Excel · study · 2026
Beyond hazard identification: Discovering mechanisms of action from a ToxCast chemical screen in zebrafish
Listed in NCBI GEO
Large-scale chemical screens are important tools for hazard identification and chemical prioritization, but they less commonly progress from identifying a phenotype to identifying its mechanism.
Description
Here, we used zebrafish embryos to screen 4,657 chemicals from the U.S. EPA ToxCast Phase III library for disruption of embryonic development and advanced selected hits through sequential validation using original library stocks, independently sourced chemicals, concentration-response analysis, transcriptomics, and functional experiments.
Of 61 primary hits subjected to repeat testing, 33 reproduced the original phenotype, and four of eight compounds subsequently tested using independently sourced chemicals exhibited reproducible concentration-dependent developmental toxicity. We prioritized two of these compounds, purpurin and 4-aminoazobenzene (4-AAB), for transcriptomic analysis because the mechanisms underlying their developmental toxicity were not well understood.
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Transcriptomic analysis of purpurin-exposed embryos revealed coordinated suppression of pathways involved in calcium regulation, ion transport, and neuronal signaling. 4-Aminoazobenzene produced a transcriptional response characterized by suppression of neuronal and receptor-mediated signaling and activation of cellular stress pathways. Increasing extracellular calcium produced a concentration-dependent rescue of purpurin-induced developmental abnormalities, whereas equivalent magnesium supplementation did not, supporting a role for calcium availability or homeostasis in purpurin developmental toxicity.
These results demonstrate that large-scale in vivo toxicity screening can be integrated with independent chemical validation and functional follow-up to move beyond hazard identification toward mechanistic understanding of how environmental chemicals disrupt embryonic development.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE345nnn/GSE345664 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE345664 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1521443 ncbi.nlm.nih.gov/bioproject/PRJNA1521443 ↗
project · from NCBI GEO
Topics
- Stated by source
- Danio rerio · Expression profiling by high throughput sequencing
- From keywords
- Life Sciences
Provenance · 1 source records, 7 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE345664 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:7955 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |