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Relationship: 1143


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 serum, Decreased leads to Decreased, Thyroxine (T4) in tissues

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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

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
Xenopus laevis Xenopus laevis Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

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

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

Thyroxine (T4) uptake from serum into tissues plays a substantial role in thyroid hormone action, as it can then be available for enzymatic conversion to the active hormone, triiodothyronine (T3). Uptake of T4 into cells/tissues is mediated by active transport proteins that exhibit unique expression profiles depending on tissue type and timing of development (Hennemann et al., 2001; Visser et al., 2011, 2007; Connors et al., 2010; Friesema et al., 2005). Specific regulation of transporter profiles plays a role in timing of thyroid hormone uptake into specific tissues for proper sequencing of development and protection against metabolism and clearance of thyroid hormone during critical developmental periods. Although several different classes of proteins have been identified as capable of transporting T4 (and T3) across plasma membranes, three proteins in particular have been shown to have high affinity and specificity toward thyroid hormone; namely, MCT8, MCT10 and OATP1c1 (Friesema et al., 2003, 2008; Pizzagalli et al., 2002; Jansen et al., 2007; Mayer et al., 2014). These transport proteins have primarily been studied in relation to mammalian brain development, so the details of their role in other species and tissues during vertebrate development are not well-understood.

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 Supporting this KER

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

The evidence supporting this KER is strong but is primarily weighted toward biochemical associations and thyroid endocrinology dogma. Specifically, much of the weight of evidence is centered around what is known about active and selective membrane transport of T4, ontogeny of deiodinase enzymes responsible for the localized metabolic activation/deactivation of T4 and tissue/organ pathologies and gene expression responses associated with hyper and hypothyroid conditions.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Thyroid hormone uptake from plasma into tissues is mediated by a number of active transport proteins exhibiting unique profiles depending on tissue type and timing of development (Hennemann et al., 2001; Visser et al., 2011; Connors et al., 2010). The scientific literature suggests that specific regulation of transporter profiles plays a role in timing of thyroid hormone uptake into specific tissues. However, when thyroid hormone levels in the plasma are deficient, it is highly plausible that tissue levels of thyroid hormone will also be deficient. Studies have shown a strong relationship between plasma and tissue thyroid hormone concentrations, but emphasize the complexity of the relationship due to presumptive local regulation of both active transport and subsequent biochemical modification of thyroid hormone within cells by deiodinase enzymes.

Decreases in tissue T4 could plausibly occur in several ways individually or in combination, (1) circulating levels of T4 decrease to critical levels that even compensatory increases in active transport cannot overcome, (2) TH-specific transporters are non-functional either due to mutation, inhibited by a xenobiotic or their transcriptional expression is repressed, (3) enhanced T4 catabolism by type III deiodinase in peripheral tissues or by phase II metabolic enzymes in the liver.

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

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


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