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AOP: 134

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

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

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

NIS and Cognitive Dysfunction

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 v1.0

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

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

Mary Gilbert (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Mary Gilbert
Kevin Crofton

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on April 27, 2026 07:27

Revision dates for related pages

Page	Revision Date/Time
Inhibition, Na+/I- symporter (NIS)	April 27, 2026 05:31
Thyroid hormone synthesis, Decreased	November 04, 2022 09:25
Decrease of Thyroidal iodide	April 04, 2019 09:00
Thyroxine (T4) in serum, Decreased	October 10, 2022 08:52
Thyroxine (T4) in neuronal tissue, Decreased	April 04, 2019 09:13
Hippocampal gene expression, Altered	August 11, 2018 09:26
Hippocampal anatomy, Altered	July 24, 2024 23:09
Hippocampal Physiology, Altered	July 24, 2024 23:15
Cognitive function, decreased	July 25, 2024 17:23
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	October 10, 2022 08:56
T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased	April 04, 2019 10:50
T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered	August 11, 2018 19:18
Hippocampal gene expression, Altered leads to Hippocampal anatomy, Altered	August 11, 2018 19:05
Hippocampal anatomy, Altered leads to Hippocampal Physiology, Altered	July 25, 2024 18:38
Hippocampal Physiology, Altered leads to Cognitive function, decreased	July 26, 2024 12:57
T4 in serum, Decreased leads to Cognitive function, decreased	April 27, 2026 05:59

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

424

Inhibition, Na+/I- symporter (NIS)

KE	277	Thyroid hormone synthesis, Decreased	TH synthesis, Decreased
KE	425	Decrease of Thyroidal iodide	Thyroidal Iodide, Decreased
KE	281	Thyroxine (T4) in serum, Decreased	T4 in serum, Decreased
KE	280	Thyroxine (T4) in neuronal tissue, Decreased	T4 in neuronal tissue, Decreased
KE	756	Hippocampal gene expression, Altered	Hippocampal gene expression, Altered
KE	757	Hippocampal anatomy, Altered	Hippocampal anatomy, Altered
KE	758	Hippocampal Physiology, Altered	Hippocampal Physiology, Altered

402

Cognitive function, decreased

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

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

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Perinatal	High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

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

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Male	High
Female	High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Taxonomic: According to the evaluation of the empirical taxonomic domain of applicability (tDOA) of an adverse outcome pathway network for thyroid hormone system disruption (THSD) by Haigis et al., 2023, the level of confidence for a linkage between NIS inhibition and reduced thyroid hormone (TH) levels as well as for a linkage between THSD and developmental neurotoxicity (DNT) in general, was considered high for mammals and moderate for amphibians. For fish, the level of confidence was evaluated to be moderate for a linkage between NIS inhibition and reduced TH levels and high for a linkage between THSD and DNT in general. In addition, the level of confidence was considered moderate for birds for a linkage between THSD and DNT in general. This was supported by structural protein conservation analysis by Lalone et al., 2018 and Haigis et al., 2023. Structural protein conservation of mammalian, fish, amphibian, reptilian and avian NIS was found compared to the human (Homo sapiens) protein target using the U.S. Environmental Protection Agency’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS v6.0; seqapass.epa.gov/seqapass/) tool, while acknowledging the potential existence of interspecies differences in conservation. However, evidence specifically linking THSD to impaired learning and memory in nonmammalian vertebrates is generally missing. No empirical evidence linking NIS inhibition to THSD was found for reptiles and birds. Furthermore, no empirical evidence linking THSD to decreased cognitive function was found for reptiles, but this taxon is considered part of the plausible tDOA based on the evaluation by Haigis et al., 2023. Scientific inference and the presence of comparable neurological structures indicate that decreased cognitive function can plausibly be measured and is plausibly linked to THSD (Hussan et al., 2022, Naumann et al., 2015, Rivera and Lock, 2008).

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

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

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Haigis A-C., Vergauwen L., LaLone C.A., Villeneuve D.L., O'Brien J.M., Knapen D. (2023). Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption. Toxicol Sci. 195, 1-27.

Hussan, M. T., Sakai, A., and Matsui, H. (2022). Glutamatergic pathways in the brains of turtles: A comparative perspective among reptiles, birds, and mammals. Front. Neuroana. 16, 937504.

Lalone, C. A., Villeneuve, D. L., Doering, J. A., Blackwell, B. R., Transue, T. R., Simmons, C. W., Swintek, J., Degitz, S. J., Williams, A. J., and Ankley, G. T. (2018).

Naumann, R. K., Ondracek, J. M., Reiter, S., Shein-Idelson, M., Tosches, M. A., Yamawaki, T. M., and Laurent, G. (2015). The reptilian brain. Curr. Biol. 25, R317–R321

Rivera, S., and Lock, B. (2008). The reptilian thyroid and parathyroid glands. Vet. Clin. North Am. Exot. Anim. Pract. 11, 163–175, viii.