PUBLICATION
Multi-behavioral fingerprints can identify potential modes of action for neuroactive environmental chemicals
- Authors
- Herold, N.K., Gutsfeld, S., Leuthold, D., Wray, C., Spath, J., Tal, T.
- ID
- ZDB-PUB-250513-8
- Date
- 2025
- Source
- Neurotoxicology : (Journal)
- Registered Authors
- Keywords
- DNT, Multi-behavioral phenotyping, behavioral profiling, developmental neurotoxicity, neuroactivity fingerprints, zebrafish
- MeSH Terms
-
- Dose-Response Relationship, Drug
- Larva/drug effects
- Behavior, Animal*/drug effects
- Motor Activity/drug effects
- Reflex, Startle/drug effects
- Animals
- Habituation, Psychophysiologic/drug effects
- Zebrafish
- PubMed
- 40354900 Full text @ Neurotoxicology
Citation
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. :.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping