PMID- 37158368
OWN - NLM
STAT- MEDLINE
DCOM- 20230721
LR  - 20230721
IS  - 1868-8551 (Electronic)
IS  - 1868-596X (Linking)
VI  - 40
IP  - 3
DP  - 2023
TI  - A human iPSC-based in vitro neural network formation assay to investigate 
      neurodevelopmental toxicity of pesticides.
PG  - 452-470
LID - 10.14573/altex.2206031 [doi]
AB  - Proper brain development is based on the orchestration of key neurodevelopmental 
      processes (KNDP), including the for-mation and function of neural networks. If at 
      least one KNDP is affected by a chemical, an adverse outcome is expected. To 
      enable a higher testing throughput than the guideline animal experiments, a 
      developmental neurotoxicity (DNT) in vitro testing battery (DNT IVB) comprising a 
      variety of assays that model several KNDPs was set up. Gap analysis revealed the 
      need for a human-based assay to assess neural network formation and function 
      (NNF). Therefore, we established the human NNF (hNNF) assay. A co-culture 
      comprised of human induced pluripotent stem cell (hiPSC)-derived excitatory and 
      inhibitory neurons as well as primary human astroglia was differentiated for 35 
      days on microelectrode arrays (MEA), and spontaneous electrical activity, 
      together with cytotoxicity, was assessed on a weekly basis after washout of the 
      compounds 24 h prior to measurements. In addition to the characterization of the 
      test system, the assay was challenged with 28 com-pounds, mainly pesticides, 
      identifying their DNT potential by evaluating specific spike-, burst-, and 
      network parameters. This approach confirmed the suitability of the assay for 
      screening environmental chemicals. Comparison of benchmark con-centrations (BMC) 
      with an NNF in vitro assay (rNNF) based on primary rat cortical cells revealed 
      differences in sensitivity. Together with the successful implementation of hNNF 
      data into a postulated stressor-specific adverse outcome pathway (AOP) network 
      associated with a plausible molecular initiating event for deltamethrin, this 
      study suggests the hNNF assay as a useful complement to the DNT IVB.
FAU - Bartmann, Kristina
AU  - Bartmann K
AD  - IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, 
      Germany.
AD  - DNTOX GmbH, Duesseldorf, Germany.
FAU - Bendt, Farina
AU  - Bendt F
AD  - IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, 
      Germany.
FAU - Donmez, Arif
AU  - Donmez A
AD  - IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, 
      Germany.
AD  - DNTOX GmbH, Duesseldorf, Germany.
FAU - Haag, Daniel
AU  - Haag D
AD  - NeuCyte Inc., Mountain View, CA, USA.
FAU - Kessel, H Eike
AU  - Kessel HE
AD  - IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, 
      Germany.
FAU - Masjosthusmann, Stefan
AU  - Masjosthusmann S
AD  - IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, 
      Germany.
FAU - Noel, Christopher
AU  - Noel C
AD  - NeuCyte Inc., Mountain View, CA, USA.
FAU - Wu, Ji
AU  - Wu J
AD  - NeuCyte Inc., Mountain View, CA, USA.
FAU - Zhou, Peng
AU  - Zhou P
AD  - NeuCyte Inc., Mountain View, CA, USA.
FAU - Fritsche, Ellen
AU  - Fritsche E
AD  - IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, 
      Germany.
AD  - DNTOX GmbH, Duesseldorf, Germany.
AD  - Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
LA  - eng
PT  - Journal Article
DEP - 20230503
PL  - Germany
TA  - ALTEX
JT  - ALTEX
JID - 100953980
RN  - 0 (Pesticides)
SB  - IM
MH  - Humans
MH  - Rats
MH  - Animals
MH  - *Induced Pluripotent Stem Cells
MH  - Cells, Cultured
MH  - *Pesticides/toxicity
MH  - Neurons/physiology
MH  - *Neurotoxicity Syndromes/metabolism
OTO - NOTNLM
OT  - developmental neurotoxicity
OT  - electrical activity
OT  - human induced pluripotent stem cells
OT  - microelectrode arrays
OT  - new approach methodologies
EDAT- 2023/05/09 13:42
MHDA- 2023/07/21 06:43
CRDT- 2023/05/09 07:23
PHST- 2022/06/03 00:00 [received]
PHST- 2023/04/24 00:00 [accepted]
PHST- 2023/07/21 06:43 [medline]
PHST- 2023/05/09 13:42 [pubmed]
PHST- 2023/05/09 07:23 [entrez]
AID - 10.14573/altex.2206031 [doi]
PST - ppublish
SO  - ALTEX. 2023;40(3):452-470. doi: 10.14573/altex.2206031. Epub 2023 May 3.