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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Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food
Knutsen, Helle Katrine ; Alexander, Jan ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl‐Kraupp, Bettina ; Hogstrand, Christer ; Nebbia, Carlo Stefano ; Oswald, Isabelle P. ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Fürst, Peter ; Håkansson, Helen ; Halldorsson, Thorhallur ; Lundebye, Anne-Katrine ; Pohjanvirta, Raimo ; Rylander, Lars ; Smith, Andrew ; Loveren, Henk van; Waalkens‐Berendsen, Ine ; Zeilmaker, Marco ; Binaglia, Marco ; Gómez Ruiz, José Ángel ; Horváth, Zsuzsanna ; Christoph, Eugen ; Ciccolallo, Laura ; Ramos Bordajandi, Luisa ; Steinkellner, Hans ; Hoogenboom, Laurentius - \ 2018
EFSA Journal 16 (2018)11. - ISSN 1831-4732
The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL‐PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre‐ and postnatal exposure. The critical study showed a NOAEL of 7.0 pg WHO2005‐TEQ/g fat in blood sampled at age 9 years based on PCDD/F‐TEQs. No association was observed when including DL‐PCB‐TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panel established a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4 pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F‐TEQ only was on average 2.4‐ and 2.7‐fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL‐PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panel was not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.
Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food
Knutsen, Helle Katrine ; Alexander, Jan ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl‐Kraupp, Bettina ; Hogstrand, Christer ; Hoogenboom, Laurentius ; Nebbia, Carlo Stefano ; Oswald, Isabelle P. ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Bodin, Laurent ; Cravedi, Jean-Pierre ; Halldorsson, Thorhallur Ingi ; Haug, Line Småstuen ; Johansson, Niklas ; Loveren, Henk van; Gergelova, Petra ; Mackay, Karen ; Levorato, Sara ; Manen, Mathijs van; Schwerdtle, Tanja - \ 2018
EFSA Journal 16 (2018)12. - ISSN 1831-4732
The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in food. Regarding PFOS and PFOA occurrence, the final data set available for dietary exposure assessment contained a total of 20,019 analytical results (PFOS n = 10,191 and PFOA n = 9,828). There were large differences between upper and lower bound exposure due to analytical methods with insufficient sensitivity. The CONTAM Panel considered the lower bound estimates to be closer to true exposure levels. Important contributors to the lower bound mean chronic exposure were ‘Fish and other seafood’, ‘Meat and meat products’ and ‘Eggs and egg products’, for PFOS, and ‘Milk and dairy products’, ‘Drinking water’ and ‘Fish and other seafood’ for PFOA. PFOS and PFOA are readily absorbed in the gastrointestinal tract, excreted in urine and faeces, and do not undergo metabolism. Estimated human half‐lives for PFOS and PFOA are about 5 years and 2–4 years, respectively. The derivation of a health‐based guidance value was based on human epidemiological studies. For PFOS, the increase in serum total cholesterol in adults, and the decrease in antibody response at vaccination in children were identified as the critical effects. For PFOA, the increase in serum total cholesterol was the critical effect. Also reduced birth weight (for both compounds) and increased prevalence of high serum levels of the liver enzyme alanine aminotransferase (ALT) (for PFOA) were considered. After benchmark modelling of serum levels of PFOS and PFOA, and estimating the corresponding daily intakes, the CONTAM Panel established a tolerable weekly intake (TWI) of 13 ng/kg body weight (bw) per week for PFOS and 6 ng/kg bw per week for PFOA. For both compounds, exposure of a considerable proportion of the population exceeds the proposed TWIs.
Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants
Shao, J. ; Stout, I. ; Volger, O.L. ; Hendriksen, P.J.M. ; Loveren, H. van; Peijnenburg, A.A.C.M. - \ 2016
Archives of Toxicology 90 (2016)7. - ISSN 0340-5761 - p. 1685 - 1694.
Directional migration of cells to specific locations is required in tissue development, wound healing, and immune responses. Immune cell migration plays a crucial role in both innate and adaptive immunity. Chemokines are small pro-inflammatory chemoattractants that control the migration of leukocytes. In addition, they are also involved in other immune processes such as lymphocyte development and immune pathology. In a previous toxicogenomics study using the Jurkat T cell line, we have shown that the model immunotoxicant TBTO inhibited chemotaxis toward the chemokine CXCL12. In the present work, we aimed at assessing a novel approach to detecting chemicals that affect the process of cell migration. For this, we first evaluated the effects of 31 chemicals on mRNA expression of genes that are known to be related to cell migration. With this analysis, seven immunotoxicants were identified as potential chemotaxis modulators, of which five (CoCl2 80 µM, MeHg 1 µM, ochratoxin A 10 µM, S9-treated ochratoxin A 10 µM, and TBTO 100 nM) were confirmed as chemotaxis inhibitor in an in vitro trans-well chemotaxis assay using the chemokine CXCL12. The transcriptome data of the five compounds together with previously obtained protein phosphorylation profiles for two out of five compounds (i.e., ochratoxin A and TBTO) revealed that the mechanisms behind the chemotaxis inhibition are different for these immunotoxicants. Moreover, the mTOR inhibitor rapamycin had no effect on the chemotaxis of Jurkat cells, indicating that the mTOR pathway is not involved in CXCL12-mediated chemotaxis of Jurkat cells, which is opposite to the findings on human primary T cells (Munk et al. in PLoS One 6(9):e24667, 2011). Thus, the results obtained from the chemotaxis assay conducted with Jurkat cells might not fully represent the results obtained with human primary T cells. Despite this difference, the present study indicated that some compounds may exert their immunotoxic effects through inhibition of CXCL12-mediated chemotaxis.
Protein phosphorylation profiling identifies potential mechanisms for direct immunotoxicity
Shao, J. ; Stout, I. ; Hendriksen, P.J.M. ; Loveren, H. van; Peijnenburg, A.A.C.M. ; Volger, O.L. - \ 2016
Journal of Immunotoxicology 13 (2016)1. - ISSN 1547-691X - p. 97 - 107.
Signaling networks are essential elements that are involved in diverse cellular processes. One group of fundamental components in various signaling pathways concerns protein tyrosine kinases (PTK). Various toxicants have been demonstrated to exert their toxicity via modulation of tyrosine kinase activity. The present study aimed to identify common cellular signaling pathways that are involved in chemical-induced direct immunotoxicity. To this end, an antibody array-based profiling approach was applied to assess effects of five immunotoxicants, two immunosuppressive drugs and two non-immunotoxic control chemicals on the phosphorylation of 28 receptor tyrosine kinases and 11 crucial signaling nodes in Jurkat T-cells. The phosphorylation of ribosomal protein S6 (RPS6) and of kinases Akt, Src and p44/42 were found to be commonly regulated by immunotoxicants and/or immunosuppressive drugs (at least three compounds), with the largest effect observed upon RPS6. Flow cytometry and Western blotting were used to further examine the effect of the model immunotoxicant TBTO on the components of the mTOR-p70S6K-RPS6 pathway. These analyses revealed that both TBTO and the mTOR inhibitor rapamycin inactivate RPS6, but via different mechanisms. Finally, a comparison of the protein phosphorylation data to previously obtained transcriptome data of TBTO-treated Jurkat cells resulted in a good correlation at the pathway level and indicated that TBTO affects ribosome biogenesis and leukocyte migration. The effect of TBTO on the latter process was confirmed using a CXCL12 chemotaxis assay.
Protein phosphorylation profiling identifies potential mechanisms for direct immunotoxicity
Peijnenburg, A.A.C.M. ; Shao, J. ; Hendriksen, P.J.M. ; Loveren, H. van; Volger, O.L. - \ 2015
Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro
Schmeits, P.C.J. ; Shao, J. ; Krieken, D.A. van der; Volger, O.L. ; Loveren, H. van; Peijnenburg, A.A.C.M. ; Hendriksen, P.J.M. - \ 2015
Journal of Applied Toxicology 35 (2015)7. - ISSN 0260-437X - p. 831 - 841.
polycyclic aromatic-hydrocarbons - brominated flame retardants - tetrabromobisphenol-a - balb/c mice - vitamin-c - chlorpyrifos - activation - exposure - rats - kinase
Previously, we identified 25 classifier genes that were able to assess immunotoxicity using human Jurkat T cells. The present study aimed to validate these classifiers. For that purpose, Jurkat cells were exposed for 6¿h to subcytotoxic doses of nine immunotoxicants, five non-immunotoxicants and four compounds for which human immunotoxicity has not yet been fully established. RNA was isolated and subjected to Fluidigm quantitative real time (qRT)–PCR analysis. The sensitivity, specificity and accuracy of the screening assay as based on the nine immunotoxicants and five non-immunotoxicants used in this study were 100%, 80% and 93%, respectively, which is better than the performance in our previous study. Only one compound was classified as false positive (benzo-e-pyrene). Of the four potential (non-)immunotoxicants, chlorantraniliprole and Hidrasec were classified immunotoxic and Sunset yellow and imidacloprid as non-immunotoxic. ToxPi analysis of the PCR data provided insight in the molecular pathways that were affected by the compounds. The immunotoxicants 2,3-dichloro-propanol and cypermethrin, although structurally different, affected protein metabolism and cholesterol biosynthesis and transport. In addition, four compounds, i.e.¿chlorpyrifos, aldicarb, benzo-e-pyrene and anti-CD3, affected genes in cholesterol metabolism and transport, protein metabolism and transcription regulation. qRT–PCR on eight additional genes coding for similar processes as defined in ToxPi analyzes, supported these results. In conclusion, the 25 immunotoxic classifiers performed very well in a screening with new non-immunotoxic and immunotoxic compounds. Therefore, the Jurkat screening assay has great promise to be applied within a tiered approach for animal free testing of human immunotoxicity.
Detection of the mechanism of immunotoxicity of cyclosporine A in murine in vitro and in vivo models
Schmeits, P.C.J. ; Schaap, M.M. ; Luijten, M. ; Someren, E. van; Boorsma, A. ; Loveren, H. van; Peijnenburg, A.A.C.M. ; Hendriksen, P.J.M. - \ 2015
Archives of Toxicology 89 (2015)12. - ISSN 0340-5761 - p. 2325 - 2337.
Transcriptomics in combination with in vitro cell systems is a powerful approach to unravel modes of action of toxicants. An important question is to which extent the modes of action as revealed by transcriptomics depend on cell type, species and study type (in vitro or in vivo). To acquire more insight into this, we assessed the transcriptomic effects of the immunosuppressive drug cyclosporine A (CsA) upon 6 h of exposure of the mouse cytotoxic T cell line CTLL-2, the thymoma EL-4 and primary splenocytes and compared these to the effects in spleens of mice orally treated with CsA for 7 days. EL-4 and CTLL-2 cells showed the highest similarities in response. CsA affected many genes in primary splenocytes that were not affected in EL-4 or CTLL-2. Pathway analysis demonstrated that CsA upregulated the unfolded protein response, endoplasmic reticulum stress and NRF2 activation in EL-4 cells, CTLL-2 cells and primary mouse splenocytes but not in mouse spleen in vivo. As expected, CsA downregulated cell cycle and immune response in splenocytes in vitro, spleens in vivo as well as CTLL-2 in vitro. Genes up- and downregulated in human Jurkat, HepG2 and renal proximal tubular cells were similarly affected in CTLL-2, EL-4 and primary splenocytes in vitro. In conclusion, of the models tested in this study, the known mechanism of immunotoxicity of CsA is best represented in the mouse cytotoxic T cell line CTLL-2. This is likely due to the fact that this cell line is cultured in the presence of a T cell activation stimulant (IL-2) making it more suitable to detect inhibitory effects on T cell activation.
Characterization of the modes of action of deoxynivalenol (DON) in the human Jurkat T-cell line
Katika, M.R. ; Hendriksen, P.J.M. ; Loveren, H. van; Peijnenburg, A.A.C.M. - \ 2015
Journal of Immunotoxicology 12 (2015)3. - ISSN 1547-691X - p. 206 - 216.
activated protein-kinases - endoplasmic-reticulum stress - kappa-b activation - gene-expression - trichothecene deoxynivalenol - vomitoxin deoxynivalenol - transcription factors - cytokine production - induced apoptosis - wheat products
Deoxynivalenol (DON) is one of the most abundant mycotoxins worldwide and mostly detected in cereals and grains. As such, DON poses a risk for many adverse health effects to human and animals. In particular, immune cells are very sensitive to DON, with the initiating step leading to toxicity being a binding to the eukaryotic 60S ribosomal subunit and induction of ribotoxic stress. The present study aimed to: (1) extend insight into the mechanism of action (MOA) of DON in immune cells; and (2) understand why immune cells are more sensitive to DON than most other cell types. Previously published microarray studies have described the effects of DON on immune cells. To build upon these findings, here, immunocytological and biochemical studies were performed using human T-lymphocyte Jurkat cells that were exposed for 3¿h to 0.5¿µM DON. Induction of ER stress by DON was confirmed by immunocytology demonstrating increased protein expression of two major ER stress markers ATF3 and DDIT3. T-cell activation was confirmed by induction of phosphorylation of protein kinases JNK and AKT, activation of NF-¿B (p65), and increased expression of NFAT target gene NUR77; each of these are known inducers of the T-cell activation response. Induction of an oxidative stress response was also confirmed by monitoring the nuclear translocation of major oxidative stress markers NRF2 and KEAP1, as well as by changes (i.e. decreases) in cell levels of reduced glutathione. Lastly, this study showed that DON induced cleavage of caspase-3, an event known to mediate apoptosis. Taken together, these results allowed us to formulate a potential mechanism of action of DON in immune cells, i.e. binding to eukaryotic 60S ribosomal subunit¿¿¿ribotoxic stress¿¿¿ER stress¿¿¿calcium release from the ER into cytoplasm¿¿¿T-cell activation and oxidative stress¿¿¿apoptosis. It is proposed that immune cells are more sensitive to DON than other cell types due to the induction of a T-cell activation response by increased intracellular calcium levels.
Mode of action of Organotins in Immune cells
Hendriksen, P.J.M. ; Schmeits, P.C.J. ; Loveren, H. van; Shao, J. ; Peijnenburg, A.A.C.M. - \ 2015
In: Molecular Immunotoxicology / Corsini, E., van Loveren, H., West Sussex : Wiley-VCH - ISBN 9783527335190 - p. 307 - 320.
This chapter focuses mainly on the effects of organotin compounds in various human and animal models and describes the research performed to elucidate the immunotoxic mechanism of action of organotin compounds. Both dibutyltin (DBT) and tributyltins (TBT) organotin compounds can cause atrophy of the rat thymus. Cooke et al. studied the lactational transfer of TBTC and DBT by analysis of the stomach contents of suckling pups. TBT levels were undetectable in all dose groups, and DBT levels were detectable in the highest dose group. Next to mammals, organotin compounds have been reported to affect the immune function of aquatic organisms. Several studies demonstrated that tributyltin oxide (TBTO) induces programmed cell death (apoptosis) in thymocytes. Toxicogenomics techniques offer the possibility to assess the effects of potential toxic components on many parameters including thousands of mRNAs, proteins, and metabolites, and processes such as imprinting of genes, alternative splicing of mRNAs, and mutagenesis.
The effects of tributyltin oxide and deoxynivalenol on the transcriptome of the mouse thymoma cell line EL-4
Schmeits, P.J.M. ; Kol, S. ; Loveren, H. van; Peijnenburg, A.A.C.M. ; Hendriksen, P.J.M. - \ 2014
Toxicology Research 3 (2014)4. - ISSN 2045-452X - p. 254 - 265.
The main goal of this study was to assess the potential of the mouse thymoma EL-4 cell line in screening for chemical induced immunotoxicity. Therefore, EL-4 cells were exposed to two well-known immunotoxicants, organotin compound tributyltin oxide (TBTO, 0.5 and 1 µM for 3 or 6 h) and the mycotoxin deoxynivalenol (DON, 0.25, 0.5 and 1 µM for 3, 6 or 11 h). Previous studies in human Jurkat T cells and mouse thymus in vivo showed that the primary mode of action of TBTO is induction of endoplasmic reticulum (ER) stress, T cell activation and apoptosis. DON induces ribotoxic stress and, similarly to TBTO, induces ER stress, T cell activation and apoptosis. In the present study, the effects of TBTO and DON on EL-4 mRNA expression were assessed by whole genome microarray analysis. The microarray data were then compared to those obtained with mouse thymuses in vivo, mouse thymocytes in vitro, and CTLL-2 cells and human Jurkat cells in vitro exposed to TBTO or DON. Analysis at the level of gene sets revealed that part of the previously detected modes of action of TBTO and DON were not observed in the EL-4 cell line. In EL-4 cells, TBTO induced genes involved in calcium signalling and ER stress but did not induce genes involved in T cell activation and apoptosis. DON induced RNA related processes and ribosome biogenesis. Furthermore, DON downregulated ER stress, T cell activation and apoptosis which is opposite to the mechanism of DON observed in the mouse thymus in vivo and in Jurkat T cells in vitro. Apparently, EL-4 cells lack factors that are necessary to link ribotoxic stress to ER stress. In addition, of the lack of T cell activation response of EL-4 cells to TBTO is likely due to the fact that these cells are in a constitutively activated state already. Based on the results obtained for TBTO and DON, it can be concluded that the EL-4 cell line has limited value for immunotoxicogenomics based screening.
Grey Area Novel Foods: An Investigation into Criteria with Clear Boundaries
Sprong, C. ; Bosch, R. van den; Iburg, S. ; Moes, K. de; Paans, E. ; Sutherland Borja, S. ; Velde, H. van der; Kranen, H. van; Loveren, H. van; Meulen, B.M.J. van der; Verhagen, H. - \ 2014
European Journal of Nutrition & Food Safety 4 (2014)4. - ISSN 2347-5641 - p. 342 - 363.
In the European Union novel foods are defined by the Novel Foods Regulation as food products and food ingredients that have not been consumed to a significant degree in the European Union before May 1997. However, there are new foods for some reason not considered as novel foods, although it may not be excluded that they differ from conventional foods to such an extent that an assessment of their safety prior to their entry to the market would be called for. Previously, we reported that this ‘grey area’ of novel foods exists and comprises: (1) food products or ingredients for which the current Novel Foods Regulation leaves too much space for different interpretations and (2) food products or ingredients that are not novel according to the current Novel Foods Regulation, because it contains gaps. This paper focuses on how to handle these interpretation differences and gaps and provides recommendations to improve these pitfalls of the current Novel Foods Regulation. To this end, we propose criteria with clear boundaries as part of an assessment tool to reduce the uncertainties in interpretation with respect to consumption to a significant degree in the European Union, which take into account the commercial availability, length, extent and frequency of use of the particular food/ingredient. In addition, biological relevant boundaries for the criteria regarding changes in the nutritional value, metabolism (better all aspects of absorption, distribution, metabolism and excretion), and levels of undesirable substances are proposed for significant changes in the composition of foods due to changes in the production process. In addition, criteria are proposed to cover ambiguities and gaps in the Novel Foods Regulation dealing with food products and food ingredients obtained from 1) animals on a new feeding regime, 2) new varieties of organisms, 3) other growth stages of crops. Finally, a criterion that takes into account the total ingredient intake rather than single product intake is added to deal with the risk of overexposure to substances. Taken together, the proposed boundaries and criteria may contribute to diminishing the interpretation issues regarding the Novel Foods Regulation and thus to reducing the extent of the grey area of novel foods. - See more at:
Assessment of the Usefulness of the Murine Thymoma Cell Line EL-4 for Immunotoxicity Screening by Transcriptomics
Schmeits, P.C.J. ; Kol, S. ; Loveren, H. van; Peijnenburg, A.A.C.M. ; Hendriksen, P.J.M. - \ 2014
Assuring safety without animal testing concept (ASAT). Integration of human disease data with in vitro data to improve toxicology testing
Stierum, R. ; Aarts, J.M.M.J.G. ; Boorsma, J. ; Bosgra, S. ; Caiment, F. ; Ezendam, J. ; Greuping, R. ; Hendriksen, P. ; Soeteman-Hernandez, L.G. ; Jennen, D. ; Kleinjans, J. ; Kroese, D. ; Kuper, F. ; Loveren, H. van; Monshouwer, M. ; Russel, F. ; Someren, E. van; Tsamou, M. ; Groothuis, G. - \ 2014
Toxicology Letters 229 (2014)suppl.10. - ISSN 0378-4274 - p. S4 - S21.
According to the Assuring Safety Without Animal Testing (ASAT) principle, risk assessment may ultimately become possible without the use of animals (Fentem et al., (2004). Altern. Lab. Anim. 32, 617–623). The ASAT concept takes human disease mechanisms as starting point and tries to define if activation of these mechanisms by chemical exposure in in vitro models can be used for toxicological risk assessment. The goal of the present research was to study if integration of public data, from human diseases and in vitro toxicology, is possible at the data level. Two human diseases, associated with chemical exposure, were included: human hepatocellular carcinoma and allergic contact dermatitis (ACD). Data were retrieved from expert knowledge and different online sources (e.g. GEO, ArrayExpress) and a Knowledge Base for storage and modelling of the data was established. Using the Knowledge Base for ACD, it was possible to discern sensitizing from non-sensitizing compounds, as defined by enrichment of clinically defined disease gene sets in in vitro genomics datasets. In addition, the strongest sensitizers most profoundly activated these gene sets. During the presentation, the Knowledge Base will be shown. In addition, the ongoing incorporation of (reverse) kinetic modelling to judge the relevance of in vitro concentrations, in relation to realistic in vivo exposure scenarios, will be illustrated. Finally, the expansion towards the development of data models for other disease areas (cholestasis) will be discussed.
Assessment of the Usefulness of the Murine Thymoma Cell Line EL-4 for Immunotoxicity Screening by Transcriptomics
Hendriksen, P.J.M. ; Schmeits, P.C. ; Loveren, H. van; Peijnenburg, A.A.C.M. - \ 2014
DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer Thapsigargin based on comparative gene expression profiling in Jurkat T cells
Schmeits, P.C.J. ; Katika, M.R. ; Peijnenburg, A.A.C.M. ; Loveren, H. van; Hendriksen, P.J.M. - \ 2014
Toxicology Letters 224 (2014)3. - ISSN 0378-4274 - p. 395 - 406.
tri-n-butyltin - unfolded protein response - tributyltin-oxide tbto - mouse thymoma cells - deoxynivalenol don - induced apoptosis - plasma-membrane - ribosomal-rna - in-vivo - activation
Previously, we studied the effects of deoxynivalenol (DON) and tributyltin oxide (TBTO) on whole genome mRNA expression profiles of human T lymphocyte Jurkat cells. These studies indicated that DON induces ribotoxic stress and both DON and TBTO induced ER stress which resulted into T-cell activation and apoptosis. The first goal of the present study was to provide final proof for these mode of actions by comparing the effects of 6 h exposure to DON and TBTO on mRNA expression to those of positive controls of ribotoxic stress (anisomycin), ER stress (thapsigargin) and T cell activation (ionomycin). Genes affected by anisomycin and the majority of genes affected by thapsigargin were affected in the same direction by DON and TBTO, respectively, confirming the expected modes of action. Pathway analysis further sustained that DON induces ribotoxic stress and both DON and TBTO induce unfolded protein response (UPR), ER stress, T cell activation and apoptosis. The second goal was to assess whether DON and/or TBTO affect other pathways above those detected before. TBTO induced groups of genes that are involved in DNA packaging and heat shock response that were not affected by thapsigargin. DON did not affect other genes than anisomycin indicating the effect of DON to be restricted to ribotoxic stress. This study also demonstrates that comparative gene expression analysis is a very promising tool for the identification of modes of action of immunotoxic compounds.
Application to study direct immnotoxicants
Katika, M.R. - \ 2014
Maastricht University. Promotor(en): H. van Loveren; Ad Peijnenburg; Peter Hendriksen. - Maastricht : Universiteit Maastricht - ISBN 9789088918162 - 278 p.
Omics-Based Testing for Direct Immunotoxicity
Volger, O.L. ; Hendriksen, P.J.M. ; Loveren, H. van; Peijnenburg, A.A.C.M. - \ 2014
In: Toxicogenomics-Based cellular models, Alternatives to Animal Testing for Safety Assessment / Kleinjans, J., Maastricht : Academic Press - ISBN 9780123978622 - p. 89 - 124.
Transcriptome-based functional classifiers for direct immunotoxicity
Shao, J. ; Berger, L.F. ; Hendriksen, P.J.M. ; Peijnenburg, A.A.C.M. ; Loveren, H. van; Volger, O.L. - \ 2014
Archives of Toxicology 88 (2014)3. - ISSN 0340-5761 - p. 673 - 689.
blood mononuclear-cells - gene-expression - cyclin g2 - in-vitro - t-cells - jurkat - toxicogenomics - bioactivation - activation - exposure
Current screening methods for direct immunotoxic chemicals are mainly based on general toxicity studies with rodents. The present study aimed to identify transcriptome- based functional classifiers that can eventually be exploited for the development of in vitro screening assays for direct immunotoxicity. To this end, a toxicogenomics approach was applied in which gene expression changes in human Jurkat lymphoblastic T cells were investigated in response to a wide range of compounds, including direct immunotoxicants, immunosuppressive drugs, and non-immunotoxic control chemicals. On the basis of DNA microarray data previously obtained by the exposure of Jurkat cells to 31 test compounds (Shao et al. in Toxicol Sci 135(2):328–346, 2013), we identified a set of 93 genes, of which 80 were significantly regulated (|numerical ratio| C1.62) by at least three compounds and the other 13 genes were significantly regulated by either one single compound or compound class. A total of 28 most differentially regulated genes were selected for qRT-PCR verification using a training set of 44 compounds consisting of the above-mentioned 31 compounds (23 immunotoxic and 8 non-immunotoxic) and 13 additional immunotoxicants. Good correlation between the results of microarray and qRT-PCR (Pearson’s correlation, R C 0.69) was found for 27 out of the 28 genes. Redundancy analysis of these 27 potential classifiers led to a final set of 25 genes. To assess the performance of these genes, Jurkat cells were exposed to 20 additional compounds (external verification set) followed by qRT-PCR. The classifier set of 25 genes gave a good performance in the external verification: accuracy 85 %, true positive rate (sensitivity) 88 %, and true negative rate (specificity) 67 %. Furthermore, on the basis of the gene ontology annotation of the 25 classifier genes, the immunotoxicants examined in this study could be categorized into distinct functional subclasses. In conclusion, we have identified and validated classifier genes that can be used for the development of an in vitro assay for the identification and initial characterization of hazards for direct immunotoxicity of chemicals and drugs. This assay promises to complement animal-free toxicity testing approaches within the field of direct immunotoxicity.
Expression data from human Jurkat T cells exposed to 31 compounds
Shao, J. ; Katika, M.R. ; Schmeits, P.C. ; Hendriksen, Peter ; Loveren, H. van; Peijnenburg, Ad ; Volger, Oscar - \ 2013
GSE46909 - Homo sapiens - PRJNA203016
Compounds with direct immunotoxic properties, including metals, mycotoxins, agricultural pesticides and industrial chemicals, form potential human health risks due to exposure through food, drinking water, and the environment. Insights into the mechanisms of action are currently lacking for the majority of these direct immunotoxicants. Therefore, the present work aimed to gain insights into the molecular mechanisms underlying direct immunotoxicity. To this end, we assessed in vitro the effects of 31 test compounds on the transcriptome of the human Jurkat T cell line. These compounds included direct immunotoxicants, immunosuppressive drugs with different mode of actions, and non-immunotoxic control chemicals. Pathway analysis of the microarray data allowed us to identify canonical pathways and Gene Ontology processes that were transcriptionally regulated in common by immunotoxicants (i) with structural similarities, such as the tributyltins TBTC and TBTO that activated the retinoic acid / X receptor (RAR / RXR) signaling pathway, and (ii) without structural similarities, such as As2O3, DBTC, diazinon, MeHg, ochratoxin A, S9 treated ochratoxin A, S9 treated cyclophosphamide, and S9 treated benzo[a]pyrene, that activated unfolded protein response, and FTY720, lindane, and propanil, that activated the cholesterol biosynthesis pathway. In addition, processes uniquely affected by individual immunotoxicants were identified, such as the induction of Notch receptor signaling and the down regulation of acute phase response genes by ochratoxin A. These findings were validated by quantitative Real-Time PCR (Q-RT-PCR) analysis of genes involved in these processes. Our study indicated that diverse modes of action are involved in direct immunotoxicity and that a set of pathways or genes, rather than one single gene can be used to screen compounds for direct immunotoxicity.
Application of "omics" to immunotoxicology: from mechanisms of action to alternative methods
Volger, O.L. ; Shao, J. ; Schmeits, P.C. ; Peijnenburg, A.A.C.M. ; Hendriksen, P.J.M. ; Loveren, H. van - \ 2013
In: Abstracts of the 49th Congress of the European Societies of Toxicology Congress. - - p. S31 - S31.
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