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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

Graphical Representation

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Click to download graphical representation template

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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   (email point of contact)

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 Do not cite 1.29 Under Development


This AOP was last modified on January 27, 2018 15:34

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Revision dates for related pages

Page Revision Date/Time
Inhibition, Na+/I- symporter (NIS) May 29, 2018 06:25
Thyroid hormone synthesis, Decreased May 31, 2018 19:43
Decrease of Thyroidal iodide September 16, 2017 10:17
Thyroxine (T4) in serum, Decreased June 02, 2018 09:41
Thyroxine (T4) in neuronal tissue, Decreased June 02, 2018 09:45
Hippocampal gene expression, Altered June 02, 2018 09:47
Hippocampal anatomy, Altered June 02, 2018 09:48
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 29, 2018 07:24
Thyroidal Iodide, Decreased leads to TH synthesis, Decreased June 04, 2018 06:11
TH synthesis, Decreased leads to T4 in serum, Decreased June 04, 2018 06:03
T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased June 02, 2018 12:05
T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered June 02, 2018 11:09
Hippocampal gene expression, Altered leads to Hippocampal anatomy, Altered June 02, 2018 11:12
Hippocampal anatomy, Altered leads to Hippocampal Physiology, Altered June 02, 2018 11:15
Hippocampal Physiology, Altered leads to Cognitive Function, Decreased April 17, 2017 08:34
T4 in serum, Decreased leads to Cognitive Function, Decreased June 02, 2018 11:36

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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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 424 Inhibition, Na+/I- symporter (NIS) Inhibition, Na+/I- symporter (NIS)
2 KE 277 Thyroid hormone synthesis, Decreased TH synthesis, Decreased
3 KE 425 Decrease of Thyroidal iodide Thyroidal Iodide, Decreased
4 KE 281 Thyroxine (T4) in serum, Decreased T4 in serum, Decreased
5 KE 280 Thyroxine (T4) in neuronal tissue, Decreased T4 in neuronal tissue, Decreased
6 KE 756 Hippocampal gene expression, Altered Hippocampal gene expression, Altered
7 KE 757 Hippocampal anatomy, Altered Hippocampal anatomy, Altered
8 KE 758 Hippocampal Physiology, Altered Hippocampal Physiology, Altered
9 KE 426 Decreased, Thyroxine (T4) in serum Decreased, Thyroxine (T4) in serum
10 AO 402 Cognitive Function, Decreased Cognitive Function, Decreased

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, Decreased adjacent High High
Thyroidal Iodide, Decreased leads to TH synthesis, Decreased adjacent High High
TH synthesis, Decreased leads to T4 in serum, Decreased adjacent High High
T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased adjacent High Low
T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered adjacent Moderate Low
Hippocampal gene expression, Altered leads to Hippocampal anatomy, Altered adjacent Moderate Low
Hippocampal anatomy, Altered leads to Hippocampal Physiology, Altered adjacent Moderate Low
Hippocampal Physiology, Altered leads to Cognitive Function, Decreased adjacent Moderate Low
T4 in serum, Decreased leads to Cognitive Function, Decreased non-adjacent High Low

Network View

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Stressors

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Life Stage Applicability

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Life stage Evidence
Perinatal High

Taxonomic Applicability

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

Sex Applicability

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Sex Evidence
Male High
Female High

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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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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