This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 746

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

T4 in neuronal tissue, Decreased

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Hippocampal gene expression, Altered

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Low	Evgeniia Kazymova (send email)	Open for citation & comment	WPHA/WNT Endorsed
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Low	Evgeniia Kazymova (send email)	Under Development: Contributions and Comments Welcome
Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent			Evgeniia Kazymova (send email)	Open for adoption	Under Development
AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	High	Moderate	Cataia Ives (send email)	Under development: Not open for comment. Do not cite
AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	Moderate	Moderate	Brendan Ferreri-Hanberry (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	Moderate	NCBI
mouse	Mus musculus	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
During brain development	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Many cellular and biochemical effects of thyroid hormones (TH) are mediated through regulation of gene expression (Oppenheimer, 1983; Bernal, 2007). Thyroxine (T4) is transferred from the serum to the brain (see KER: Thyroxine (T4) in Serum, Decreased leads to Thyroxine (T4) in Neuronal Tissue, Decreased), where it converted to triiodothyronine (T3), the level of which is highly controlled by deiodinases. T3 binds to thyroid receptors (TR) in the nucleus of neuronal and glial cells to control gene expression. It is generally accepted that the modulation of TR gene expression in the hippocampus, or any other brain region, must therefore depend on the presence of hormone in these tissues.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

There are no inconsistencies in this KER, but there are uncertainties. Uncertainties remain in the relationship of neuronal TH concentrations and gene expression in the brain because of the lack of studies simultaneously examining brain hormone and gene expression in the same study. This stems from the technological challenges associated with measuring brain hormone and the sometimes-subtle changes in brain gene expression induced by manipulations of the thyroid system. In addition, there are also some physiological actions of T4 that are mediated non-genomically at the cell membrane (Davis et al., 2016). However, the exact role for the non-genomic effects is not well accepted or understood (Galton, 2017).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

There is only one study available to date that provides empirical data on both TH concentrations and measures of gene expression changes in brain. O'Shaughnessy et al (2018) demostrates dose-response relationships between brain T4 and T3 concentrations and changes in a variety of genes (e.g., Parv, Col11a2, Hr, Ngf) that were "statistically significant at doses that decreased brain t4 and/or T3". There was no quantitation of this relationship reported.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Most of the data available has come from rodent models. The evolutionary conservation of thyroid receptors (Holzer et al., 2017) coupled with their role in TR regulated gene transcription in neurodevelopment, suggests that this KER may also be applicable to other species (see text above).