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AOP: 572

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

BMP4 Suppression Disrupting Cytoskeletal Remodeling Leading to Neural Tube Closure Defects

Short name
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BMP4 Inhibition Leading to Neural Tube Closure Defects
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.7

Graphical Representation

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Authors

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Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Job Berkhout   (email point of contact)

Contributors

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  • Job Berkhout

Coaches

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OECD Information Table

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OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on April 02, 2025 19:06

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Abstract

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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

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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

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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

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Events:

Molecular Initiating Events (MIE)
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Key Events (KE)
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Adverse Outcomes (AO)
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Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Prototypical Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Known Modulating Factors

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Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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