Archives of Toxicology

, Volume 91, Issue 1, pp 1–33

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities

  • Béla Z. Schmidt
  • Martin Lehmann
  • Simon Gutbier
  • Erastus Nembo
  • Sabrina Noel
  • Lena Smirnova
  • Anna Forsby
  • Jürgen Hescheler
  • Hasan X. Avci
  • Thomas Hartung
  • Marcel Leist
  • Julianna Kobolák
  • András Dinnyés
Review Article

DOI: 10.1007/s00204-016-1805-9

Cite this article as:
Schmidt, B.Z., Lehmann, M., Gutbier, S. et al. Arch Toxicol (2017) 91: 1. doi:10.1007/s00204-016-1805-9

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.

Keywords

Stem cells Neurodevelopment Electrophysiology Cell death High-throughput screening Assay development In vitro testing Neurotoxicity Developmental neurotoxicity 

Abbreviations

AD

Alzheimer’s disease

ALS

Amyotrophic lateral sclerosis

APC

Automated patch-clamp

ASD

Autism spectrum disorders

BBB

Blood–brain barrier

CMP

Cell membrane potential

CNS

Central nervous system

DA

Dopaminergic

DNT

Developmental neurotoxicity

ECs

Endothelial cells

ENT

Engineered neural tissue

ER

Endoplasmic reticulum

EST

Embryonic stem cell test

FI

Fluorescence intensity

FTD

Frontotemporal dementia

hESCs

Human embryonic stem cells

hiPSCs

Human-induced pluripotent stem cells

HT

High throughput

IATA

Integrated approaches to testing and assessment

ITS

Integrated testing strategies

KE

Key event

MEA

Multielectrode array or microelectrode array

NPC

Neural progenitor cell

NT

Neurotoxicity

OECD

Organisation for Economic Co-operation and Development

PD

Parkinson’s disease

PNS

Peripheral nervous system

SOD1

Cu/Zn-binding superoxide dismutase

TALEN

Transcription activator-like effector nucleases

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Béla Z. Schmidt
    • 1
    • 2
  • Martin Lehmann
    • 1
    • 3
  • Simon Gutbier
    • 4
  • Erastus Nembo
    • 1
    • 3
  • Sabrina Noel
    • 5
  • Lena Smirnova
    • 6
  • Anna Forsby
    • 7
    • 8
  • Jürgen Hescheler
    • 3
  • Hasan X. Avci
    • 1
    • 9
  • Thomas Hartung
    • 6
  • Marcel Leist
    • 4
  • Julianna Kobolák
    • 1
  • András Dinnyés
    • 1
    • 10
  1. 1.BioTalentum Ltd.GödöllőHungary
  2. 2.Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, Stem Cell Institute LeuvenKU LeuvenLeuvenBelgium
  3. 3.Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC)University of CologneCologneGermany
  4. 4.Doerenkamp-Zbinden Chair for In Vitro Toxicology and BiomedicineUniversity of KonstanzConstanceGermany
  5. 5.Louvain Centre for Toxicology and Applied PharmacologyUniversité Catholique de LouvainBrusselsBelgium
  6. 6.Center for Alternatives to Animal Testing, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA
  7. 7.Swedish Toxicology Research Center (Swetox)SödertäljeSweden
  8. 8.Department of NeurochemistryStockholm UniversityStockholmSweden
  9. 9.Department of Medical ChemistryUniversity of SzegedSzegedHungary
  10. 10.Molecular Animal Biotechnology LaboratorySzent István UniversityGödöllőHungary

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