High Throughput Screening and Test Development
Rapid progress in scientific knowledge as well as the development of emerging technologies offers the opportunity to improve safety assessments of industrial chemicals, chemicals in consumer products as well as pesticides and biocides while reducing the number of experimental animals.
New strategies based on a comprehensive mechanistic understanding of how chemicals can cause adverse effects in humans have been proposed and are currently further developed as part of huge research programmes such as the Research Initiative "Towards the replacement of in vivo repeated dose systemic toxicity testing” that has been launched by the 'Health' Theme of the Directorate General for Research and Innovation of the European Commission and Cosmetics Europe.
Before this new generation of mechanism based in vitro tests can be used in routine toxicological applications, the relevance of these tools needs to be carefully assessed. In this context EURL ECVAM 'Test development and HTS' team is focusing on:
- Development of concepts for the establishment of stem cell based in vitro tests that are able to assess the perturbation of physiological pathways (“toxicity pathways”)
- Analysis of cellular models in particular stem cell models whether they are fit for purpose including the definition of quality controls
- The qualification of selected intermediate effects or biomarker, their sensitivity and specificity
- The suitability of related readout technologies in particular imaging techniques
- Prevalence assessment of “toxicity” pathways in a defined chemical domain by using high throughput screening.
- Toxicological profiling of chemicals and nanoparticles leading to the formation categories based on common mechanisms by using data deriving from high throughput testing
More information on our projects and the laboratories:
- Klaric M, Winkler J, Vojnits K, Meganathan K, Jagtap S, Ensenat-Waser R, Hescheler J, Sachinidis A, Bremer-Hoffmann S. Current status of human pluripotent stem cell based in vitro toxicity tests . Front Biosci (Schol Ed). 2013 Jan 1;5:118-33.
- Francesca Pistollato, Susanne Bremer-Hoffmann, Lyn Healy, Lesley Young & Glyn Stacey Standardization of pluripotent stem cell cultures for toxicity testing. Expert Opin Drug Metab Toxicol 8:239 (2012)
- Silvia Nerini-Molteni, Milena Mennecozzi, Marco Fabbri, Maria Grazia Sacco, Kinga Vojnits, Anna Compagnoni, Laura Gribaldo, Susanne Bremer-Hoffmann, MicroRNA profiling as a tool for pathway analysis in a human in vitro model for neural development. Current Medicinal Chemistry, 201219, 6214-6223
- Vojnits K, Ensenat-Waser R, Gaspar JA, Meganathan K, Jagtap S, Hescheler J, Sachinidis A, Bremer-Hoffmann S. A transcriptomics study to elucidate the toxicological mechanism of methylmercury chloride in a human stem cell based in vitro test. Curr Med Chem. 2012 Dec 1;19(36):6224-32.
- Krug AK, Kolde R, Gaspar JA, Rempel E, Balmer NV, Meganathan K, Vojnits K, Baquié M, Waldmann T, Ensenat-Waser R, Jagtap S, Evans RM, Julien S, Peterson H, Zagoura D, Kadereit S, Gerhard D, Sotiriadou I, Heke M, Natarajan K, Henry M, Winkler J, Marchan R, Stoppini L, Bosgra S, Westerhout J, Verwei M, Vilo J, Kortenkamp A, Hescheler J, Hothorn L, Bremer S, van Thriel C, Krause KH, Hengstler JG, Rahnenführer J, Leist M, Sachinidis A. Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
- Grignard E, Lapenna S, Bremer S., Weak estrogenic transcriptional activities of Bisphenol A and Bisphenol S. Toxicol In Vitro. 2012 Aug;26(5):727-31.
- Stummann TC, Bremer S. Embryonic stem cells in safety pharmacology and toxicology. Adv Exp Med Biol. 2012;745:14-25
- Mandenius CF, Steel D, Noor F, Meyer T, Heinzle E, Asp J, Arain S, Kraushaar U, Bremer S, Class R, Sartipy P, Cardiotoxicity testing using pluripotent stem cell-derived human cardiomyocytes and state-of-the-art bioanalytics: a review. J Appl Toxicol. 2011 Apr;31(3):191-205.
- Schenk B, Weimer M, Bremer S, van der Burg B, Cortvrindt R, Freyberger A, Lazzari G, Pellizzer C, Piersma A, Schäfer WR, Seiler A, Witters H, Schwarz M.The ReProTect Feasibility Study, a novel comprehensive in vitro approach to detect reproductive toxicants. Reprod Toxicol. 2010 Aug;30(1):200-18.
- Pazos P, Pellizzer C, Stummann TC, Hareng L, Bremer S.The test chemical selection procedure of the European Centre for the Validation of Alternative Methods for the EU Project ReProTect. Reprod Toxicol. 2010 Aug;30(1):161-99
- Witters H, Freyberger A, Smits K, Vangenechten C, Lofink W, Weimer M, Bremer S, Ahr PH, Berckmans P. The assessment of estrogenic or anti-estrogenic activity of chemicals by the human stably transfected estrogen sensitive MELN cell line: results of test performance and transferability. Reprod Toxicol. 2010 Aug;30(1):60-72.
- Uibel F, Mühleisen A, Köhle C, Weimer M, Stummann TC, Bremer S, Schwarz M. ReProGlo: a new stem cell-based reporter assay aimed to predict embryotoxic potential of drugs and chemicals. Reprod Toxicol. 2010 Aug;30(1):103-12.
- Vojnits K, Bremer S. Challenges of using pluripotent stem cells for safety assessments of substances. Toxicology. 2010 Mar 30;270(1):10-7. Review.
- Marx-Stoelting P, Adriaens E, Ahr HJ, Bremer S, Garthoff B, Gelbke HP, Piersma A, Pellizzer C, Reuter U, Rogiers V, Schenk B, Schwengberg S, Seiler A, Spielmann H, Steemans M, Stedman DB, Vanparys P, Vericat JA, Verwei M, van der Water F, Weimer M, Schwarz M. A review of the implementation of the embryonic stem cell test (EST). The report and recommendations of an ECVAM/ReProTect Workshop. Altern Lab Anim. 2009 Jul;37(3):313-28. Review.
- Stummann TC, Hareng L, Bremer S. Hazard assessment of methylmercury toxicity to neuronal induction in embryogenesis using human embryonic stem cells. Toxicology. 2009 Mar 29;257(3):117-26.
- Stummann TC, Wronski M, Sobanski T, Kumpfmueller B, Hareng L, Bremer S, Whelan MP. Digital movie analysis for quantification of beating frequencies, chronotropic effects, and beating areas in cardiomyocyte cultures. Assay Drug Dev Technol. 2008 Jun;6(3):375-85.
- Bremer S, Pellizzer C, Hoffmann S, Seidle T, Hartung T. The development of new concepts for assessing reproductive toxicity applicable to large scale toxicological programmes. Curr Pharm Des. 2007;13(29):3047-58. Review.
- Stummann TC, Beilmann M, Duker G, Dumotier B, Fredriksson JM, Jones RL, Hasiwa M, Kang YJ, Mandenius CF, Meyer T, Minotti G, Valentin YJ, Zünkler BJ, Bremer S. Report and recommendations of the workshop of the European Centre for the Validation of Alternative Methods for Drug-Induced Cardiotoxicity. Cardiovasc Toxicol. 2009 Sep;9(3):107-25
Photos: a) Cell plate. Copyright EU 2012. b) In House QCs for iPSCs characterization. Copyright EU 2012.