Publication Details |
| Category | Text Publication |
| Reference Category | Journals |
| DOI | 10.1016/j.neuro.2025.05.001 |
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| Title (Primary) | Multi-behavioral fingerprints can identify potential modes of action for neuroactive environmental chemicals |
| Author | Herold, N.K.; Gutsfeld, S.; Leuthold, D.; Wray, C.; Spath, J.; Tal, T.
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| Source Titel | NeuroToxicology |
| Year | 2025 |
| Department | ETOX |
| Volume | 108 |
| Page From | 377 |
| Page To | 399 |
| Language | englisch |
| Topic | T9 Healthy Planet |
| Data and Software links | https://doi.org/10.17632/97f3yffwz9.1 |
| Supplements | Supplement 1 Supplement 2 Supplement 3 Supplement 4 |
| Keywords | Multi-behavioral phenotyping; behavioral profiling; neuroactivity fingerprints; developmental neurotoxicity; DNT; zebrafish |
| Abstract | There is a lack of confidence in the relevance of zebrafish-based behavior data for chemical risk assessment. We extended an automated Visual and Acoustic Motor Response (VAMR) new approach method (NAM) in 5-day post-fertilization (dpf) zebrafish to include 26, behavior-based endpoints that measure visual-motor responses, visual and acoustic startle responses, habituation learning, and memory retention. A correlation analysis from 5,159 control larvae revealed that more complex endpoints for learning- and memory-related behavior yielded unique behavior patterns. To build confidence in the VAMR NAM, we established neuroactivity fingerprints using concentration-response profiles derived from 63 reference chemicals targeting neurotransmission, neurodevelopmental signaling, or toxicologically-relevant pathways. Hierarchical clustering revealed diverse toxicity fingerprints. Compounds that targeted the N-Methyl-D-aspartic acid (NMDA) or gamma-aminobutyric acid type A (GABAA) receptors reduced habituation learning. Pathway modulators targeting peroxisome proliferator-activated receptor delta (PPARδ) or gamma (PPARγ), GABAA, dopamine, ryanodine, aryl hydrocarbon (AhR), or G-protein-coupled receptors or the tyrosine kinase SRC inappropriately accelerated habituation learning. Reference chemicals targeting GABAA, NMDA, dopamine, PPARα, PPARδ, epidermal growth factor, bone morphogenetic protein, AhR, retinoid X, or α2-adreno receptors triggered inappropriate hyperactivity. Exposure to GABAA receptor antagonists elicited paradoxical excitation characterized by dark-phase sedation and increased startle responses while exposure to GABAA/B receptor agonists altered the same endpoints with opposite directionality. Relative to reference chemicals, environmental chemicals known to be GABA receptor antagonists (Lindane, Dieldrine) or agonists (Tetrabromobisphenol A (TBBPA)) elicited predicted behavior fingerprints. When paired with the phenotypically rich VAMR NAM, behavior fingerprints are a powerful approach to identify neuroactive chemicals. |
| Persistent UFZ Identifier | https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=30773 |
| Herold, N.K., Gutsfeld, S., Leuthold, D., Wray, C., Spath, J., Tal, T. (2025): Multi-behavioral fingerprints can identify potential modes of action for neuroactive environmental chemicals NeuroToxicology 108 , 377 - 399 10.1016/j.neuro.2025.05.001 |
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