detection of sports antidoping prohibited substances, mainly for AAS. The method also comprises of the quantitative analysis of the WADA's Athlete Biological Passport (ABP) endogenous steroidal parameters. The applied preparation of urine samples includes enzymatic hydrolysis for the cleavage of the Phase II glucuronide conjugates, generic liquid–liquid extraction and trimethylsilyl (TMS) derivatization steps. Tandem mass spectrometry (MS/MS) acquisition was applied on few selected ions to enhance the specificity and sensitivity of GC/TOF signal of few compounds. The full scan high resolution acquisition of analytical signal, for known and unknown TMS derivatives of AAS provides the antidoping system with a new analytical tool for the detection designer drugs and novel metabolites, which prolongs the AAS detection, after electronic data files’ reprocessing. The current method is complementary to the respective liquid chromatography coupled to mass spectrometry (LC/MS) methodology widely used to detect prohibited molecules in sport, which cannot be efficiently ionized with atmospheric pressure ionization interface.

Validation of an automated screening method for persistent organic contaminants in fats and oils by GC × GC-ToFMS
Lopez Sanchez, Patricia ; Tienstra, Marc ; Lommen, Arjen ; Mol, Hans G.J. - \ 2016
Food Chemistry 211 (2016). - ISSN 0308-8146 - p. 645 - 653.
Fat - GC × GC-ToFMS - Qualitative analysis - Screening - Validation

An screening method, comprised of straightforward sample treatment based on silica clean-up, GC × GC-ToFMS detection and automated data processing with the non-proprietary free downloadable software MetAlignID, has been successfully validated with respect to false negatives for the sum PCB 28, 52, 101, 138, 153 and 180), for the sum of BDE 28, 47, 99, 100, 153, 154 and 183, for the four markers of PAHs and for a number of emerging brominated flame retardants. A screening detection limit (SDL) equal to or lower than the maximum regulatory level was always achieved. MetAlignID considerably decreased the time needed for data treatment from 20 to 5 min/file. Automated identification of the signature mass spectral patterns was applied to identify chlorinated- and brominated-containing substances with more than two halogen atoms, and PAH derivates. Although the success rate was variable and needs to be further improved, the tool was considered to be of added value.

Improved batch correction in untargeted MS-based metabolomics
Wehrens, Ron ; Hageman, Jos A. ; Eeuwijk, Fred van; Kooke, Rik ; Flood, Pádraic J. ; Wijnker, Erik ; Keurentjes, Joost J.B. ; Lommen, Arjen ; Eekelen, Henriëtte D.L.M. van; Hall, Robert D. ; Mumm, Roland ; Vos, Ric C.H. de - \ 2016
Metabolomics 12 (2016)5. - ISSN 1573-3882
Arabidopsis thaliana - Batch correction - Mass spectrometry - Non-detects - Untargeted metabolomics

Introduction: Batch effects in large untargeted metabolomics experiments are almost unavoidable, especially when sensitive detection techniques like mass spectrometry (MS) are employed. In order to obtain peak intensities that are comparable across all batches, corrections need to be performed. Since non-detects, i.e., signals with an intensity too low to be detected with certainty, are common in metabolomics studies, the batch correction methods need to take these into account. Objectives: This paper aims to compare several batch correction methods, and investigates the effect of different strategies for handling non-detects. Methods: Batch correction methods usually consist of regression models, possibly also accounting for trends within batches. To fit these models quality control samples (QCs), injected at regular intervals, can be used. Also study samples can be used, provided that the injection order is properly randomized. Normalization methods, not using information on batch labels or injection order, can correct for batch effects as well. Introducing two easy-to-use quality criteria, we assess the merits of these batch correction strategies using three large LC–MS and GC–MS data sets of samples from Arabidopsis thaliana. Results: The three data sets have very different characteristics, leading to clearly distinct behaviour of the batch correction strategies studied. Explicit inclusion of information on batch and injection order in general leads to very good corrections; when enough QCs are available, also general normalization approaches perform well. Several approaches are shown to be able to handle non-detects—replacing them with very small numbers such as zero seems the worst of the approaches considered. Conclusion: The use of quality control samples for batch correction leads to good results when enough QCs are available. If an experiment is properly set up, batch correction using the study samples usually leads to a similar high-quality correction, but has the advantage that more metabolites are corrected. The strategy for handling non-detects is important: choosing small values like zero can lead to suboptimal batch corrections.

Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes
Jetten, M.J.A. ; Blanco Garcia, Ainhoa ; Coonen, M.L.J. ; Claessen, Sandra ; Herwijnen, M.H.M. van; Lommen, Arjen ; Delft, J.H.M. van; Peijnenburg, A.A.C.M. ; Kleinjans, J.C.S. - \ 2016
Archives of Toxicology (2016). - ISSN 0340-5761 - p. 1103 - 1115.
Aflatoxin b1 - Benzo(a)pyrene - DNA methylation - Gene expression - Interindividual variation - Primary human hepatocytes

Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this variability in susceptibility are still largely unknown. The aim of this study was to better understand this variability in response to APAP by evaluating interindividual differences in gene expression changes and APAP metabolite formation in primary human hepatocytes (PHH) from several donors (n = 5) exposed in vitro to a non-toxic to toxic APAP dose range. To evaluate interindividual variation, gene expression data/levels of metabolites were plotted against APAP dose/donor. The correlation in APAP dose response between donors was calculated by comparing data points from one donor to the data points of all other donors using a Pearson-based correlation analysis. From that, a correlation score/donor for each gene/metabolite was defined, representing the similarity of the omics response to APAP in PHH of a particular donor to all other donors. The top 1 % highest variable genes were selected for further evaluation using gene set overrepresentation analysis. The biological processes in which the genes with high interindividual variation in expression were involved include liver regeneration, inflammatory responses, mitochondrial stress responses, hepatocarcinogenesis, cell cycle, and drug efficacy. Additionally, the interindividual variation in the expression of these genes could be associated with the variability in expression levels of hydroxyl/methoxy-APAP and C8H13O5N-APAP-glucuronide. The before-mentioned metabolites or their derivatives have also been reported in blood of humans exposed to therapeutic APAP doses. Possibly these findings can contribute to elucidating the causative factors of interindividual susceptibility toward APAP.

Analysis of effects of Herbabolus on milk quality
Groot, M.J. ; Alewijn, M. ; Driessen-van Lankveld, W.D.M. ; Lommen, A. ; Stoopen, G.M. ; Venema, D.P. ; Pikkemaat, M.G. ; Rijk, T.C. de - \ 2015
Wageningen : RIKILT Wageningen UR (RIKILT report 2015.007)
melkproductie - melkkwaliteit - melkveehouderij - melkkoeien - vergelijkend onderzoek - geneeskrachtige kruiden - milk production - milk quality - dairy farming - dairy cows - comparative research - herbal drugs
The Herbabolus is a mix of plant components for cows to improve their health during the transition period. The bolus contains a mixture of herbs including garlic (Garlicin), oregano and yucca. The effects of the bolus on milk quality is investigated. The results are discussed in this report.
Risk assessment of paracetamol induced liver toxicity based on human in vitro data
Groothuis, G.M.M. ; Mafirakureva, N. ; Proost, J. ; Jetten, M. ; Kleinjans, J. ; Lommen, A. ; Peijnenburg, A.A.C.M. ; Vredenburg, G. ; Vermeulen, N. ; Russel, F. - \ 2014
In: Proceedings of the 53rd Annual meeting and ToxExpo. - - p. 281 - 281.
Currently risk assessment is based on animal experiments with limited success. The aim of this study was to explore the feasibility to replace the use of animals in risk assessment for drug-induced liver injury, by hazard identification and kinetic modeling based on human in vitro data for metabolism and toxicity. Paracetamol was used as model compound. Human hepatocytes were used to elucidate the toxic mechanisms by transcriptomics and metabolite formation. Time- and dose-dependent toxicant exposure of the human liver was modeled with a mechanism-based physiology-based toxicokinetic (PBTK) model (Simcyp®) and time and concentration- dependent metabolite production and exposure of the hepatocytes to the toxic reactive metabolite was modeled with an in vitro biokinetic model using experimentally derived and literature data on metabolism. Plasma concentration profiles were adequately modeled and the effect of individual variability in metabolism was assessed. Phase 2 metabolism as observed in human hepatocytes was well predicted by the biokinetic model. However the rate of phase 1 metabolism was over predicted in both models. Pathway analysis learned that oxidative phosphorylation, drug metabolism and immune response were consistently regulated, suggesting that adverse effects of paracetamol are related to oxidative stress and immune dysfunction. The results indicate the feasibility of in vitro-based risk assessment of xenobiotics for the human population without the use of animals taking into account the individual variation in drug metabolism. For future refinement more data on metabolizing enzyme and transporter protein abundance is requ
Gas Chromatography/Mass Spectrometry Analysis: Nontargeted Metabolomics Based on Scan Mode Analysis
Tsugawa, H. ; Lommen, A. - \ 2014
In: Mass Spectrometry-Based Metabolomics: A Practical Guide / Prama Putri, S., Fukusaki, E., CRC Press - p. 103 - 136.
Integrative cross-omics analysis in primary mouse hepatocytes unravels mechanisms of cyclosporin A-induced hepatotoxicity
Hof, W.F.P.M. ; Summeren, A. van; Lommen, A. ; Coonen, M.L.J. ; Brauers, K. ; Herwijnen, M. van; Wodzig, W.K.W.H. ; Kleinjans, J.C.S. - \ 2014
Toxicology 324 (2014). - ISSN 0300-483X - p. 18 - 26.
drug-induced hepatotoxicity - gene-expression - micrornas - repression - normalization - accumulation - metabonomics - translation - activation - biomarkers
The liver is responsible for drug metabolism and drug-induced hepatotoxicity is the most frequent reason for drug withdrawal, indicating that better pre-clinical toxicity tests are needed. In order to bypass animal models for toxicity screening, we exposed primary mouse hepatocytes for exploring the prototypical hepatotoxicant cyclosporin A. To elucidate the mechanisms underlying cyclosporin A-induced hepatotoxicity, we analyzed expression levels of proteins, mRNAs, microRNAs and metabolites.
Ultrafast PubChem Searching Combined with Improved Filtering Rules for Elemental Composition Analysis
Lommen, A. - \ 2014
Analytical Chemistry 86 (2014)11. - ISSN 0003-2700 - p. 5463 - 5469.
mass-spectrometry - identification - metabolomics - database
A new and improved software tool for elemental composition annotation of molecular ions detected in mass spectrometry, based on improved filtering rules followed by ultrafast querying in publicly available compound databases, is provided. Pubchem is used as a general source of 1.3 million unique chemical formulas. A plant metabolomics database containing ca. 100¿000 formulas is used as a source of naturally occurring compounds. Four modes with different sets of rules for heuristic filtering of candidate formulas coming from elemental composition analysis are incorporated and tested on both databases. The elemental composition analysis is then coupled to ultrafast PubChem searching based on a mass-indexed intermediate system. The performance of the filters is compared and discussed. When reactive compounds are assumed not to be present, 99.95% of the 1.3 million PubChem formulas is correctly found, while ca. 30% less formulas per mass are given compared to previously published rules. For the ca. 100¿000 plant metabolomics based formulas, 100% fit the improved rules.
Identification of Cisplatin-Regulated Metabolic Pathways in Pluripotent Stem Cells
Stechow, L. von; Ruiz-Aracama, A. ; Water, B. ; Peijnenburg, A. ; Danen, E. ; Lommen, A. - \ 2013
PLoS ONE 8 (2013)10. - ISSN 1932-6203 - 13 p.
dna-damage response - platinum anticancer drugs - mass-spectrometry - modified nucleosides - arginine metabolism - profiling reveals - cancer - resistance - gene - proline
The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations that, to a major extent, point to DNA damage response (DDR) signaling. The orchestrated DDR signaling network is important to arrest the cell cycle and repair the lesions or, in case of damage beyond repair, eliminate affected cells. Failure to properly balance the various aspects of the DDR in stem cells contributes to ageing and cancer. Here, we performed metabolic profiling by mass spectrometry of embryonic stem (ES) cells treated for different time periods with cisplatin. We then integrated metabolomics with transcriptomics analyses and connected cisplatin-regulated metabolites with regulated metabolic enzymes to identify enriched metabolic pathways. These included nucleotide metabolism, urea cycle and arginine and proline metabolism. Silencing of identified proline metabolic and catabolic enzymes indicated that altered proline metabolism serves as an adaptive, rather than a toxic response. A group of enriched metabolic pathways clustered around the metabolite S-adenosylmethionine, which is a hub for methylation and transsulfuration reactions and polyamine metabolism. Enzymes and metabolites with pro- or anti-oxidant functions were also enriched but enhanced levels of reactive oxygen species were not measured in cisplatin-treated ES cells. Lastly, a number of the differentially regulated metabolic enzymes were identified as target genes of the transcription factor p53, pointing to p53-mediated alterations in metabolism in response to genotoxic stress. Altogether, our findings reveal interconnecting metabolic pathways that are responsive to cisplatin and may serve as signaling modules in the DDR in pluripotent stem cells.
Metabolic profiling of steroidogenesis in the human H295R adrenocortaical cell line for detection of endocrine disruptors
Rijk, J.C.W. ; Bovee, T.F.H. ; Lommen, A. ; Hoogenboom, L.A.P. ; Peijnenburg, A.A.C.M. - \ 2012
Use of NMR metabolomic plasma profiling methodologies to identify illicit growth-promoting administrations
Graham, S.F. ; Ruiz Aracama, A. ; Lommen, A. ; Cannizzo, F.T. ; Biolatti, B. ; Elliott, C.T. ; Mooney, M.H. - \ 2012
Analytical and Bioanalytical Chemistry 403 (2012)2. - ISSN 1618-2642 - p. 573 - 582.
veal calves - cattle - dexamethasone - spectroscopy - urine - h-1 - 17-beta-estradiol - metabolites - hormones - h-1-nmr
Detection of growth-promoter use in animal production systems still proves to be an analytical challenge despite years of activity in the field. This study reports on the capability of NMR metabolomic profiling techniques to discriminate between plasma samples obtained from cattle treated with different groups of growth-promoting hormones (dexamethasone, prednisolone, oestradiol) based on recorded metabolite profiles. Two methods of NMR analysis were investigated-a Carr-Purcell-Meiboom-Gill (CPMG)-pulse sequence technique and a conventional H-1 NMR method using pre-extracted plasma. Using the CPMG method, 17 distinct metabolites could be identified from the spectra. H-1 NMR analysis of extracted plasma facilitated identification of 23 metabolites-six more than the alternative method and all within the aromatic region. Multivariate statistical analysis of acquired data from both forms of NMR analysis separated the plasma metabolite profiles into distinct sample cluster sets representative of the different animal study groups. Samples from both sets of corticosteroid-treated animals-dexamethasone and prednisolone-were found to be clustered relatively closely and had similar alterations to identified metabolite panels. Distinctive metabolite profiles, different from those observed within plasma from corticosteroid-treated animal plasma, were observed in oestradiol-treated animals and samples from these animals formed a cluster spatially isolated from control animal plasma samples. These findings suggest the potential use of NMR methodologies of plasma metabolite analysis as a high-throughput screening technique to aid detection of growth promoter use.
'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans
Jetten, M.J.A. ; Gaj, S. ; Ruiz Aracama, A. ; Kok, T.M. de; Delft, J.H.M. van; Lommen, A. ; Someren, E.P. van; Jennen, D. ; Claessen, S.M. ; Peijnenburg, A.A.C.M. ; Stierum, R. ; Kleinjans, J.C.S. - \ 2012
Toxicology and Applied Pharmacology 259 (2012)3. - ISSN 0041-008X - p. 320 - 328.
induced liver-injury - gene-expression - induced hepatotoxicity - circulating micrornas - liquid-chromatography - potential biomarkers - toxicity - metabolomics - metabolites - paracetamol
Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites.
Data (pre-)processing of nominal and accurate mass LC-MS or GC-MS data using MetAlign
Lommen, A. - \ 2012
Methods in molecular biology 860 (2012). - ISSN 1064-3745 - p. 229 - 253.
This paper gives a step-by-step account of how to install, set up, and run MetAlign software, which can be downloaded freely ( The software is used for accurate mass and nominal mass data coming from different kinds of GC-MS and LC-MS platforms. The algorithms are beyond the scope of this paper and were published separately
Application of an untargeted metabolomics approach for the identification of compounds that may be responsible for observed differential effects in chickens fed an organic and a conventional diet
Ruiz-Aracama, A. ; Lommen, A. ; Huber, M. ; Vijver, L. van de; Hoogenboom, L.A.P. - \ 2012
Food Additives & Contaminants. Pt. A, Chemistry, Analysis, Control, Exposure & Risk Assessment 29 (2012)3. - ISSN 1944-0049 - p. 323 - 332.
liquid-chromatography - phenolic-compounds - mass-spectrometry - farming system - food safety - antioxidant - health - corn - biosynthesis - metabolism
The aim of this study was to apply an untargeted NMR and LC-MS-based metabolomics approach to detect potential differences between an organically and a conventionally produced feed, which caused statistically significant differences in growth, in the response to an immunological challenge and in the gene expression profiles in the small intestine of laying hens. A fractionation procedure was set up to create multiple fractions of the feed, which were subsequently analysed by NMR and UPLC-TOF/MS operating in positive mode. Comparison of the profiles revealed that the most apparent differences came from the isoflavones in the soy as well as a compound with a molecular mass of 441.202 (M¿+¿1)+, which was identified as N,N'-diferuloylputrescine (DFP) and came from the corn. Whether the observed differences in effects are due to the higher levels of isoflavones and DFP is unclear, as is the fact whether the observed differences are typical for organic or conventional produced corn and soy. However, this study shows that this metabolomics approach is suitable for detecting potential differences between products, even in levels of compounds that would have been overlooked with a more targeted approach. As such, the method is suitable for a more systematic study on differences between conventionally and organically produced food. View full textDownload full text
Screening for Modulatory Effects on Steroidogenesis Using the Human H295R Adrenocortical Cell Line: A Metabolomics Approach
Rijk, J.C.W. ; Peijnenburg, A.A.C.M. ; Blokland, M.H. ; Lommen, A. ; Hoogenboom, L.A.P. ; Bovee, T.F.H. - \ 2012
Chemical Research in Toxicology 25 (2012)8. - ISSN 0893-228X - p. 1720 - 1731.
mass-spectrometry - in-vitro - expression - receptor - assay - disruption - inhibitors - chemicals - bioassays - model
The recently OECD validated H295R steroidogenesis assay provides an in vitro alternative to evaluate the potential interference of exogenous compounds with endogenous steroid hormone synthesis. Currently, this assay is used for a simple negative-positive screening of compounds using testosterone and estradiol levels as end points, measured with specific enzyme immunoassays (EIAs) or targeted liquid chromatography (LC) and gas chromatography (GC)–mass spectrometry (MS) methods. However, recent developments in LC-MS and bioinformatics allow for more comprehensive approaches to evaluate changes in steroid profiles. In the current work, the H295R cell model was combined with a metabolomics approach to monitor changes in metabolite profiles in both a targeted and untargeted way. H295R cells were exposed for 48 h to model compounds, i.e., forskolin, abiraterone, prochloraz, ketoconazole, trilostane, formestane, aminoglutethimide, fadrozole, etomidate, and metyrapone, known to affect steroidogenesis. After exposure, the levels of 9 natural steroids were determined by a quantitative targeted GC-MS/MS method and compared to a metabolomics method using Ultra Performance Liquid Chromatography–Time-of-Flight–Mass Spectrometry (UPLC-ToF-MS). Like the EIAs, both methods were suited for negative-positive screening, but the MS methods also generated specific fingerprints, allowing chemical class prediction of the compound under investigation. Although the targeted GC-MS/MS was more sensitive, which was an advantage regarding analysis of the estrogens 17ß-estradiol and estrone, the untargeted UPLC-ToF-MS was able to evaluate effects on the synthesis of the corticosteroids. Moreover, untargeted comparison of the aligned chemical profiles allowed identification of all m/z-values that are differential between exposed and nonexposed H295R cells. In conclusion, application of a comprehensive metabolite profiling methodology not only provides a tool to screen compounds for steroidogenic modulating properties, but also allows chemical class prediction. As such, steroid profiling methodologies in conjunction with the H295R assay can contribute to the prioritization of chemicals for additional safety testing.
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