Assessment of the usefulness of the murine cytotoxic T cell line CTLL-2 for immunotoxicity screening by transcriptomics

Schmeits, Peter C. J.; Volger, Oscar L.; Zandvliet, Ella T.; Loveren, Henk Van; Peijnenburg, Ad; Hendriksen, Peter J.M.

doi:10.1016/j.toxlet.2012.12.005

Cited by 16 publications

(13 citation statements)

References 69 publications

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“…The EL-4 results are very similar to those obtained in DON exposed CTLL-2 cells. Before, 12 we hypothesized that CTLL-2 cells might lack genes that play a role in the connection between ribotoxic stress and ER stress. Likely, EL-4 cells lack these genes as well.…”

Section: Discussionmentioning

confidence: 99%

“…Genes affected by TBTO or DON in other studies. 4,5,[12][13][14]18 Genes involved in ribosomal function, ER stress, T cell activation and apoptosis…”

Section: Comparative Data Analysismentioning

confidence: 99%

“…The criterion for selecting doses for microarray exposures was the same as used before. 5,12,14 Doses were selected that resulted in a decrease in viability of less than 20% after 24 h exposure. Furthermore, for both compounds one dose resulting in more than 20% reduction in cell viability was selected to assess the gene expression profile at cytotoxic conditions.…”

Section: Time and Dose Selectionmentioning

confidence: 99%

“…Both compounds have been used before in human and rodent transcriptomics studies. 4,5,[12][13][14][15][16][17][18] TBTO is an organotin compound that has been applied for various industrial purposes. It was for instance utilized as marine anti-fouling agent in ship paint, as a wood preservative and in the production of plastic floor tiles.…”

Section: Introductionmentioning

confidence: 99%

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The effects of tributyltin oxide and deoxynivalenol on the transcriptome of the mouse thymoma cell line EL-4

et al. 2014

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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. † Electronic supplementary information (ESI) available. See

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Section: Discussionmentioning

confidence: 99%

“…Genes affected by TBTO or DON in other studies. 4,5,[12][13][14]18 Genes involved in ribosomal function, ER stress, T cell activation and apoptosis…”

Section: Comparative Data Analysismentioning

confidence: 99%

Section: Time and Dose Selectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effects of tributyltin oxide and deoxynivalenol on the transcriptome of the mouse thymoma cell line EL-4

et al. 2014

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“…Besides primary cells, well-characterized and validated cell lines (human or animal) can be used for immunotoxicity testing of NMs (Gennari et al, 2005). Recently, several research groups published alternative approaches, using various cell lines -human Jurkat T-cell, human lymphoid T-cell (MOLT-4) or B-cell (IM-9), human acute myeloid leukemia HL-60 cell, murine Tcell (CTLL-2) or THP-1 (human monocytic cell line derived from acute monocytic leukemia patient) (Minervini et al, 2005;Schmeits et al, 2013Schmeits et al, , 2015Song et al, 2014;Markovi c et al, 2015). Precision-cut tissue slices are also being used (Sewald and Braun, 2013).…”

Section: Testing Methodsmentioning

confidence: 99%

Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?

Dušinská

Tulinská

Yamani

et al. 2017

Food and Chemical Toxicology

116

101

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a b s t r a c tThe unique properties of nanomaterials (NMs) are beneficial in numerous industrial and medical applications. However, they could also induce unintended effects. Thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. Toxicity can be tested in vivo and in vitro; in compliance with the 3Rs, alternative strategies for in vitro testing should be further developed for NMs. Robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. Oxidative stress has been shown to be an underlying mechanism of possible toxicity of NMs, causing both immunotoxicity and genotoxicity. For testing NMs in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. Novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. However, to initiate epigenetic toxicity screens for NM exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity.

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Mode of Action of Organotins in Immune Cells

Hendriksen

Schmeits

Loveren

et al. 2014

Molecular Immunotoxicology

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Assessment of the usefulness of the murine cytotoxic T cell line CTLL-2 for immunotoxicity screening by transcriptomics

Cited by 16 publications

References 69 publications

The effects of tributyltin oxide and deoxynivalenol on the transcriptome of the mouse thymoma cell line EL-4

The effects of tributyltin oxide and deoxynivalenol on the transcriptome of the mouse thymoma cell line EL-4

Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?

Mode of Action of Organotins in Immune Cells

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