title: In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities.
abstract: Neurotoxicity and developmental neurotoxicity are important issues of chemical hazard assessment. Since the interpretation of animal data and their extrapolation to man is challenging, and the amount of substances with information gaps exceeds present animal testing capacities, there is a big demand for in vitro tests to provide initial information and to prioritize for further evaluation. During the last decade, many in vitro tests emerged. These are based on animal cells, human tumour cell lines, primary cells, immortalized cell lines, embryonic stem cells, or induced pluripotent stem cells. They differ in their read-outs and range from simple viability assays to complex functional endpoints such as neural crest cell migration. Monitoring of toxicological effects on differentiation often requires multiomics approaches, while the acute disturbance of neuronal functions may be analysed by assessing electrophysiological features. Extrapolation from in vitro data to humans requires a deep understanding of the test system biology, of the endpoints used, and of the applicability domains of the tests. Moreover, it is important that these be combined in the right way to assess toxicity. Therefore, knowledge on the advantages and disadvantages of all cellular platforms, endpoints, and analytical methods is essential when establishing in vitro test systems for different aspects of neurotoxicity. The elements of a test, and their evaluation, are discussed here in the context of comprehensive prediction of potential hazardous effects of a compound. We summarize the main cellular characteristics underlying neurotoxicity, present an overview of cellular platforms and read-out combinations assessing distinct parts of acute and developmental neurotoxicology, and highlight especially the use of stem cell-based test systems to close gaps in the available battery of tests.
authors: BioTalentum Ltd., Gödöllő, Hungary.|Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium.
authors: Béla Z
authors: http://orcid.org/0000-0003-1085-9372
authors: BZ
authors: Schmidt
authors: BioTalentum Ltd., Gödöllő, Hungary.|Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Martin
authors: M
authors: Lehmann
authors: Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Constance, Germany.
authors: Simon
authors: S
authors: Gutbier
authors: BioTalentum Ltd., Gödöllő, Hungary.|Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Erastus
authors: E
authors: Nembo
authors: Louvain Centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium.
authors: Sabrina
authors: S
authors: Noel
authors: Center for Alternatives to Animal Testing, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors: Lena
authors: L
authors: Smirnova
authors: Swedish Toxicology Research Center (Swetox), Södertälje, Sweden.|Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
authors: Anna
authors: A
authors: Forsby
authors: Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Jürgen
authors: J
authors: Hescheler
authors: BioTalentum Ltd., Gödöllő, Hungary.|Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
authors: Hasan X
authors: HX
authors: Avci
authors: Center for Alternatives to Animal Testing, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors: Thomas
authors: T
authors: Hartung
authors: Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Constance, Germany.
authors: Marcel
authors: M
authors: Leist
authors: BioTalentum Ltd., Gödöllő, Hungary.
authors: Julianna
authors: J
authors: Kobolák
authors: BioTalentum Ltd., Gödöllő, Hungary. andras.dinnyes@biotalentum.hu.|Molecular Animal Biotechnology Laboratory, Szent István University, Gödöllő, 2100, Hungary. andras.dinnyes@biotalentum.hu.
authors: András
authors: A
authors: Dinnyés
mesh_terms: D000826:Animal Testing Alternatives / Q000639:trends; D000818:Animals; D057205:Automation, Laboratory; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D017408:Guidelines as Topic; D057166:High-Throughput Screening Assays / Q000592:standards; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D018570:Risk Assessment / Q000639:trends; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity*; D023382:Toxicity Tests, Acute / Q000592:standards; D066007:Toxicokinetics; D014116:Toxicology / Q000379:methods* / Q000639:trends
chemical_list: D009153:Mutagens; D009498:Neurotoxins; D013723:Teratogens
keywords: Assay development; Cell death; Developmental neurotoxicity; Electrophysiology; High-throughput screening; In vitro testing; Neurodevelopment; Neurotoxicity; Stem cells