Aop:134

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Status

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

https://aopwiki.org/aops/134


AOP Title

Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals
Short name: NIS and Cognitive Dysfunction

Authors

Mary Gilbert, National Health and Environmental Effects Research Laboratory, US EPA, RTP, NC USA <gilbert.mary@epa.gov>

Anna Price, European Commission Joint Research Centre, Institute for Health and Consumer Protection, Ispra, Italy <anna.price@jrc.ec.europa.eu>

Kevin Crofton, National Center for Computational Toxicology, US EPA, RTP, NC USA <crofton.kevin@epa.gov>

Status

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Under development: Do not distribute or cite.

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

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Abstract

This AOP describes one adverse outcome that results from the inhibition of the sodium iodine symporter (NIS) during mammalian development. Inhibition of NIS, the molecular-initiating event (MIE), results in decreased iodine uptake, decreased thyroidal iodine content, subsequent decreased synthesis of thyroid hormones (THs), and reduction in circulating levels of THs. THs are essential for normal human brain development, both prenatally and postnatally. Therefore, chemicals that interfere with TH synthesis have the potential to cause TH insufficiency that may result in adverse neurodevelopmental effects in offspring. This AOP includes changes in brain TH concentrations and subsequent impacts on hippocampal development that lead to declines in cognitive spatial behavior. The weight of evidence for this AOP is strong. And, while there are currently computational quantitative models that can predict serum TH levels from NIS inhibition, there is currently a lack of quantitative understanding of the degree of serum TH disruption that leads to the adverse outcome.

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Na+/I- symporter (NIS), Inhibition Strong

Key Events

Event Support for Essentiality
Thyroidal iodide uptake, Decreased Strong
Thyroid hormone synthesis, Decreased Strong
Thyroxin (T4) in serum, Decreased Strong
Thyroxine (T4) in neuronal tissue, Decreased Strong
Hippocampal gene expression, Altered Moderate
Hippocampal anatomy, Altered Moderate
Hippocampal function, Decreased Moderate

Adverse Outcome

Adverse Outcome
Cognitive Function, Decreased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Na+/I- symporter (NIS), Inhibition Directly Leads to Thyroidal iodide uptake, Decreased Strong Strong
Thyroidal iodide uptake, Decreased Directly Leads to Thyroid hormone synthesis, Decreased Strong Strong
Thyroid hormone synthesis, Decreased Directly Leads to Thyroxin (T4) in serum, Decreased Strong Strong
Thyroxin (T4) in serum, Decreased Directly Leads to Thyroxine (T4) in neuronal tissue, Decreased Strong Weak
Thyroxine (T4) in neuronal tissue, Decreased Directly Leads to Hippocampal gene expression, Altered Moderate Weak
Hippocampal gene expression, Altered Directly Leads to Hippocampal anatomy, Altered Moderate Weak
Hippocampal anatomy, Altered Directly Leads to Hippocampal function, Decreased Moderate Weak
Hippocampal function, Decreased Directly Leads to Cognitive Function, Decreased Moderate Weak
Thyroxin (T4) in serum, Decreased Indirectly Leads to Cognitive Function, Decreased Strong Weak

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Life Stage Applicability

Life Stage Evidence Links
Perinatal Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
rat Rattus sp. Strong NCBI
Homo sapiens Homo sapiens Strong NCBI

Sex Applicability

Sex Evidence Links
Male Strong
Female Strong

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References