This AOP is licensed under a Creative Commons Attribution 4.0 International License.
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.
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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.
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NIS and Cognitive Dysfunction
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.
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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.
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Evgeniia Kazymova
(email point of contact)
Contributors
Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact.
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- Mary Gilbert
- Kevin Crofton
- Evgeniia Kazymova
Status
Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators.
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| Author status | OECD status | OECD project | SAAOP status |
|---|---|---|---|
| Under Development: Contributions and Comments Welcome | 1.29 | Under Development |
This AOP was last modified on July 16, 2022 18:37
Revision dates for related pages
| Page | Revision Date/Time |
|---|---|
| Inhibition, Na+/I- symporter (NIS) | April 04, 2019 08:52 |
| Thyroid hormone synthesis, Decreased | July 08, 2022 06:44 |
| Decrease of Thyroidal iodide | April 04, 2019 09:00 |
| Thyroxine (T4) in serum, Decreased | July 08, 2022 06:52 |
| Thyroxine (T4) in neuronal tissue, Decreased | April 04, 2019 09:13 |
| Hippocampal gene expression, Altered | August 11, 2018 09:26 |
| Hippocampal anatomy, Altered | May 20, 2022 05:45 |
| Hippocampal Physiology, Altered | August 11, 2018 09:41 |
| Cognitive Function, Decreased | August 09, 2018 11:55 |
| 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 | July 08, 2022 08:05 |
| 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 | August 11, 2018 19:21 |
| Hippocampal Physiology, Altered leads to Cognitive Function, Decreased | August 11, 2018 19:24 |
| T4 in serum, Decreased leads to Cognitive Function, Decreased | August 11, 2018 19:44 |
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.
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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.
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.
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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).
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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.
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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.
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Key Events (KE)
A measurable event within a specific biological level of organisation.
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Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP.
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| Type | Event ID | Title | Short name |
|---|
| MIE | 424 | Inhibition, Na+/I- symporter (NIS) | 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 |
| AO | 402 | Cognitive Function, Decreased | 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.
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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
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.
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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.
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Life Stage Applicability
The life stage for which the AOP is known to be applicable.
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| 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.
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Sex Applicability
The sex for which the AOP is known to be applicable.
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| 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).
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Domain of Applicability
Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context.
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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.
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Evidence Assessment
Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP.
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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.
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Quantitative Understanding
Optional field to provide quantitative weight of evidence descriptors.
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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.
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References
List of the literature that was cited for this AOP.
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