API

Aop: 134

AOP Title

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Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals

Short name:

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NIS and Cognitive Dysfunction

Authors

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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>

Point of Contact

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Mary Gilbert

Contributors

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  • Mary Gilbert
  • Kevin Crofton

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.29 Included in OECD Work Plan


This AOP was last modified on September 19, 2017 09:55

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Revision dates for related pages

Page Revision Date/Time
Inhibition, Na+/I- symporter (NIS) September 16, 2017 10:15
Thyroid hormone synthesis, Decreased September 17, 2017 18:27
Decrease of Thyroidal iodide September 16, 2017 10:17
Thyroxine (T4) in serum, Decreased September 17, 2017 18:37
Thyroxine (T4) in neuronal tissue, Decreased September 17, 2017 17:11
Hippocampal gene expression, Altered September 17, 2017 17:14
Hippocampal anatomy, Altered September 16, 2017 10:14
Hippocampal Physiology, Altered September 17, 2017 17:17
Cognitive Function, Decreased April 16, 2017 13:45
Decreased, Thyroxine (T4) in serum September 16, 2017 10:16
Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, Decreased May 15, 2017 10:07
Thyroidal Iodide, Decreased leads to TH synthesis, Decreased May 15, 2017 10:29
TH synthesis, Decreased leads to T4 in serum, Decreased September 17, 2017 17:36
T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased September 17, 2017 18:09
T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered September 17, 2017 19:12
Hippocampal gene expression, Altered leads to Hippocampal anatomy, Altered April 17, 2017 08:27
Hippocampal anatomy, Altered leads to Hippocampal Physiology, Altered April 17, 2017 08:31
Hippocampal Physiology, Altered leads to Cognitive Function, Decreased April 17, 2017 08:34
T4 in serum, Decreased leads to Cognitive Function, Decreased September 17, 2017 19:22

Abstract

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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.


Background (optional)

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Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
Inhibition, Na+/I- symporter (NIS) Inhibition, Na+/I- symporter (NIS)

Key Events

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Title Short name
Thyroid hormone synthesis, Decreased TH synthesis, Decreased
Decrease of Thyroidal iodide Thyroidal Iodide, Decreased
Thyroxine (T4) in serum, Decreased T4 in serum, Decreased
Thyroxine (T4) in neuronal tissue, Decreased T4 in neuronal tissue, Decreased
Hippocampal gene expression, Altered Hippocampal gene expression, Altered
Hippocampal anatomy, Altered Hippocampal anatomy, Altered
Hippocampal Physiology, Altered Hippocampal Physiology, Altered
Decreased, Thyroxine (T4) in serum Decreased, Thyroxine (T4) in serum

Adverse Outcome

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Title Short name
Cognitive Function, Decreased Cognitive Function, Decreased

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Life stage Evidence
Perinatal Strong

Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus Strong NCBI
Homo sapiens Homo sapiens Strong NCBI

Sex Applicability

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Sex Evidence
Male Strong
Female Strong

Graphical Representation

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Click to download graphical representation template

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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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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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