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Relationship: 1506

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

TH synthesis, Decreased leads to Impairment, Learning and memory

Upstream event

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

TH synthesis, Decreased

Downstream event

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

Impairment, Learning and memory

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 Na+/I- symporter (NIS) leads to learning and memory impairment	non-adjacent	High	Moderate	Arthur Author (send email)	Open for citation & comment	WPHA/WNT Endorsed

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
human	Homo sapiens	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
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

It is widely accepted that the thyroid hormones (TH) play a prominent role in the development and function of the CNS, including hippocampus and neocortex, two critical brain structure closely linked to the cognitive function (Gilbert et al., 2012). Brain concentrations of T4 are dependent on transfer of T4 from serum, through the vascular endothelia, into astrocytes. In astrocytes, T4 is converted to T3 by deiodinase and subsequently transferred to neurons cellular membrane transporters. In the brain T3 controls transcription and translation of genes responsible for normal hippocampal structural and functional development. Normal hippocampal structure and physiology are critical for the development of cognitive function. Thus, there is an indisputable indirect link between TH synthesis, controlling the levels of T4 in serum, and cognitive function, including learning and memory processes.

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

Numerous studies reported that iodine deficiency in critical periods of brain development and growth causes severe and permanent growth and cognitive impairment (cretinism) (Pesce and Kopp, 2014; de Escobar et al., 2007; de Escobar et al., 2008; Zimmermann, 2007; Melse-Boonstra and Jaiswal, 2010; Horn and Heuer, 2010; Zimmermann, 2012). However, direct quantitative correlation between decreased TH synthesis (as a consequence of TPO inhibition) and decreased cognition, in support to this KER, were not assessed in these reports.

Moreover, Wheeler et al., 2012 used fMRI visuospatial memory task to assess hippocampal activation in adolescents with CH (N = 14; age range, 11.5-14.7 years) compared with controls (N = 15; age range, 11.2-15.5 years). Despite, adolescents with congenital hypothyroidism showed both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls, no group differences were recorded in task performance.

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

Temporal concordance between decrease of TH synthesis and disrupted brain development leading to learning and memory impairment has repeatedly been documented by demonstrating that there are critical windows during brain development where permanent changes are triggered. Hormone replacement studies have also demonstrated that structural alterations in brain are reduced or eliminated if T4 (and/or T3) treatment is given during critical developmental windows (Goodman and Gilbert., 2007; Auso et al., 2004; Lavado-Autric et al., 2003; Berbel et al., 2010; Koibuchi and Chin, 2000). However, quantitative data in support of this indirect KER are not available.

Response-response Relationship

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

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

Deficiencies in learning and memory following developmental hypothyroidism (TH synthesis inhibition) have been documented mainly in rodents and humans.