204 results on '"Limonciel, A."'
Search Results
2. Mid-gestation low-dose LPS administration results in female-specific excessive weight gain upon a western style diet in mouse offspring
- Author
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Dijkstra, Dorieke J., Verkaik-Schakel, Rikst Nynke, Eskandar, Sharon, Limonciel, Alice, Stojanovska, Violeta, Scherjon, Sicco A., and Plösch, Torsten
- Published
- 2020
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3. Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq
- Author
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Limonciel, Alice, Ates, Gamze, Carta, Giada, Wilmes, Anja, Watzele, Manfred, Shepard, Peter J., VanSteenhouse, Harper C., Seligmann, Bruce, Yeakley, Joanne M., van de Water, Bob, Vinken, Mathieu, and Jennings, Paul
- Published
- 2018
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- View/download PDF
4. Corrigendum: Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases
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Elias Zgheib, Alice Limonciel, Xiaoqi Jiang, Anja Wilmes, Steven Wink, Bob van de Water, Annette Kopp-Schneider, Frederic Y. Bois, and Paul Jennings
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transcriptomics ,Nrf2 ,AhR ,ATF4 ,toxicity pathways ,toxicogenomic ,Genetics ,QH426-470 - Published
- 2019
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5. Improving global feature detectabilities through scan range splitting for untargeted metabolomics by high-performance liquid chromatography-Orbitrap mass spectrometry
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Ranninger, Christina, Schmidt, Lukas E., Rurik, Marc, Limonciel, Alice, Jennings, Paul, Kohlbacher, Oliver, and Huber, Christian G.
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- 2016
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6. Persistence of Epigenomic Effects After Recovery From Repeated Treatment With Two Nephrocarcinogens
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Alice Limonciel, Simone G. van Breda, Xiaoqi Jiang, Gregory D. Tredwell, Anja Wilmes, Lydia Aschauer, Alexandros P. Siskos, Agapios Sachinidis, Hector C. Keun, Annette Kopp-Schneider, Theo M. de Kok, Jos C. S. Kleinjans, and Paul Jennings
- Subjects
recovery ,persistence ,epigenomics ,stress responses ,ochratoxin A ,potassium bromate ,Genetics ,QH426-470 - Abstract
The discovery of the epigenetic regulation of transcription has provided a new source of mechanistic understanding to long lasting effects of chemicals. However, this information is still seldom exploited in a toxicological context and studies of chemical effect after washout remain rare. Here we studied the effects of two nephrocarcinogens on the human proximal tubule cell line RPTEC/TERT1 using high-content mRNA microarrays coupled with miRNA, histone acetylation (HA) and DNA methylation (DM) arrays and metabolomics during a 5-day repeat-dose exposure and 3 days after washout. The mycotoxin ochratoxin A (OTA) was chosen as a model compound for its known impact on HA and DM. The foremost effect observed was the modulation of thousands of mRNAs and histones by OTA during and after exposure. In comparison, the oxidant potassium bromate (KBrO3) had a milder impact on gene expression and epigenetics. However, there was no strong correlation between epigenetic modifications and mRNA changes with OTA while with KBrO3 the gene expression data correlated better with HA for both up- and down-regulated genes. Even when focusing on the genes with persistent epigenetic modifications after washout, only half were coupled to matching changes in gene expression induced by OTA, suggesting that while OTA causes a major effect on the two epigenetic mechanisms studied, these alone cannot explain its impact on gene expression. Mechanistic analysis confirmed the known activation of Nrf2 and p53 by KBrO3, while OTA inhibited most of the same genes, and genes involved in the unfolded protein response. A few miRNAs could be linked to these effects of OTA, albeit without clear contribution of epigenetics to the modulation of the pathways at large. Metabolomics revealed disturbances in amino acid balance, energy catabolism, nucleotide metabolism and polyamine metabolism with both chemicals. In conclusion, the large impact of OTA on transcription was confirmed at the mRNA level but also with two high-content epigenomic methodologies. Transcriptomic data confirmed the previously reported activation (by KBrO3) and inhibition (by OTA) of protective pathways. However, the integration of omic datasets suggested that HA and DM were not driving forces in the gene expression changes induced by either chemical.
- Published
- 2018
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- View/download PDF
7. Transcriptomics hit the target: Monitoring of ligand-activated and stress response pathways for chemical testing
- Author
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Limonciel, Alice, Moenks, Konrad, Stanzel, Sven, Truisi, Germaine L., Parmentier, Céline, Aschauer, Lydia, Wilmes, Anja, Richert, Lysiane, Hewitt, Philip, Mueller, Stefan O., Lukas, Arno, Kopp-Schneider, Annette, Leonard, Martin O., and Jennings, Paul
- Published
- 2015
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- View/download PDF
8. Application of RPTEC/TERT1 cells for investigation of repeat dose nephrotoxicity: A transcriptomic study
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Aschauer, Lydia, Limonciel, Alice, Wilmes, Anja, Stanzel, Sven, Kopp-Schneider, Annette, Hewitt, Philip, Lukas, Arno, Leonard, Martin O., Pfaller, Walter, and Jennings, Paul
- Published
- 2015
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9. Development of an in vitro renal epithelial disease state model for xenobiotic toxicity testing
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Crean, Daniel, Bellwon, Patricia, Aschauer, Lydia, Limonciel, Alice, Moenks, Konrad, Hewitt, Philip, Schmidt, Tobias, Herrgen, Karin, Dekant, Wolfgang, Lukas, Arno, Bois, Frederic, Wilmes, Anja, Jennings, Paul, and Leonard, Martin O.
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- 2015
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10. Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics
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Wilmes, Anja, Bielow, Chris, Ranninger, Christina, Bellwon, Patricia, Aschauer, Lydia, Limonciel, Alice, Chassaigne, Hubert, Kristl, Theresa, Aiche, Stephan, Huber, Christian G., Guillou, Claude, Hewitt, Philipp, Leonard, Martin O., Dekant, Wolfgang, Bois, Frederic, and Jennings, Paul
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- 2015
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11. Adverse outcome pathways: opportunities, limitations and open questions
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Leist, Marcel, Ghallab, Ahmed, Graepel, Rabea, Marchan, Rosemarie, Hassan, Reham, Bennekou, Susanne Hougaard, Limonciel, Alice, Vinken, Mathieu, Schildknecht, Stefan, Waldmann, Tanja, Danen, Erik, van Ravenzwaay, Ben, Kamp, Hennicke, Gardner, Iain, Godoy, Patricio, Bois, Frederic Y., Braeuning, Albert, Reif, Raymond, Oesch, Franz, Drasdo, Dirk, Höhme, Stefan, Schwarz, Michael, Hartung, Thomas, Braunbeck, Thomas, Beltman, Joost, Vrieling, Harry, Sanz, Ferran, Forsby, Anna, Gadaleta, Domenico, Fisher, Ciarán, Kelm, Jens, Fluri, David, Ecker, Gerhard, Zdrazil, Barbara, Terron, Andrea, Jennings, Paul, van der Burg, Bart, Dooley, Steven, Meijer, Annemarie H., Willighagen, Egon, Martens, Marvin, Evelo, Chris, Mombelli, Enrico, Taboureau, Olivier, Mantovani, Alberto, Hardy, Barry, Koch, Bjorn, Escher, Sylvia, van Thriel, Christoph, Cadenas, Cristina, Kroese, D., van de Water, Bob, and Hengstler, Jan G.
- Published
- 2017
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12. Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases
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Elias Zgheib, Alice Limonciel, Xiaoqi Jiang, Anja Wilmes, Steven Wink, Bob van de Water, Annette Kopp-Schneider, Frederic Y. Bois, and Paul Jennings
- Subjects
transcriptomics ,Nrf2 ,AhR ,ATF4 ,toxicity pathways ,toxicogenomic ,Genetics ,QH426-470 - Abstract
Toxicological responses to chemical insult are largely regulated by transcriptionally activated pathways that may be independent, correlated and partially or fully overlapping. Investigating the dynamics of the interactions between stress responsive transcription factors from toxicogenomic data and defining the signature of each of them is an additional step toward a system level understanding of perturbation driven mechanisms. To this end, we investigated the segregation of the genes belonging to the three following transcriptionally regulated pathways: the AhR pathway, the Nrf2 pathway and the ATF4 pathway. Toxicogenomic datasets from three projects (carcinoGENOMICS, Predict-IV and TG-GATEs) obtained in various experimental conditions (in human and rat in vitro liver and kidney models and rat in vivo, with bolus administration and with repeated doses) were combined and consolidated where overlaps between datasets existed. A bioinformatic analysis was performed to refine pathways' signatures and to create chemical activation capacity scores to classify chemicals by their potency and selectivity of activation of each pathway. With some refinement such an approach may improve chemical safety classification and allow biological read across on a pathway level.
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- 2018
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13. Inter-laboratory study of human in vitro toxicogenomics-based tests as alternative methods for evaluating chemical carcinogenicity: a bioinformatics perspective
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Herwig, R., Gmuender, H., Corvi, R., Bloch, K. M., Brandenburg, A., Castell, J., Ceelen, L., Chesne, C., Doktorova, T. Y., Jennen, D., Jennings, P., Limonciel, A., Lock, E. A., McMorrow, T., Phrakonkham, P., Radford, R., Slattery, C., Stierum, R., Vilardell, M., Wittenberger, T., Yildirimman, R., Ryan, M., Rogiers, V., and Kleinjans, J.
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- 2016
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14. “Watching the Detectives” report of the general assembly of the EU project DETECTIVE Brussels, 24–25 November 2015
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Fernando, Ruani N., Chaudhari, Umesh, Escher, Sylvia E., Hengstler, Jan G., Hescheler, Jürgen, Jennings, Paul, Keun, Hector C., Kleinjans, Jos C. S., Kolde, Raivo, Kollipara, Laxmikanth, Kopp-Schneider, Annette, Limonciel, Alice, Nemade, Harshal, Nguemo, Filomain, Peterson, Hedi, Prieto, Pilar, Rodrigues, Robim M., Sachinidis, Agapios, Schäfer, Christoph, Sickmann, Albert, Spitkovsky, Dimitry, Stöber, Regina, van Breda, Simone G. J., van de Water, Bob, Vivier, Manon, Zahedi, René P., Vinken, Mathieu, and Rogiers, Vera
- Published
- 2016
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15. A Review of the Evidence that Ochratoxin A Is an Nrf2 Inhibitor: Implications for Nephrotoxicity and Renal Carcinogenicity
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Alice Limonciel and Paul Jennings
- Subjects
proximal tubule ,ochratoxin ,oxidative ,Nrf2 ,Medicine - Abstract
Several studies have demonstrated that ochratoxin A (OTA) inhibits the nuclear factor, erythroid 2-like 2 (Nrf2) oxidative stress response pathway. At the cellular level this would attenuate (i) glutathione synthesis; (ii) recycling of oxidised glutathione; (iii) activity of oxidoreductases; and (iv) phase II metabolism inducibility. The effects combined would render the cell and tissue more vulnerable to oxidative stress. Indeed, Nrf2 knock out animals exhibit increased susceptibility to various types of chemical-induced injury. Several studies have shown that OTA exposure can inhibit Nrf2 responses. Such an action would initially lead to increased susceptibility to both physiological and chemical-induced cell stress. However, chronic exposure to OTA may also act as a selective pressure for somatic mutations in Nrf2 or its inhibitor Keap-1, leading to constitutive Nrf2 activation. Nrf2 overexpression confers a survival advantage and is often associated with cancer cell survival. Here we review the evidence for OTA’s role as an Nrf2 inhibitor and discuss the implications of this mechanism in nephrotoxicity and carcinogenicity.
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- 2014
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16. Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress
- Author
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Wilmes, Anja, Limonciel, Alice, Aschauer, Lydia, Moenks, Konrad, Bielow, Chris, Leonard, Martin O., Hamon, Jeremy, Carpi, Donatella, Ruzek, Silke, Handler, Andreas, Schmal, Olga, Herrgen, Karin, Bellwon, Patricia, Burek, Christof, Truisi, Germaine L., Hewitt, Philip, Di Consiglio, Emma, Testai, Emanuela, Blaauboer, Bas J., Guillou, Claude, Huber, Christian G., Lukas, Arno, Pfaller, Walter, Mueller, Stefan O., Bois, Frederic Y., Dekant, Wolfgang, and Jennings, Paul
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- 2013
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17. Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action
- Author
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Escher, Sylvia E., Aguayo-Orozco, Alejandro, Benfenati, Emilio, Bitsch, Annette, Braunbeck, Thomas, Brotzmann, Katharina, Bois, Frederic, van der Burg, Bart, Castel, Jose, Exner, Thomas, Gadaleta, Domenico, Gardner, Iain, Goldmann, Daria, Hatley, Oliver, Golbamaki, Nazanin, Graepel, Rabea, Jennings, Paul, Limonciel, Alice, Long, Anthony, Maclennan, Richard, Mombelli, Enrico, Norinder, Ulf, Jain, Sankalp, Capinha, Liliana Santos, Taboureau, Olivier T., Tolosa, Laia, Vrijenhoek, Nanette G., van Vugt-Lussenburg, Barbara M.A., Walker, Paul, van de Water, Bob, Wehr, Matthias, White, Andrew, Zdrazil, Barbara, Fisher, Ciarán, Escher, Sylvia E., Aguayo-Orozco, Alejandro, Benfenati, Emilio, Bitsch, Annette, Braunbeck, Thomas, Brotzmann, Katharina, Bois, Frederic, van der Burg, Bart, Castel, Jose, Exner, Thomas, Gadaleta, Domenico, Gardner, Iain, Goldmann, Daria, Hatley, Oliver, Golbamaki, Nazanin, Graepel, Rabea, Jennings, Paul, Limonciel, Alice, Long, Anthony, Maclennan, Richard, Mombelli, Enrico, Norinder, Ulf, Jain, Sankalp, Capinha, Liliana Santos, Taboureau, Olivier T., Tolosa, Laia, Vrijenhoek, Nanette G., van Vugt-Lussenburg, Barbara M.A., Walker, Paul, van de Water, Bob, Wehr, Matthias, White, Andrew, Zdrazil, Barbara, and Fisher, Ciarán
- Abstract
Read-across approaches often remain inconclusive as they do not provide sufficient evidence on a common mode of action across the category members. This read-across case study on thirteen, structurally similar, branched aliphatic carboxylic acids investigates the concept of using human-based new approach methods, such as in vitro and in silico models, to demonstrate biological similarity. Five out of the thirteen analogues have preclinical in vivo studies. Three out of them induced lipid accumulation or hypertrophy in preclinical studies with repeated exposure, which leads to the read-across hypothesis that the analogues can potentially induce hepatic steatosis. To confirm the selection of analogues, the expression patterns of the induced differentially expressed genes (DEGs) were analysed in a human liver model. With increasing dose, the expression pattern within the tested analogues got more similar, which serves as a first indication of a common mode of action and suggests differences in the potency of the analogues. Hepatic steatosis is a well-known adverse outcome, for which over 55 adverse outcome pathways have been identified. The resulting adverse outcome pathway (AOP) network, comprised a total 43 MIEs/KEs and enabled the design of an in vitro testing battery. From the AOP network, ten MIEs, early and late KEs were tested to systematically investigate a common mode of action among the grouped compounds. The targeted testing of AOP specific MIE/KEs shows that biological activity in the category decreases with side chain length. A similar trend was evident in measuring liver alterations in zebra fish embryos. However, activation of single MIEs or early KEs at in vivo relevant doses did not necessarily progress to the late KE “lipid accumulation”. KEs not related to the read-across hypothesis, testing for example general mitochondrial stress responses in liver cells, showed no trend or biological similarity. Testing scope is a key issue in the design of in
- Published
- 2022
18. Interleukin-19 as a translational indicator of renal injury
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Jennings, Paul, Crean, Daniel, Aschauer, Lydia, Limonciel, Alice, Moenks, Konrad, Kern, Georg, Hewitt, Philip, Lhotta, Karl, Lukas, Arno, Wilmes, Anja, and Leonard, Martin O.
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- 2015
- Full Text
- View/download PDF
19. Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action
- Author
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Escher, Sylvia E., primary, Aguayo-Orozco, Alejandro, additional, Benfenati, Emilio, additional, Bitsch, Annette, additional, Braunbeck, Thomas, additional, Brotzmann, Katharina, additional, Bois, Frederic, additional, van der Burg, Bart, additional, Castel, Jose, additional, Exner, Thomas, additional, Gadaleta, Domenico, additional, Gardner, Iain, additional, Goldmann, Daria, additional, Hatley, Oliver, additional, Golbamaki, Nazanin, additional, Graepel, Rabea, additional, Jennings, Paul, additional, Limonciel, Alice, additional, Long, Anthony, additional, Maclennan, Richard, additional, Mombelli, Enrico, additional, Norinder, Ulf, additional, Jain, Sankalp, additional, Capinha, Liliana Santos, additional, Taboureau, Olivier T., additional, Tolosa, Laia, additional, Vrijenhoek, Nanette G., additional, van Vugt-Lussenburg, Barbara M.A., additional, Walker, Paul, additional, van de Water, Bob, additional, Wehr, Matthias, additional, White, Andrew, additional, Zdrazil, Barbara, additional, and Fisher, Ciarán, additional
- Published
- 2022
- Full Text
- View/download PDF
20. A read-across case study on chronic toxicity of branched carboxylic acids (1): Integration of mechanistic evidence from new approach methodologies (NAMs) to explore a common mode of action
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Escher SE, Aguayo-Orozco A, Benfenati E, Bitsch A, Braunbeck T, Brotzmann K, Bois F, van der Burg B, Castel J, Exner T, Gadaleta D, Gardner I, Goldmann D, Hatley O, Golbamaki N, Graepel R, Jennings P, Limonciel A, Long A, Maclennan R, Mombelli E, Norinder U, Jain S, Capinha LS, Taboureau OT, Tolosa L, Vrijenhoek NG, van Vugt-Lussenburg BMA, Walker P, van de Water B, Wehr M, White A, Zdrazil B, and Fisher C
- Subjects
AOP-network, Liver steatosis, Mechanistic hazard assessment, NAM, Read-across - Abstract
This read-across case study characterises thirteen, structurally similar carboxylic acids demonstrating the application of in vitro and in silico human-based new approach methods, to determine biological similarity. Based on data from in vivo animal studies, the read-across hypothesis is that all analogues are steatotic and so should be considered hazardous. Transcriptomic analysis to determine differentially expressed genes (DEGs) in hepatocytes served as first tier testing to confirm a common mode-of-action and identify differences in the potency of the analogues. An adverse outcome pathway (AOP) network for hepatic steatosis, informed the design of an in vitro testing battery, targeting AOP relevant MIEs and KEs, and Dempster-Shafer decision theory was used to systematically quantify uncertainty and to define the minimal testing scope. The case study shows that the read-across hypothesis is the critical core to designing a robust, NAM-based testing strategy. By summarising the current mechanistic understanding, an AOP enables the selection of NAMs covering MIEs, early KEs, and late KEs. Experimental coverage of the AOP in this way is vital since MIEs and early KEs alone are not confirmatory of progression to the AO. This strategy exemplifies the workflow previously published by the EUTOXRISK project driving a paradigm shift towards NAM-based NGRA.
- Published
- 2022
21. Lactate is an ideal non-invasive marker for evaluating temporal alterations in cell stress and toxicity in repeat dose testing regimes
- Author
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Limonciel, Alice, Aschauer, Lydia, Wilmes, Anja, Prajczer, Sinikka, Leonard, Martin O., Pfaller, Walter, and Jennings, Paul
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- 2011
- Full Text
- View/download PDF
22. Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action
- Author
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Alejandro Aguayo-Orozco, Liliana Capinha, Nazanin Golbamaki, Enrico Mombelli, Matthias Wehr, Bart van der Burg, Daria Goldmann, Nanette G Vrijenhoek, Thomas Exner, Richard Maclennan, Katharina Brotzmann, Ulf Norinder, Oliver Hatley, Alice Limonciel, Thomas Braunbeck, Sylvia Escher, Barbara Zdrazil, Frédéric Y. Bois, Paul Jennings, Emilio Benfenati, Domenico Gadaleta, Jose Castel, Ciarán Fisher, Sankalp Jain, Anthony Long, Rabea Graepel, Laia Tolosa, Andrew White, Bob van de Water, Barbara M.A. van Vugt-Lussenburg, Paul Walker, Annette Bitsch, Olivier Taboureau, Iain Gardner, AIMMS, Molecular and Computational Toxicology, and Publica
- Subjects
Test strategy ,Mechanistic hazard assessment ,Adverse Outcome Pathways ,Computer science ,In silico ,Gene Expression Profiling ,Liver steatosis ,Carboxylic Acids ,General Medicine ,Computational biology ,Toxicology ,AOP-network ,Fatty Liver ,Differentially expressed genes ,Workflow ,Action (philosophy) ,NAM ,Read-across ,Adverse Outcome Pathway ,Animals ,Humans ,Computer Simulation ,Zebrafish - Abstract
Read-across approaches often remain inconclusive as they do not provide sufficient evidence on a common mode of action across the category members. This read-across case study on thirteen, structurally similar, branched aliphatic carboxylic acids investigates the concept of using human-based new approach methods, such as in vitro and in silico models, to demonstrate biological similarity. Five out of the thirteen analogues have preclinical in vivo studies. Three out of them induced lipid accumulation or hypertrophy in preclinical studies with repeated exposure, which leads to the read-across hypothesis that the analogues can potentially induce hepatic steatosis. To confirm the selection of analogues, the expression patterns of the induced differentially expressed genes (DEGs) were analysed in a human liver model. With increasing dose, the expression pattern within the tested analogues got more similar, which serves as a first indication of a common mode of action and suggests differences in the potency of the analogues. Hepatic steatosis is a well-known adverse outcome, for which over 55 adverse outcome pathways have been identified. The resulting adverse outcome pathway (AOP) network, comprised a total 43 MIEs/KEs and enabled the design of an in vitro testing battery. From the AOP network, ten MIEs, early and late KEs were tested to systematically investigate a common mode of action among the grouped compounds. The targeted testing of AOP specific MIE/KEs shows that biological activity in the category decreases with side chain length. A similar trend was evident in measuring liver alterations in zebra fish embryos. However, activation of single MIEs or early KEs at in vivo relevant doses did not necessarily progress to the late KE “lipid accumulation”. KEs not related to the read-across hypothesis, testing for example general mitochondrial stress responses in liver cells, showed no trend or biological similarity. Testing scope is a key issue in the design of in vitro test batteries. The Dempster-Shafer decision theory predicted those analogues with in vivo reference data correctly using one human liver model or the CALUX reporter assays. The case study shows that the read-across hypothesis is the key element to designing the testing strategy. In the case of a good mechanistic understanding, an AOP facilitates the selection of reliable human in vitro models to demonstrate a common mode of action. Testing DEGs, MIEs and early KEs served to show biological similarity, whereas the late KEs become important for confirmation, as progression from MIEs to AO is not always guaranteed.
- Published
- 2021
23. An overview of transcriptional regulation in response to toxicological insult
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Jennings, Paul, Limonciel, Alice, Felice, Luca, and Leonard, Martin O.
- Published
- 2013
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24. Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells
- Author
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Limonciel, Alice, Wilmes, Anja, Aschauer, Lydia, Radford, Robert, Bloch, Katarzyna M., McMorrow, Tara, Pfaller, Walter, van Delft, Joost H., Slattery, Craig, Ryan, Michael P., Lock, Edward A., and Jennings, Paul
- Published
- 2012
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25. The Past, Present, and Future of Chemical Risk Assessment
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Limonciel, Alice, primary
- Published
- 2014
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26. Stress Response Pathways
- Author
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Leonard, Martin O., primary, Limonciel, Alice, additional, and Jennings, Paul, additional
- Published
- 2014
- Full Text
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27. Translational Biomarkers, In Vitro and In Vivo
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Wilmes, Anja, primary, Limonciel, Alice, additional, Leonard, Martin O., additional, and Jennings, Paul, additional
- Published
- 2014
- Full Text
- View/download PDF
28. Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model
- Author
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Jennings, Paul, Weiland, Christina, Limonciel, Alice, Bloch, Katarzyna M., Radford, Robert, Aschauer, Lydia, McMorrow, Tara, Wilmes, Anja, Pfaller, Walter, Ahr, Hans J., Slattery, Craig, Lock, Edward A., Ryan, Michael P., and Ellinger-Ziegelbauer, Heidrun
- Published
- 2012
- Full Text
- View/download PDF
29. Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel
- Author
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Wilmes, Anja, Aschauer, Lydia, Limonciel, Alice, Pfaller, Walter, and Jennings, Paul
- Published
- 2014
- Full Text
- View/download PDF
30. The EU-ToxRisk method documentation, data processing and chemical testing pipeline for the regulatory use of new approach methods
- Author
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Anja Wilmes, Tobias Strassfeld, Harry Vrieling, Manoj Kumar, Balázs Mihalik, Costanza Rovida, Giorgia Pallocca, Nanette G Vrijenhoek, Ciarán Fisher, Bart van der Burg, Thomas Braunbeck, Xenia Dolde, Alice Krebs, Zofia Janstova, Béla Z. Schmidt, Wiebke Albrecht, Jan G. Hengstler, Tim Brecklinghaus, David A. Fluri, J. J. W. A. Boei, Thomas Exner, Marcel Leist, Tanja Waldmann, Jaffar Kisitu, Anna-Katharina Holzer, Manuel Pastor, Joh Dokler, Andrea Paola Cediel Ulloa, Paul Jennings, Barbara M.A. van Vugt-Lussenburg, Bas ter Braak, Bob van de Water, Anna Forsby, Maja Brajnik, Wolfgang Moritz, Catherine M. Verfaillie, Johannes P Schimming, Rebecca von Hellfeld, Alice Limonciel, Francois Busquet, Julianna Kobolák, Ugis Sarkans, Regina Stöber, Jessica Lundqvist, Andras Dinnyes, Molecular and Computational Toxicology, and AIMMS
- Subjects
0301 basic medicine ,Test data generation ,Computer science ,Health, Toxicology and Mutagenesis ,Data validation ,HAZARD ASSESSMENT ,Toxicology ,CELL-CULTURE PRACTICE ,Documentation ,Policy Making ,Cells, Cultured ,Zebrafish ,media_common ,EPITHELIAL-CELLS ,General Medicine ,data processing ,GIVIMP ,in vitro toxicology ,metadata ,nuclear receptor ,Test (assessment) ,Strategy implementation ,Europe ,Data processing ,In Vitro Systems ,NEURAL CREST MIGRATION ,Life Sciences & Biomedicine ,REPRODUCTIVE TOXICITY ,Risk Assessment ,03 medical and health sciences ,SDG 17 - Partnerships for the Goals ,ddc:570 ,Terminology as Topic ,Toxicity Tests ,media_common.cataloged_instance ,Animals ,Humans ,European union ,Retrospective Studies ,In vitro toxicology ,Electronic Data Processing ,Metadata ,Science & Technology ,business.industry ,030111 toxicology ,Reproducibility of Results ,CALUX METHOD ,IN-VITRO ,Pipeline (software) ,DRUG DISCOVERY ,030104 developmental biology ,Nuclear receptor ,DEVELOPMENTAL NEUROTOXICITY DNT ,Government Regulation ,Software engineering ,business ,EMBRYONIC STEM-CELLS - Abstract
Hazard assessment, based on new approach methods (NAM), requires the use of batteries of assays, where individual tests may be contributed by different laboratories. A unified strategy for such collaborative testing is presented. It details all procedures required to allow test information to be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. The EU-ToxRisk project developed a strategy to provide regulatorily valid data, and exemplified this using a panel of > 20 assays (with > 50 individual endpoints), each exposed to 19 well-known test compounds (e.g. rotenone, colchicine, mercury, paracetamol, rifampicine, paraquat, taxol). Examples of strategy implementation are provided for all aspects required to ensure data validity: (i) documentation of test methods in a publicly accessible database; (ii) deposition of standard operating procedures (SOP) at the European Union DB-ALM repository; (iii) test readiness scoring accoding to defined criteria; (iv) disclosure of the pipeline for data processing; (v) link of uncertainty measures and metadata to the data; (vi) definition of test chemicals, their handling and their behavior in test media; (vii) specification of the test purpose and overall evaluation plans. Moreover, data generation was exemplified by providing results from 25 reporter assays. A complete evaluation of the entire test battery will be described elsewhere. A major learning from the retrospective analysis of this large testing project was the need for thorough definitions of the above strategy aspects, ideally in form of a study pre-registration, to allow adequate interpretation of the data and to ensure overall scientific/toxicological validity. Electronic supplementary material The online version of this article (10.1007/s00204-020-02802-6) contains supplementary material, which is available to authorized users.
- Published
- 2020
31. Mid-gestation low-dose LPS administration results in female-specific excessive weight gain upon a western style diet in mouse offspring
- Author
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Dijkstra, D.J., Verkaik-Schakel, R.N., Eskandar, S., Limonciel, A., Stojanovska, Violeta, Scherjon, S.A., Plösch, T., Dijkstra, D.J., Verkaik-Schakel, R.N., Eskandar, S., Limonciel, A., Stojanovska, Violeta, Scherjon, S.A., and Plösch, T.
- Abstract
Gestational complications, including preeclampsia and gestational diabetes, have long-term adverse consequences for offspring’s metabolic and cardiovascular health. A low-grade systemic inflammatory response is likely mediating this. Here, we examine the consequences of LPS-induced gestational inflammation on offspring’s health in adulthood. LPS was administered to pregnant C57Bl/6J mice on gestational day 10.5. Maternal plasma metabolomics showed oxidative stress, remaining for at least 5 days after LPS administration, likely mediating the consequences for the offspring. From weaning on, all offspring was fed a control diet; from 12 to 24 weeks of age, half of the offspring received a western-style diet (WSD). The combination of LPS-exposure and WSD resulted in hyperphagia and increased body weight and body fat mass in the female offspring. This was accompanied by changes in glucose tolerance, leptin and insulin levels and gene expression in liver and adipose tissue. In the hypothalamus, expression of genes involved in food intake regulation was slightly changed. We speculate that altered food intake behaviour is a result of dysregulation of hypothalamic signalling. Our results add to understanding of how maternal inflammation can mediate long-term health consequences for the offspring. This is relevant to many gestational complications with a pro-inflammatory reaction in place.
- Published
- 2020
32. Adverse outcome pathways: opportunities, limitations and open questions
- Author
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Alberto Mantovani, Tanja Waldmann, Bob van de Water, Cristina Cadenas, Hennicke Kamp, Thomas Braunbeck, Annemarie H. Meijer, Mathieu Vinken, Sylvia Escher, Domenico Gadaleta, Patricio Godoy, Anna Forsby, Stefan Schildknecht, Chris T. Evelo, Stefan Höhme, Rosemarie Marchan, Gerhard F. Ecker, Harry Vrieling, Susanne Hougaard Bennekou, Ciarán Fisher, Alice Limonciel, Enrico Mombelli, Rabea Graepel, Marcel Leist, Ahmed Ghallab, Michael Schwarz, Joost B. Beltman, Jens M. Kelm, Albert Braeuning, Olivier Taboureau, Bart van der Burg, Andrea Terron, Ferran Sanz, Frédéric Y. Bois, Steven Dooley, Dinant Kroese, Jan G. Hengstler, Paul Jennings, Egon Willighagen, Barbara Zdrazil, Barry Hardy, Erik H.J. Danen, Bjørn E. V. Koch, David A. Fluri, Christoph van Thriel, Dirk Drasdo, Ben van Ravenzwaay, Iain Gardner, Franz Oesch, Reham Hassan, Raymond Reif, Marvin Martens, Thomas Hartung, University of Konstanz, Department of Forensic Medicine and Veterinary Toxicology [Qena], Faculty of Veterinary Medicine [Qena], South Valley University [Qena]-South Valley University [Qena], Universiteit Leiden, Leibniz Research Centre for Working Environment and Human Factors [Dortmund] (IFADO), Technische Universität Dortmund [Dortmund] (TU), The Danish Epidemiology Science Centre, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Vrije Universiteit Brussel (VUB), BASF [Ludwigshafen], SimCYP Ltd, Institut National de l'Environnement Industriel et des Risques (INERIS), Bundesinstitut für Risikobewertung - Federal Institute for Risk Assessment (BfR), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Modelling and Analysis for Medical and Biological Applications (MAMBA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universität Leipzig, Medical University Graz, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), University of Heidelberg, Medical Faculty, Universitat Pompeu Fabra [Barcelona] (UPF), Karolinska Institutet [Stockholm], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), InSphero [Schlieren], University of Vienna [Vienna], Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), BioDetection Systems, Universität Mannheim, Maastricht University [Maastricht], Institut National de la Santé et de la Recherche Médicale (INSERM), IT University of Copenhagen (ITU), Istituto Superiore di Sanità (ISS), Douglas Connect GmbH, Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Carl Zeiss SMT AG, Carl Zeiss, Oberkochen, Faculty of Biology, Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University [Austria] (IMU), BASF, DRC/VIVA/METO, Institut National de l'Environnement Industriel et des Risques, Department of Experimental and Clinical Pharmacology andToxicology [Tübingen], Eberhard Karls Universität Tübingen, Interdisciplinary Centre for Bioinformatics [Leipzig] (IZBI), Universität Leipzig [Leipzig], Institute for Health and Consumer Protection, European Commission - Joint Research Centre, Université Grenoble Alpes - UFR Médecine [ ?-2019] (UGA UFRM [ ?-2019]), Molecular Hepatology - Alcohol Associated Diseases, Department of Medicine II, University of Heidelberg, Medical Faculty of Mannheim-University of Heidelberg, Medical Faculty of Mannheim, BigCat - Bioinformatics and Systems Biology Research Group, UMR-S973, MTi, Université Paris Diderot - Paris 7 (UPD7), Department of Immunology and Cell Biology, Mario Negri Institute, Leiden University, Vrije Universiteit [Brussels] (VUB), Universiteit Leiden [Leiden], BASF SE, 67056 Ludwigshafen, Johannes Gutenberg - University of Mainz (JGU), Centre for Alternatives to Animal Testing (CAAT EU), Universitat Pompeu Fabra [Barcelona], European Food Safety Authority = Autorité européenne de sécurité des aliments, Université Grenoble Alpes (UGA), Universität Mannheim [Mannheim], Istituto Superiore di Sanita [Rome], Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Johannes Gutenberg - Universität Mainz (JGU), IT University of Copenhagen, Molecular and Computational Toxicology, AIMMS, Bioinformatica, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: NUTRIM - R4 - Gene-environment interaction, Promovendi NTM, RS: FHML MaCSBio, Publica, Pharmaceutical and Pharmacological Sciences, Connexin Signalling Research Group, Liver Connexin and Pannexin Research Group, and Experimental in vitro toxicology and dermato-cosmetology
- Subjects
CCl4 ,0301 basic medicine ,Proof of non-toxicity ,Health, Toxicology and Mutagenesis ,CCl ,RAPID - Risk Analysis for Products in Development ,Biomedical Innovation ,Signal transduction ,Ecotoxicology ,Toxicology ,NATURAL-KILLER-CELLS ,Prioritization of compounds ,Life ,Adverse Outcome Pathway ,ACTIVATED STELLATE CELLS ,ComputingMilieux_MISCELLANEOUS ,Risk assessment ,TUMOR-NECROSIS-FACTOR ,Event (computing) ,EVIDENCE-BASED TOXICOLOGY ,ENVIRONMENTAL CHEMICALS ,General Medicine ,Toxicokinetics ,Multiple hit events Proof of non-toxicity ,Evidence-based toxicology ,Identification (information) ,Paracetamol ,Risk analysis (engineering) ,Vinyl acetate ,RISK-ASSESSMENT ,Systems biology ,Construct (philosophy) ,Healthy Living ,Human ,Quality Control ,READ-ACROSS ,Vinyl Compounds ,Plasticity ,Liver fibrosis ,Nanotechnology ,Harmonization ,Multiple hit events ,Biology ,History, 21st Century ,Risk Assessment ,Binning of events ,Adverse outcome ,03 medical and health sciences ,Adverse outcome pathway ,SDG 3 - Good Health and Well-being ,ddc:570 ,Tumor promotion ,Journal Article ,Animals ,Humans ,Vinyl acetate Tumor promotion ,Regulatory toxicology ,Set (psychology) ,Epidemiological data ,Adverse Outcome Pathways ,Interspecies extrapolation ,030111 toxicology ,SYSTEMS TOXICOLOGY ,Nonhuman ,Toxicity assay ,[INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation ,Mice, Inbred C57BL ,Multi-scale integration ,Metabolism ,030104 developmental biology ,DEVELOPMENTAL NEUROTOXICITY ,Computational toxicology ,ELSS - Earth, Life and Social Sciences ,Pathway unidirectionality - Abstract
Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field. © 2017, Springer-Verlag GmbH Germany.
- Published
- 2017
33. Corrigendum: Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases
- Author
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Frédéric Y. Bois, Annette Kopp-Schneider, Anja Wilmes, Steven Wink, Alice Limonciel, Xiaoqi Jiang, Bob van de Water, Paul Jennings, and Elias Zgheib
- Subjects
lcsh:QH426-470 ,In kind ,Toxicogenomic ,Public administration ,Nrf2 ,03 medical and health sciences ,0302 clinical medicine ,SDG 17 - Partnerships for the Goals ,Political science ,Genetics ,media_common.cataloged_instance ,European commission ,ATF4 ,European union ,Transcriptomics ,Genetics (clinical) ,Original Research ,030304 developmental biology ,media_common ,0303 health sciences ,Toxicity pathways ,AhR ,3. Good health ,lcsh:Genetics ,Work (electrical) ,Oxidative stress ,030220 oncology & carcinogenesis ,Molecular Medicine - Abstract
In the original article, we neglected to mention that this work was partly supported by the EU-ToxRisk project (An Integrated European "Flagship" Program Driving Mechanism-Based Toxicity Testing and Risk Assessment for the 21st Century) funded by the European Commission under the Horizon 2020 programme (Grant Agreement No. 681002). A correction has therefore been made to the Acknowledgments: "The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (IMIJU) under grant agreement number 115439, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. This work was supported by the 2015 CEFIC-LRI award (AL) and partly supported by the EU-ToxRisk project (An Integrated European "Flagship" Program Driving Mechanism-Based Toxicity Testing and Risk Assessment for the 21st Century) funded by the European Commission under the Horizon 2020 programme (Grant Agreement No. 681002). This publication reflects only the author's views and neither the IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein." The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
- Published
- 2019
34. Application of three approaches for quantitative AOP development to renal toxicity
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Ghislaine Gayraud, Magdalini Sachana, Alice Limonciel, Cleo Tebby, Elias Zgheib, Wang Gao, Huan Yang, Paul Jennings, Joost B. Beltman, Hristo Aladjov, Frédéric Y. Bois, Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Molecular and Computational Toxicology, and AIMMS
- Subjects
Calibration (statistics) ,Computer science ,Health, Toxicology and Mutagenesis ,Systems biology ,Quantitative AOP Systems biology model ,010501 environmental sciences ,Hazard analysis ,Toxicology ,Machine learning ,computer.software_genre ,01 natural sciences ,Quantitative AOP ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Chronic kidney disease ,Predictive toxicology ,Adverse Outcome Pathway ,SDG 14 - Life Below Water ,Systems biology model ,Representation (mathematics) ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0105 earth and related environmental sciences ,0303 health sciences ,business.industry ,Bayesian network ,Experimental data ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Computer Science Applications ,Bayesian networks ,Potassium bromate ,Artificial intelligence ,business ,Risk assessment ,computer - Abstract
While hazard assessment of chemicals can make direct use of descriptive adverse outcome pathways (AOPs), risk assessment requires quantitative relationships from exposure to effect timing and magnitude. To seamlessly integrate the data generated by alternative methods or in vivo testing, quantitative AOPs (qAOPs) providing dose-time-response predictions are more valuable than qualitative AOPs. Here, we compare three approaches to qAOP building: empirical dose-response modeling, Bayesian network (BN) calibration, and systems biology (SB) modeling. These methods were applied to the quantification of a simplified oxidative stress induced chronic kidney disease AOP, on the basis of in vitro data obtained on RPTEC/TERT1 cells exposed to potassium bromate. Effectopedia was used to store the experimental data and the developed models in a unified representation so they can be compared and further analyzed. We argue that despite the fact that dose-response models give adequate fits to the data they should be accompanied by mechanistic SB modeling to gain a proper perspective on the quantification. BNs can be both more precise than dose-response models and simpler than SB models, but more experience with their usage is needed.
- Published
- 2019
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35. Inter-laboratory study of human in vitro toxicogenomics-based tests as alternative methods for evaluating chemical carcinogenicity: a bioinformatics perspective
- Author
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Pascal Phrakonkham, Mireia Vilardell, Rob Stierum, A. Brandenburg, Hans Gmuender, Liesbeth Ceelen, Alice Limonciel, Craig Slattery, Tatyana Y. Doktorova, Christophe Chesne, Edward A. Lock, Robert J. Radford, Michael P. Ryan, Katarzyna M. Bloch, Ralf Herwig, Timo Wittenberger, Jos C. S. Kleinjans, Tara McMorrow, Vera Rogiers, Raffaella Corvi, Paul Jennings, Danyel Jennen, José V. Castell, Reha Yildirimman, Pharmaceutical and Pharmacological Sciences, Experimental in vitro toxicology and dermato-cosmetology, Connexin Signalling Research Group, Toxicogenomics, and RS: GROW - R1 - Prevention
- Subjects
0301 basic medicine ,Laboratory Proficiency Testing ,Time Factors ,Bioinformatics ,Health, Toxicology and Mutagenesis ,Alternatives to animal testing ,Genome-wide association study ,Biology ,Toxicology ,Risk Assessment ,Toxicogenetics ,Workflow ,Transcriptome ,Kidney Tubules, Proximal ,03 medical and health sciences ,Inter-laboratory assessment ,Cell Line, Tumor ,Humans ,Oligonucleotide Array Sequence Analysis ,Observer Variation ,Carcinogenicity ,Dose-Response Relationship, Drug ,Gene Expression Profiling ,Pre-validation ,In vitro toxicology ,Computational Biology ,Reproducibility of Results ,General Medicine ,Toxicogenomics ,3. Good health ,Gene expression profiling ,030104 developmental biology ,Gene Expression Regulation ,Liver ,Carcinogens ,In vitro assays ,DNA microarray ,Genome-Wide Association Study - Abstract
The assessment of the carcinogenic potential of chemicals with alternative, human-based in vitro systems has become a major goal of toxicogenomics. The central read-out of these assays is the transcriptome, and while many studies exist that explored the gene expression responses of such systems, reports on robustness and reproducibility, when testing them independently in different laboratories, are still uncommon. Furthermore, there is limited knowledge about variability induced by the data analysis protocols. We have conducted an inter-laboratory study for testing chemical carcinogenicity evaluating two human in vitro assays: hepatoma-derived cells and hTERT-immortalized renal proximal tubule epithelial cells, representing liver and kidney as major target organs. Cellular systems were initially challenged with thirty compounds, genome-wide gene expression was measured with microarrays, and hazard classifiers were built from this training set. Subsequently, each system was independently established in three different laboratories, and gene expression measurements were conducted using anonymized compounds. Data analysis was performed independently by two separate groups applying different protocols for the assessment of inter-laboratory reproducibility and for the prediction of carcinogenic hazard. As a result, both workflows came to very similar conclusions with respect to (1) identification of experimental outliers, (2) overall assessment of robustness and inter-laboratory reproducibility and (3) re-classification of the unknown compounds to the respective toxicity classes. In summary, the developed bioinformatics workflows deliver accurate measures for inter-laboratory comparison studies, and the study can be used as guidance for validation of future carcinogenicity assays in order to implement testing of human in vitro alternatives to animal testing.
- Published
- 2016
36. Improving global feature detectabilities through scan range splitting for untargeted metabolomics by high-performance liquid chromatography-Orbitrap mass spectrometry
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Oliver Kohlbacher, Marc Rurik, Paul Jennings, Christian G. Huber, Christina Ranninger, Lukas E Schmidt, and Alice Limonciel
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Chromatography ,Metabolite ,Electrospray ionization ,Biomolecule ,Analytical chemistry ,Orbitrap ,Mass spectrometry ,Biochemistry ,High-performance liquid chromatography ,Mass Spectrometry ,Analytical Chemistry ,law.invention ,Ion ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,law ,Metabolomics ,Environmental Chemistry ,Gas chromatography–mass spectrometry ,Chromatography, High Pressure Liquid ,Spectroscopy - Abstract
Untargeted metabolomics aims at obtaining quantitative information on the highest possible number of low-molecular biomolecules present in a biological sample. Rather small changes in mass spectrometric spectrum acquisition parameters may have a significant influence on the detectabilities of metabolites in untargeted global-scale studies by means of high-performance liquid chromatography-mass spectrometry (HPLC-MS). Employing whole cell lysates of human renal proximal tubule cells, we present a systematic global-scale study of the influence of mass spectrometric scan parameters and post-acquisition data treatment on the number and intensity of metabolites detectable in whole cell lysates. Ion transmission and ion collection efficiencies in an Orbitrap-based mass spectrometer basically depend on the m/z range scanned, which, ideally, requires different instrument settings for the respective mass ranges investigated. Therefore, we split a full scan range of m/z 50-1000 relevant for metabolites into two separate segments (m/z 50-200 and m/z 200-1,000), allowing an independent tuning of the ion transmission parameters for both mass ranges. Three different implementations, involving either scanning from m/z 50-1000 in a single scan, or scanning from m/z 50-200 and from m/z 200-1000 in two alternating scans, or performing two separate HPLC-MS runs with m/z 50-200 and m/z 200-1000 scan ranges were critically assessed. The detected features were subjected to rigorous background filtering and quality control in order to obtain reliable metabolite features for subsequent differential quantification. The most efficient approach in terms of feature number, which forms the basis for statistical analysis, identification, and for generating biological hypotheses, was the separate analysis of two different mass ranges. This lead to an increase in the number of detectable metabolite features, especially in the higher mass range (m/z greater than 400), by 2.5 (negative mode) to 6-fold (positive mode) as compared to analysis involving a single scan range. The total number of features confidently detectable was 560 in positive ion mode, and 436 in negative ion mode.
- Published
- 2016
37. Transcriptomics hit the target: Monitoring of ligand-activated and stress response pathways for chemical testing
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Philip G. Hewitt, Germaine L. Truisi, Sven Stanzel, Konrad Moenks, Céline Parmentier, Lysiane Richert, Anja Wilmes, Alice Limonciel, Arno Lukas, Martin O. Leonard, Lydia Aschauer, Paul Jennings, Stefan O. Mueller, and Annette Kopp-Schneider
- Subjects
Chromatin Immunoprecipitation ,XBP1 ,Databases, Factual ,Population ,Computational biology ,Biology ,Ligands ,Toxicology ,Hazardous Substances ,Cell Line ,Transcriptome ,Stress, Physiological ,Animals ,Humans ,education ,Transcription factor ,Oligonucleotide Array Sequence Analysis ,Genetics ,Regulation of gene expression ,education.field_of_study ,Gene Expression Profiling ,ATF4 ,Sequence Analysis, DNA ,General Medicine ,Gene expression profiling ,Gene Expression Regulation ,Chromatin immunoprecipitation ,Software ,Transcription Factors - Abstract
High content omic methods provide a deep insight into cellular events occurring upon chemical exposure of a cell population or tissue. However, this improvement in analytic precision is not yet matched by a thorough understanding of molecular mechanisms that would allow an optimal interpretation of these biological changes. For transcriptomics (TCX), one type of molecular effects that can be assessed already is the modulation of the transcriptional activity of a transcription factor (TF). As more ChIP-seq datasets reporting genes specifically bound by a TF become publicly available for mining, the generation of target gene lists of TFs of toxicological relevance becomes possible, based on actual protein-DNA interaction and modulation of gene expression. In this study, we generated target gene signatures for Nrf2, ATF4, XBP1, p53, HIF1a, AhR and PPAR gamma and tracked TF modulation in a large collection of in vitro TCX datasets from renal and hepatic cell models exposed to clinical nephro- and hepato-toxins. The result is a global monitoring of TF modulation with great promise as a mechanistically based tool for chemical hazard identification.
- Published
- 2015
38. Development of an in vitro renal epithelial disease state model for xenobiotic toxicity testing
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Wolfgang Dekant, Patricia Bellwon, Frédéric Y. Bois, Konrad Moenks, Martin O. Leonard, Tobias Schmidt, Karin Herrgen, Arno Lukas, Lydia Aschauer, Anja Wilmes, Alice Limonciel, Paul Jennings, Daniel Crean, and Philip G. Hewitt
- Subjects
Organophosphonates ,Protein Array Analysis ,Biology ,Pharmacology ,Toxicology ,Epithelium ,Cell Line ,Xenobiotics ,Nephrotoxicity ,Kidney Tubules, Proximal ,chemistry.chemical_compound ,Toxicity Tests ,Adefovir ,medicine ,Humans ,Hypoxia ,Regulation of gene expression ,Adenine ,General Medicine ,Hypoxia (medical) ,Oxygen ,Gene Expression Regulation ,chemistry ,Toxicity ,Reverse Transcriptase Inhibitors ,Kidney Diseases ,Efflux ,medicine.symptom ,Xenobiotic ,Intracellular ,medicine.drug - Abstract
There is a growing impetus to develop more accurate, predictive and relevant in vitro models of renal xenobiotic exposure. As part of the EU-FP7, Predict-IV project, a major aim was to develop models that recapitulate not only normal tissue physiology but also aspects of disease conditions that exist as predisposing risk factors for xenobiotic toxicity. Hypoxia, as a common micro-environmental alteration associated with pathophysiology in renal disease, was investigated for its effect on the toxicity profile of a panel of 14 nephrotoxins, using the human proximal tubular epithelial RPTECT/TERT1 cell line. Changes in ATP, glutathione and resazurin reduction, after 14 days of daily repeat exposure, revealed a number of compounds, including adefovir dipivoxil with enhanced toxicity in hypoxia. We observed intracellular accumulation of adefovir in hypoxia and suggest decreases in the efflux transport proteins MRP4, MRP5, NHERF1 and NHERF3 as a possible explanation. MRP5 and NHERF3 were also down-regulated upon treatment with the HIF-1 activator, dimethyloxalylglycine. Interestingly, adefovir dependent gene expression shifted from alterations in cell cycle gene expression to an inflammatory response in hypoxia. The ability to investigate aspects of disease states and their influence on renal toxin handling is a key advantage of in vitro systems developed here. They also allow for detailed investigations into mechanisms of compound toxicity of potential importance for compromised tissue exposure.
- Published
- 2015
39. Exploring the quantification of renal adverse outcome pathways
- Author
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Limonciel, Alice, Tebby, Cléo, Gao, Wang, Zgheib, Elias, Murphy, Cormac, Carta, Giada, Aladjov, Hristo, Jennings, Paul, Bois, Frédéric Y., and Civs, Gestionnaire
- Subjects
[SDV.TOX] Life Sciences [q-bio]/Toxicology - Published
- 2018
40. Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases
- Author
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Steven Wink, Paul Jennings, Anja Wilmes, Annette Kopp-Schneider, Alice Limonciel, Xiaoqi Jiang, Frédéric Y. Bois, Elias Zgheib, Bob van de Water, Institut National de l'Environnement Industriel et des Risques (INERIS), Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit Amsterdam [Amsterdam] (VU), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Leiden University, AIMMS, and Molecular and Computational Toxicology
- Subjects
0301 basic medicine ,lcsh:QH426-470 ,transcriptomics, Nrf2, AhR, ATF4, toxicity pathways, toxicogenomic, oxidative stress ,AHR ,Toxicogenomic ,Computational biology ,Biology ,Nrf2 ,NRF2 ,Transcriptome ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,In vivo ,Genetics ,TRANSCRIPTOMICS ,ATF4 ,OXIDATIVE STRESS ,Transcriptomics ,Gene ,Transcription factor ,Genetics (clinical) ,Toxicity pathways ,Liver and kidney ,AhR ,Correction ,TOXICOGENOMIC ,In vitro ,lcsh:Genetics ,030104 developmental biology ,Oxidative stress ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Molecular Medicine ,Toxicogenomics ,TOXICITY PATHWAYS - Abstract
Toxicological responses to chemical insult are largely regulated by transcriptionally activated pathways that may be independent, correlated and partially or fully overlapping. Investigating the dynamics of the interactions between stress responsive transcription factors from toxicogenomic data and defining the signature of each of them is an additional step toward a system level understanding of perturbation driven mechanisms. To this end, we investigated the segregation of the genes belonging to the three following transcriptionally regulated pathways: the AhR pathway, the Nrf2 pathway and the ATF4 pathway. Toxicogenomic datasets from three projects (carcinoGENOMICS, Predict-IV and TG-GATEs) obtained in various experimental conditions (in human and rat in vitro liver and kidney models and rat in vivo, with bolus administration and with repeated doses) were combined and consolidated where overlaps between datasets existed. A bioinformatic analysis was performed to refine pathways' signatures and to create chemical activation capacity scores to classify chemicals by their potency and selectivity of activation of each pathway. With some refinement such an approach may improve chemical safety classification and allow biological read across on a pathway level.Corrigendum: Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases10.3389/fgene.2019.00517
- Published
- 2018
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41. Prediction of microvesicular liver steatosis: a read-across case study with branched carboxylic acids
- Author
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Escher, Sylvia E., Tolosa Pardo, L., Maclennan, R., Stöber, R., Limonciel, A., Fisher, C., Brotzmann, K., Vugt-Lussenburg, B.M. van, Vrijenhoek, N.G., Gräpel, R., and Publica
- Abstract
To date, toxicologists use in vivo animal studies to estimate a threshold below which the exposure of in vivo humans to a compounds is safe. EU-ToxRisk aims to support the use of new approach methods (NAMs), such as in vitro and in silico models, in risk assessment. Here we describe a proof of concept case study that investigates the toxicity of a group of (un)branched aliphatic carboxylic acids. Five carboxylic acids induce microvesicular liver steatosis in repeated dose toxicity studies (termed in vivo positive), whereas six structurally highly similar compounds do not (in vivo negative). Here we demonstrate the use of NAMs for a category approach comprising ethylbutyric acid and valproic acid, 4-ene valproic acid, 2-ethylhexanoic acid and pivalic acid. All compounds were tested in HepG2 cells. Exposure of HepG2 cells to test compounds resulted in lipid accumulation at subcytotoxic concentrations after 1 and 3 days of treatment. The onset of lipid accumulation was seen at lower concentration with longer exposure periods. A panel of 27 CALUX reporter gene assays and BAC GFP reporter cell lines showed activation of cellular stress pathways in acute exposures (up to 72h). All assays distinguish clearly between in vivo positive and negative compounds. The nominal EC20 values correlate to NOELs of in vivo studies. These data are compared to recent results obtained from repeated exposures of 3D HepaRG cells, PHHs and zebra fish embryos. We also used an in silico model to predict the corresponding intracellular concentration in the in vitro models. These data are included as additional information into the in vitro to in vivo correlations. This exemplary category approach demonstrates that NAMs from the EU-ToxRisk predict the toxicity of compounds after repeated exposure in a qualitative and quantitative manner. The continued development of integrated testing strategies represents the beginning of a paradigm shift, reducing, and ultimately replacing, in vivo studies in human risk assessment.
- Published
- 2018
42. Application of three approaches for quantitative AOP development to renal toxicity
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Zgheib, Elias, primary, Gao, Wang, additional, Limonciel, Alice, additional, Aladjov, Hristo, additional, Yang, Huan, additional, Tebby, Cleo, additional, Gayraud, Ghislaine, additional, Jennings, Paul, additional, Sachana, Magdalini, additional, Beltman, Joost B., additional, and Bois, Frederic Y., additional
- Published
- 2019
- Full Text
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43. Corrigendum: Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases
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Zgheib, Elias, primary, Limonciel, Alice, additional, Jiang, Xiaoqi, additional, Wilmes, Anja, additional, Wink, Steven, additional, van de Water, Bob, additional, Kopp-Schneider, Annette, additional, Bois, Frederic Y., additional, and Jennings, Paul, additional
- Published
- 2019
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44. Persistence of Epigenomic Effects After Recovery From Repeated Treatment With Two Nephrocarcinogens
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Limonciel, Alice, primary, van Breda, Simone G., additional, Jiang, Xiaoqi, additional, Tredwell, Gregory D., additional, Wilmes, Anja, additional, Aschauer, Lydia, additional, Siskos, Alexandros P., additional, Sachinidis, Agapios, additional, Keun, Hector C., additional, Kopp-Schneider, Annette, additional, de Kok, Theo M., additional, Kleinjans, Jos C. S., additional, and Jennings, Paul, additional
- Published
- 2018
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45. Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline
- Author
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Oliver Kohlbacher, Marc Rurik, Roland Reischl, Silke Ruzek, Alice Limonciel, Paul Jennings, Christian G. Huber, Wolfgang Dekant, Christina Ranninger, Anja Wilmes, and Philip G. Hewitt
- Subjects
Metabolite ,Antineoplastic Agents ,Acetaldehyde ,Computational biology ,Biology ,Proteomics ,Bioinformatics ,Tandem mass spectrometry ,Biochemistry ,Cell Line ,Transcriptome ,chemistry.chemical_compound ,Metabolomics ,Tandem Mass Spectrometry ,Liquid chromatography–mass spectrometry ,Metabolome ,Humans ,Chloroacetaldehyde ,Molecular Biology ,Chromatography, High Pressure Liquid ,Nephrons ,Cell Biology ,Metabolism ,chemistry ,Software - Abstract
Untargeted metabolomics has the potential to improve the predictivity of in vitro toxicity models and therefore may aid the replacement of expensive and laborious animal models. Here we describe a long term repeat dose nephrotoxicity study conducted on the human renal proximal tubular epithelial cell line, RPTEC/TERT1, treated with 10 and 35 μmol·liter(-1) of chloroacetaldehyde, a metabolite of the anti-cancer drug ifosfamide. Our study outlines the establishment of an automated and easy to use untargeted metabolomics workflow for HPLC-high resolution mass spectrometry data. Automated data analysis workflows based on open source software (OpenMS, KNIME) enabled a comprehensive and reproducible analysis of the complex and voluminous metabolomics data produced by the profiling approach. Time- and concentration-dependent responses were clearly evident in the metabolomic profiles. To obtain a more comprehensive picture of the mode of action, transcriptomics and proteomics data were also integrated. For toxicity profiling of chloroacetaldehyde, 428 and 317 metabolite features were detectable in positive and negative modes, respectively, after stringent removal of chemical noise and unstable signals. Changes upon treatment were explored using principal component analysis, and statistically significant differences were identified using linear models for microarray assays. The analysis revealed toxic effects only for the treatment with 35 μmol·liter(-1) for 3 and 14 days. The most regulated metabolites were glutathione and metabolites related to the oxidative stress response of the cells. These findings are corroborated by proteomics and transcriptomics data, which show, among other things, an activation of the Nrf2 and ATF4 pathways.
- Published
- 2015
46. Persistence of Epigenomic Effects After Recovery From Repeated Treatment With Two Nephrocarcinogens
- Author
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Limonciel, Alice, van Breda, Simone G., Jiang, Xiaoqi, Tredwell, Gregory D., Wilmes, Anja, Aschauer, Lydia, Siskos, Alexandros P., Sachinidis, Agapios, Keun, Hector C., Kopp-Schneider, Annette, de Kok, Theo M., Kleinjans, Jos C. S., Jennings, Paul, Limonciel, Alice, van Breda, Simone G., Jiang, Xiaoqi, Tredwell, Gregory D., Wilmes, Anja, Aschauer, Lydia, Siskos, Alexandros P., Sachinidis, Agapios, Keun, Hector C., Kopp-Schneider, Annette, de Kok, Theo M., Kleinjans, Jos C. S., and Jennings, Paul
- Abstract
The discovery of the epigenetic regulation of transcription has provided a new source of mechanistic understanding to long lasting effects of chemicals. However, this information is still seldom exploited in a toxicological context and studies of chemical effect after washout remain rare. Here we studied the effects of two nephrocarcinogens on the human proximal tubule cell line RPTEC/TERT1 using high-content mRNA microarrays coupled with miRNA, histone acetylation (HA) and DNA methylation (DM) arrays and metabolomics during a 5-day repeat-dose exposure and 3 days after washout. The mycotoxin ochratoxin A (OTA) was chosen as a model compound for its known impact on HA and DM. The foremost effect observed was the modulation of thousands of mRNAs and histones by OTA during and after exposure. In comparison, the oxidant potassium bromate (KBrO3) had a milder impact on gene expression and epigenetics. However, there was no strong correlation between epigenetic modifications and mRNA changes with OTA while with KBrO3 the gene expression data correlated better with HA for both up-and down-regulated genes. Even when focusing on the genes with persistent epigenetic modifications after washout, only half were coupled to matching changes in gene expression induced by OTA, suggesting that while OTA causes a major effect on the two epigenetic mechanisms studied, these alone cannot explain its impact on gene expression. Mechanistic analysis confirmed the known activation of Nrf2 and p53 by KBrO3, while OTA inhibited most of the same genes, and genes involved in the unfolded protein response. A few miRNAs could be linked to these effects of OTA, albeit without clear contribution of epigenetics to the modulation of the pathways at large. Metabolomics revealed disturbances in amino acid balance, energy catabolism, nucleotide metabolism and polyamine metabolism with both chemicals. In conclusion, the large impact of OTA on transcription was confirmed at the mRNA level but also with
- Published
- 2018
47. EU-ToxRisk - Prediction of microvesicular liver steatosis : read across case study with VPA and analogues
- Author
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Grapel, Rabea, Tluczkiewicz, Inga, Abdelaziz, Ahmed, van Vugt, Barbara, Fisher, Ciaran, Hatley, Oliver, Pawar, Gopal, Zdrazil, Barbara, Jain, Sankalp, Bois, Frédéric Y., Tolosa, Laia, Jennings, Paul, Limonciel, Alice, Stober, Regina, Maclennan, Richard, Exner, Thomas, Lindberg, Johann, Brotzmann, Katharina, Braunbeck, Thomas, Norinder, Ulf, Taboreau, Olivier, Drewe, Will, Long, Tony, Aguayo, Alejandro, Bischoff, Luc, Hengstler, Jan, Escher, Sylvia, and Civs, Gestionnaire
- Subjects
[SDV.TOX] Life Sciences [q-bio]/Toxicology - Published
- 2017
48. Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases
- Author
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Zgheib, Elias, primary, Limonciel, Alice, additional, Jiang, Xiaoqi, additional, Wilmes, Anja, additional, Wink, Steven, additional, van de Water, Bob, additional, Kopp-Schneider, Annette, additional, Bois, Frederic Y., additional, and Jennings, Paul, additional
- Published
- 2018
- Full Text
- View/download PDF
49. Delineation of the Key Aspects in the Regulation of Epithelial Monolayer Formation
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Philip G. Hewitt, Walter Pfaller, Martin O. Leonard, Regina Grillari, Toby J. Athersuch, Abdulhameed Khan, Alice Limonciel, Rachel Cavill, Paul Jennings, Anja Wilmes, Leonhard Gruber, Gerhard Gstraunthaler, Johannes Grillari, Lydia Aschauer, Toxicogenomics, RS: GROW - School for Oncology and Reproduction, and RS: FSE DACS
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Magnetic Resonance Spectroscopy ,Gene Expression ,Biology ,Kidney Tubules, Proximal ,Mesoderm ,Adherens junction ,Transcriptome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Antigens, CD ,Cell Movement ,Gene expression ,Cell Adhesion ,Transcriptional regulation ,Humans ,Cilia ,Cell adhesion ,Telomerase ,Molecular Biology ,Transcription factor ,Cells, Cultured ,Fatty acid synthesis ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Cadherin ,Gene Expression Profiling ,Fatty Acids ,G1 Phase ,Epithelial Cells ,Adherens Junctions ,Articles ,Cell Biology ,Cadherins ,Cell biology ,Oxygen ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Claudins ,Glycogen ,Transcription Factors - Abstract
The formation, maintenance, and repair of epithelial barriers are of critical importance for whole-body homeostasis. However, the molecular events involved in epithelial tissue maturation are not fully established. To this end, we investigated the molecular processes involved in renal epithelial proximal-tubule monolayer maturation utilizing transcriptomic, metabolomic, and functional parameters. We uncovered profound dynamic alterations in transcriptional regulation, energy metabolism, and nutrient utilization over the maturation process. Proliferating cells exhibited high glycolytic rates and high transcript levels for fatty acid synthesis genes (FASN), whereas matured cells had low glycolytic rates, increased oxidative capacity, and preferentially expressed genes for beta oxidation. There were dynamic alterations in the expression and localization of several adherens (CDH1, -4, and -16) and tight junction (TJP3 and CLDN2 and -10) proteins. Genes involved in differentiated proximal-tubule function, cilium biogenesis (BBS1), and transport (ATP1A1 and ATP1B1) exhibited increased expression during epithelial maturation. Using TransAM transcription factor activity assays, we could demonstrate that p53 and FOXO1 were highly active in matured cells, whereas HIF1A and c-MYC were highly active in proliferating cells. The data presented here will be invaluable in the further delineation of the complex dynamic cellular processes involved in epithelial cell regulation.
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- 2013
50. Adverse outcome pathways:opportunities, limitations and open questions
- Author
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Leist, Marcel, Ghallab, Ahmed, Graepel, Rabea, Marchan, Rosemarie, Hassan, Reham, Bennekou, Susanne Hougaard, Limonciel, Alice, Vinken, Mathieu, Schildknecht, Stefan, Waldmann, Tanja, Danen, Erik, van Ravenzwaay, Ben, Kamp, Hennicke, Gardner, Iain, Godoy, Patricio, Bois, Frederic Y, Braeuning, Albert, Reif, Raymond, Oesch, Franz, Drasdo, Dirk, Höhme, Stefan, Schwarz, Michael, Hartung, Thomas, Braunbeck, Thomas, Beltman, Joost, Vrieling, Harry, Sanz, Ferran, Forsby, Anna, Gadaleta, Domenico, Fisher, Ciarán, Kelm, Jens, Fluri, David, Ecker, Gerhard, Zdrazil, Barbara, Terron, Andrea, Jennings, Paul, van der Burg, Bart, Dooley, Steven, Meijer, Annemarie H, Willighagen, Egon, Martens, Marvin, Evelo, Chris, Mombelli, Enrico, Taboureau, Olivier, Mantovani, Alberto, Hardy, Barry, Koch, Bjorn, Escher, Sylvia, van Thriel, Christoph, Cadenas, Cristina, Kroese, D, van de Water, Bob, Hengstler, Jan G, Leist, Marcel, Ghallab, Ahmed, Graepel, Rabea, Marchan, Rosemarie, Hassan, Reham, Bennekou, Susanne Hougaard, Limonciel, Alice, Vinken, Mathieu, Schildknecht, Stefan, Waldmann, Tanja, Danen, Erik, van Ravenzwaay, Ben, Kamp, Hennicke, Gardner, Iain, Godoy, Patricio, Bois, Frederic Y, Braeuning, Albert, Reif, Raymond, Oesch, Franz, Drasdo, Dirk, Höhme, Stefan, Schwarz, Michael, Hartung, Thomas, Braunbeck, Thomas, Beltman, Joost, Vrieling, Harry, Sanz, Ferran, Forsby, Anna, Gadaleta, Domenico, Fisher, Ciarán, Kelm, Jens, Fluri, David, Ecker, Gerhard, Zdrazil, Barbara, Terron, Andrea, Jennings, Paul, van der Burg, Bart, Dooley, Steven, Meijer, Annemarie H, Willighagen, Egon, Martens, Marvin, Evelo, Chris, Mombelli, Enrico, Taboureau, Olivier, Mantovani, Alberto, Hardy, Barry, Koch, Bjorn, Escher, Sylvia, van Thriel, Christoph, Cadenas, Cristina, Kroese, D, van de Water, Bob, and Hengstler, Jan G
- Abstract
Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.
- Published
- 2017
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