Aop: 300

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

Thyroid Receptor Antagonism 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
TR Antagonism and DNT

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
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Authors

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

Kevin M. Crofton, R3Fellows LLC, Durham, NC USA <croftonwork@outlook.com> <orcid.org/0000-0003-1749-9971>

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
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. More help
  • 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. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.84 Included in OECD Work Plan
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
Antagonism, Thyroid Receptor January 11, 2021 10:14
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
TR Antagnoism leads to Hippocampal gene expression, Altered June 08, 2019 17:42
TR Antagnoism leads to Cognitive Function, Decreased June 08, 2019 17:48
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

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 may result from the antagoism of thyroid receptors (TR) durng brain. Chemical or other stressor antagnoism of TR, the molecular-initiating event (MIE), results in abnormal gene transcription.  TR mediated genes are essential for normal mammalian brain development, both prenatally and postnatally, and abnormal modulation of the these genes during critical developmental windows for brain development can resutl in atypical  neuroanatomical and neurophysiocal development, with subsequent adverse effects on teh developmetn of cognitive functions.  Therefore, chemicals or other stressors that interfere with TR mediated genes have the potential to cause  result in adverse neurodevelopmental effects in offspring. Herein, we discuss the implications of developmental TR antagonism for hippocampal anatomy, function, and ultimately neural function controlled by the hippocampus. The biochemistry of normal  TR function is well known across species. The hippocampus is known to be critically involved in cognitive, emotional, and memory function. The adverse consequences of TR antagnoism depends the severity, developmental timing, and impacts on different TR isoforms, indicating that exposure to TR antagonoists may produce different effects at different developmental windows of exposure. The overall weight of evidence for this AOP is strong. Gaps in our understanding include the roles of TR isoforms and the relationship of TH-dependent gene expression in the complexities of brain development. Although quantitative information at all levels of KERs is limited a number of applications of this AOP have been identified.

Note that this AOP links the MIE, TR antagonism through a new KER to an existing KE in the AOP42.  So all of the KEs, KERs and AO subsequent to the new MIE and KE already exist in the AOPWIki and have been reviewed by EAGMST.

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 1656 Antagonism, Thyroid Receptor TR Antagnoism
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. More help

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
During brain development 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
human Homo sapiens High NCBI
mouse Mus musculus 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
  • Chemicals: This AOP may be restricted to a limited number of chemical structures that antagonize thyroid receptors.  Recent work from high-throughput testing of the Tox21 library of pharmaceutial and environmental chemcials suggests that only a 3 of the 8,305 unique structures tested were confirmed as antagonists (Paul-Friedman et al., 2019).  This is likely due to the very restrictive ligand-binding pocket for TRs (Meerts et al. 2001).
  • Sex: This AOP applies to males and females. Disruption of thyroid receptor mediated gene expression during fetal and early postnatal develop, as well as the subsequent adverse impacts on nervous system development are similar in both sexes. There are no compelling data to suggest sex differences in susceptibility.
  • Life stages: The relevant life stages for this AOP are fetal and early postnatal ages during critical windows of nervous system development where thyroid receptor gene expresion guides normal development of the brain. Many studies have demonstrated clear windows of developmental susceptibility, with different brain regions showing distinct ontogenetic profiles for TH driven brain development.  It should be noted that the majority of evidence for this statement is derived from stressor expsoures that alter TH levels in tissues rather than perturbations of TR action. This AOP does not apply to adult life states.
  • Taxonomic: Based on the majority of the available evidence the taxonomic applicability domains of this AOP is mammals. Most evidence for this AOP has been gathered primarily from laboratory rodents and humans. However, there are supporting data from amphibians demonstrating the importance of TR mediatived gene expresion for development of the brain.  Due to the conserved nature of TR transcriptional activity, this AOP is likely to be applicable to other classes of vertebrates where thyroid hormones drive development of the nervous system (e.g., birds, fish, reptiles). However, species-specific differences in development and compensatory endocrine responses may influence the outcomes, particularly from a quantitative standpoint.

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

It is widely accepted that each of the key events is essential.

  • Molecular Initiating Event: The molecular initiating event, i.e. antagonism fo TRs, is the essential event that initiates this AOP, as supported by in vitro and in vivo evidence. TRs control and mediate a wide varity of genes during development.  A number of studies have demonstrated that mutations in TRA1 and TRa2 result in clear alteration in gene expression in the developing brain.
  • Hippocampal Gene Expression, Altered: It is well established specific genomic pathways underlie the progression of a number of neurodevelopmental processes in the hippocampus. There is some evidence from ex vivo studies that administration of growth factors will reverse the hippocampal dysplasia seen in Jacob/Nsfm knockout mice (Spilker et al., 2016). Less is known about the impact of hormone replacement on TH-responsive gene expression and the qualitative and quantitative relationships between altered TH-dependent gene expression in this brain region and altered hippocampal cytoarchitectural anatomy.
  • Hippocampal anatomy, altered: It is well accepted that normal hippocampal anatomy is critical for hippocampal physiological function, and that alterations in anatomy lead to altered neuronal activity in the hippocampus (Lee et al., 2015; Grant et al., 1992; Spilker et al., 2016).
  • Hippocampal physiology, altered: It is a well-accepted assertion that hippocampal synaptic integrity and neuronal plasticity are essential for spatial information processing in animals and spatial and episodic memory in humans. However, other brain regions also can influence these complex behaviors. Limited data from studies in BDNF knockout animals demonstrate that deficits in hippocampal synaptic transmission and plasticity, and downstream behaviors can be rescued with recombinant BDNF (Aarse et al., 2016; Andero et al., 2014).
  • Cognitive function, decreased: It is a well-known fact that TH are critical for normal nervous system development (Williams et al., 2008). And this includes development of the hippocampus which plays a major role in spatial, temporal, and contextual memory. Indeed, most developed countries check for childhood hypothyroidism at birth to immediately begin replacement therapy. This has been shown to alleviate most adverse impacts of hypothyroidism in congenitally hypothyroid children (Derksen-Lubsen and Verkerk 1996; Zoeller and Rovet, 2004). The essentiality of the relationship between decreased TH levels and this adverse outcome is well accepted. Decreased cognitive function specific to the hippocampal region are particularly associated with decrements in memory and learning domains of cognition.

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

Quantitative Understanding

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

Assessment of quantitative understanding of the AOP:  Currently, there are no data that allow a quantiative assement of the impact of modulation of TR mediated gene expression and changes in gene expression in the brain.  The majority of the evidence for the KER linking the MIE to altered gene expression in the brain is derived from TR knockout models in mice and mutations in both mice and humans.  For the rest of the KERs in this AOP, there is a limited amount of data from dose-response studies (mostly from studies on TPO inhition - see AOP42)  demonstrating increasing impact with increasing chemical dose for all the KEs, and the direct and indirect KERs. At present, the overall quantitative understanding of the AOP is insufficient to directly link a measure of chemical potency as a TR antagonist to a quantitative prediction of effect on cognitive function (e.g., IQ in humans, learning deficits in rodents). Empirical information on dose-response relationships for the MIE and intermediate KEs, currently unavailable, would inform a computational, predictive model for TR antagonist mediated gene changes that resutl in adverse congnitive development.

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

Applications of the AOP for chemical induced changes in cognitive development may be limited by the very restrictive ligand-binding pockets for TRs (Meerts et al. 2001).

References

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