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Skill improvement of dynamical seasonal Arctic sea ice forecasts
Krikken, Folmer ; Schmeits, Maurice ; Vlot, Willem ; Guemas, Virginie ; Hazeleger, Wilco - \ 2016
Geophysical Research Letters 43 (2016)10. - ISSN 0094-8276 - p. 5124 - 5132.
Arctic sea ice - Bias correction - Ensemble calibration - Seasonal forecasting
We explore the error and improve the skill of the outcome from dynamical seasonal Arctic sea ice reforecasts using different bias correction and ensemble calibration methods. These reforecasts consist of a five-member ensemble from 1979 to 2012 using the general circulation model EC-Earth. The raw model reforecasts show large biases in Arctic sea ice area, mainly due to a differently simulated seasonal cycle and long term trend compared to observations. This translates very quickly (1-3months) into large biases. We find that (heteroscedastic) extended logistic regressions are viable ensemble calibration methods, as the forecast skill is improved compared to standard bias correction methods. Analysis of regional skill of Arctic sea ice shows that the Northeast Passage and the Kara and Barents Sea are most predictable. These results show the importance of reducing model error and the potential for ensemble calibration in improving skill of seasonal forecasts of Arctic sea ice.
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.
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.
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
|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.
|Toxicogenomics ans Systems Toxicology Databases and Resources: Chemical Effects in Biological Systems (CEBS) and Data Integration by Applying Models in Design and Safety (DIAMONDS)
Fostel, J. ; Someren, E. van; Pronk, T. ; Pennings, J. ; Schmeits, P. ; Shao, J. ; Kroese, D. ; Stierum, R. - \ 2014
In: Toxicogenomics-Based cellular models, Alternatives to Animal Testing for Safety Assessment / Kleinjans, J., Maastricht : Academic Press Elsevier - ISBN 9780123978622 - p. 275 - 290.
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.
|Comparison of the effects of deoxynivalenol and tributylin oxide to that model compounds inducing endoplasmic reticulum stress, ribotoxic stress and T cell activation
Schmeits, P.C. ; Katika, M.R. ; Peijnenburg, A.A.C.M. ; Loveren, H. van; Hendriksen, P.J.M. - \ 2013
In: 52nd Annual Meeting and ToxExpo, San Antonio, Texas, 10 - 14 March, 2013. - Reston : Society of Toxicology (The Toxicologist ) - p. 445 - 445.
Toxicogenomics-Based Identification of Mechanisms for Direct Immunitoxicity
Shao, J. ; Katika, M.R. ; Schmeits, P.C. ; Hendriksen, P.J.M. ; Loveren, H. van; Peijnenburg, A.A.C.M. ; Volger, O.L. - \ 2013
Toxicological sciences 135 (2013)2. - ISSN 1096-6080 - p. 328 - 346.
unfolded protein response - nf-kappa-b - endoplasmic-reticulum stress - blood mononuclear-cells - liver-x-receptor - proliferator-activated receptor - gene-expression profiles - in-vitro - ochratoxin-a - human-lymphocytes
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 nonimmunotoxic 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 (1) with structural similarities, such as tributyltin chloride and tributyltin oxide that activated the retinoic acid/X receptor signaling pathway and (2) without structural similarities, such as As2O3, dibutyltin chloride, diazinon, MeHg, ochratoxin A (OTA), S9-treated OTA, S9-treated cyclophosphamide, and S9-treated benzo[a]pyrene, which activated unfolded protein response, and FTY720, lindane, and propanil, which 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 downregulation of acute-phase response genes by OTA. These findings were validated by quantitative real-time 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.
Assessment of the usefulness of the murine cytotoxic T cell line CTLL-2 for immunotoxicity screening by transcriptomics
Schmeits, P.C. ; Volger, O.L. ; Zandvliet, E.T. ; Loveren, H. van; Peijnenburg, A. ; Hendriksen, P.J. - \ 2013
Toxicology Letters 217 (2013)1. - ISSN 0378-4274 - p. 1 - 13.
ribotoxic stress-response - activated protein-kinase - tri-n-butyltin - proinflammatory gene-expression - oxidative-phosphorylation - organotin compounds - in-vitro - deoxynivalenol don - heme oxygenase - rat thymocytes
A toxicogenomics approach was applied to assess the usefulness of the mouse cytotoxic T cell line CTLL-2 for in vitro immunotoxicity testing. CTLL-2 cells were exposed for 6 h to two model immunotoxic compounds: (1) the mycotoxin deoxynivalenol (DON, 1 and 2 µM), a ribotoxic stress inducer, and (2) the organotin compound tributyltin oxide (TBTO, 100 and 200 nM), an endoplasmic reticulum (ER) stress inducer. Effects on whole-genome mRNA expression were assessed by microarray analysis. The biological interpretation of the microarray data indicated that TBTO (200 nM) induced genes involved in T cell activation, ER stress, NF¿B activation and apoptosis, which agreed very well with results obtained before on TBTO exposed Jurkat cells and mouse primary thymocytes. Remarkably, DON (2 µM) downregulated genes involved in T cell activation, ER stress and apoptosis, which is opposite to results obtained before for DON-exposed Jurkat cells and mouse primary thymocytes. Furthermore, the results for DON in CTLL-2 cells are also opposite to the results obtained for TBTO in CTLL-2 cells. In agreement with the lack of induction of ER stress and apoptosis, viability assays showed that CTLL-2 cells are much more resistant to the toxicity of DON than Jurkat cells and primary thymocytes. We propose that CTLL-2 cells lack the signal transduction that induces ER stress and apoptosis in response to ribotoxic stress. Based on the results for TBTO and DON, the CTLL-2 cell line does not yield an added value for immunotoxicity compared to the human Jurkat T cell line
Comparing the immunosuppressive effects of cyclosporin A on mouse splenocytes in vivo with mouse and human T-cells in vitro by transcriptome profiling
Schmeits, P. ; Peijnenburg, A.A.C.M. ; Loveren, H. van; Volger, O.L. - \ 2012
In: 51st Annual Meeting of the Society of Toxicology and ToxExpo, March 11-15, 2012, San Fransisco, California. - Oxford University Press - p. 352 - 352.