Aop:94

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/94


AOP Title

Sodium channel inhibition leading to congenital malformations
Short name: sodium channel inhibition

Authors

Kellie Fay

Status

OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification Please follow the link to snapshots page to view and create Snapshots of this AOP.

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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Abstract

Anti-epileptic and anti-arrhythmic drugs which block voltage-gated ion channels (e.g., voltage-gated sodium channels) are associated with major congenital malformations including amputations.


Background (optional)

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
sodium channel, Inhibition Strong

Key Events

Event Support for Essentiality
Atrioventricular block and bradycardia, Increased
Respiratory distress/arrest, Increased
hypoxia, N/A
Sodium conductance, Decreased Strong

Adverse Outcome

Adverse Outcome
amputations, Increased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Atrioventricular block and bradycardia, Increased Directly Leads to Respiratory distress/arrest, Increased Moderate
Respiratory distress/arrest, Increased Directly Leads to hypoxia, N/A
hypoxia, N/A Indirectly Leads to amputations, Increased Moderate
sodium channel, Inhibition Directly Leads to Sodium conductance, Decreased Strong
Sodium conductance, Decreased Directly Leads to Atrioventricular block and bradycardia, Increased Moderate

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Life Stage Applicability

Life Stage Evidence Links
Foetal Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
Human, rat, mouse

Sex Applicability

Sex Evidence Links

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
Mammals exposed in utero to sodium channel blockers (or similar) have significantly higher rates of cardiovascular anomalies and amputations (shortened limbs, missing digits, etc). Hypoxic conditions generated from poor heart function during development result in hemorrhages in distal parts of the embryo/fetus (Danielsson et al., 2003; Webster et al., 1996; Webster 2007). Similar amputations may not be relevant for species which develop in an egg and receive their oxygen supply via diffusion from the surrounding environment (air or water).

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
Rat whole embryo cultures exposed to sodium channel blockers (experimental drugs AZA and AZB)for 1 hr had severly reduced heart rates (bradycardia) but returned to normal within 1 hr of drug washout (Nilsson et al., 2013).

Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

References

Danielsson, B.R., Skold, A., and Azarbayjani, F. 2001. Class III Antiarrhythmics and Phenytoin: Teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage. Current Pharmaceutical Design 7:787-802.

Webster, W., Brown-Woodman, P., Snow, M., and Danielsson, B. 1996. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology 53:168-175.

Webster, W.S. and Abela, D. 2007. The effect of hypoxia in development. Birth Defects Research Part C: Embryo Today: Reviews 81:215-228.