Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals
Creators
- Jonathan Blum1
- Stefan Masjosthusmann2
- Kristina Bartmann2
- Farina Bendt2
- Xenia Dolde1
- Arif Dönmez2
- Nils Förster3
- Anna-Katharina Holzer1
- Ulrike Hübenthal2
- Hagen Eike Keßel2
- Sadiye Kilic1
- Jördis Klose2
- Melanie Pahl2
- Lynn-Christin Stürzl2
- Iris Mangas4
- Andrea Terron4
- Kevin M. Crofton5
- Martin Scholze6
- Axel Mosig3
- Marcel Leist1
- Ellen Fritsche2
- 1. In Vitro Toxicology and Biomedicine, Dept Inaugurated By the Doerenkamp-Zbinden Foundation, University of Konstanz
- 2. IUF - Leibniz Research Institute for Environmental Medicine
- 3. Bioinformatics Group, Ruhr University Bochum
- 4. European Food Safety Authority
- 5. R3Fellows LLC
- 6. Institute of Environment Health and Societies, Brunel University London,
Description
Developmental neurotoxicity (DNT) is a major safety concern for all chemicals of the human exposome. However, DNT data from animal studies are available for only a small percentage of manufactured compounds. Test methods with a higher throughput than current regulatory guideline methods, and with improved human relevance are urgently needed. We therefore explored the feasibility of DNT hazard assessment based on new approach methods (NAMs). An in vitro battery (IVB) was assembled from ten individual NAMs that had been developed during the past years to probe effects of chemicals on various fundamental neurodevelopmental processes. All assays used human neural cells at different developmental stages. This allowed us to assess disturbances of: (i) proliferation of neural progenitor cells (NPC); (ii) migration of neural crest cells, radial glia cells, neurons and oligodendrocytes; (iii) differentiation of NPC into neurons and oligodendrocytes; and (iv) neurite outgrowth of peripheral and central neurons. In parallel, cytotoxicity measures were obtained. The feasibility of concentration-dependent screening and of a reliable biostatistical processing of the complex multi-dimensional data was explored with a set of 120 test compounds, containing subsets of pre-defined positive and negative DNT compounds. The battery provided alerts (hit or borderline) for 24 of 28 known toxicants (82% sensitivity), and for none of the 17 negative controls. Based on the results from this screen project, strategies were developed on how IVB data may be used in the context of risk assessment scenarios employing integrated approaches for testing and assessment (IATA).
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Additional details
Funding
- RISK-HUNT3R – RISK assessment of chemicals integrating HUman centric Next generation Testing strategies promoting the 3Rs 964537
- European Commission
- TOX-Free – TOXicity assessment on neurons and cardiomyocytes by means of FluoRescence Emitting Electrodes 964518
- European Commission
- PARC – Partnership for the Assessment of Risks from Chemicals 101057014
- European Commission
- ENDpoiNTs – Novel Testing Strategies for Endocrine Disruptors in the Context of Developmental NeuroToxicity 825759
- European Commission