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AOP: 572
Title
BMP4 Suppression Disrupting Cytoskeletal Remodeling Leading to Neural Tube Closure Defects
Short name
Graphical Representation
Point of Contact
Contributors
- Job Berkhout
Coaches
OECD Information Table
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This AOP was last modified on April 02, 2025 19:06
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Abstract
Neural tube closure shapes the vertebrate central nervous system. Chick embryos (Liu et al., 2016) show that imidacloprid, a neonicotinoid insecticide, disrupts neurulation by altering BMP4 signaling and cytoskeletal organization in dorsolateral hinge-point (DLHP) regions. This alteration blocks apical constriction and produces an open or mis-patterned neural tube (NTD). Two resources strengthen this AOP: Heusinkveld et al. (2021) developed an ontology-based map of key steps for proper neural tube closure, and Berkhout et al. (2025) provided a computational model that predicts morphological disruptions leading to NTDs. Together, these approaches reveal how BMP4 inhibition, impairs cytoskeletal remodeling, and culminates in neural tube defects.
AOP Development Strategy
Context
Neural tube defects (NTDs) are among the most prevalent congenital malformations in humans. They can arise from both genetic and environmental disruptions to key developmental signaling pathways. This AOP focuses on the inhibition of BMP4, a morphogen essential for cytoskeletal remodeling and dorsolateral hinge-point formation during neurulation. Evidence from chick embryos has shown that imidacloprid, a neonicotinoid insecticide, impairs DLHP formation by reducing BMP4 expression and disrupting cytoskeletal organization (Liu et al., 2016). Recent advances in neural tube closure ontologies (Heusinkveld et al., 2021) and computational modeling (Berkhout et al., 2025) further support the role of BMP4-driven cytoskeletal dynamics in proper neural tube morphogenesis.
Strategy
We assembled this AOP with a multi-step approach:
Literature Mining and Ontology Alignment We began with the detailed ontology of neurulation from Heusinkveld et al. (2021) and focused on cell behaviors needed for neural fold elevation, dorsolateral hinge-point (DLHP) formation, and tube fusion. Next, we screened peer-reviewed articles on imidacloprid, including Liu et al. (2016), along with relevant toxicology databases and neonicotinoid literature. We looked for evidence that tied BMP4 and cytoskeleton changes to neural tube defects (NTDs).
Evaluating Mechanistic Evidence We compared key references on imidacloprid-induced gene expression changes in chick embryonic neural tubes (e.g., decreases in BMP4 transcripts, lower F-actin at the apical side) against canonical morphogen gradients known from mammalian models. We then matched these data to known NTD triggers in mice, such as BMP4 knockouts, Noggin deficiency, or disruptions in dorsolateral bending.
Incorporating Computational Insights Berkhout et al. (2025) developed a dynamic agent-based model for mammalian neural tube closure, and we reviewed their in silico “knockdown” or “hyperactivation” scenarios for BMP4 and antagonists. These simulated open neural tubes, midline fusion defects, or other morphological outcomes. The model’s predictions aligned with experimental data in chick and mouse, and thus reinforced the notion that interrupting BMP4 signaling or cytoskeletal remodeling predisposes embryos to NTDs.
Defining Key Events and Relationships We synthesized in vivo, in vitro, and computational modeling results to name five key events:
- BMP4 expression declines
- Cytoskeleton remodeling fails (loss of apical F-actin)
- Apical constriction stops
- DLHP formation halts
- Neural tube closure defect
Applicability to Regulatory Testing Vertebrates share highly conserved neurulation processes, so these findings may apply across species. However, species-specific features—like the number or placement of hinge points—warrant caution when applying chick or mouse data to humans. This AOP can guide Integrated Approaches to Testing and Assessment (IATA) by highlighting early BMP/cytoskeleton disturbances measurable in embryonic stem cell or neurosphere assays, prior to overt morphological defects.
By combining lab-based experiments, in vivo evidence, and in silico modeling, we built a mechanistically robust pathway from imidacloprid exposure to BMP4 disruption and resulting neural tube defects. This strategy shows the power of linking classical teratological findings with updated ontologies and computational tools to improve regulatory assessments for embryotoxic chemicals.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Relationships Between Two Key Events (Including MIEs and AOs)
Network View
Prototypical Stressors
Life Stage Applicability
Taxonomic Applicability
Sex Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Evidence Assessment
Known Modulating Factors
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