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Relationship: 1389


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 Hippocampal Physiology, Altered

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

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 non-adjacent Moderate Low Evgeniia Kazymova (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 High NCBI
mouse Mus musculus High NCBI
human Homo sapiens 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

Thyroid hormones are critical for normal development of the structure and function of the brain, including the hippocampus (Anderson et al., 2003; Bernal, 2007). Brain concentrations of T4 are dependent on transport of primarily T4 from serum, with subsequent conversion to T3 in the astrocytes by deiodinase and transfer to nuclear receptors within the neuron. This is followed by TH dependent gene transcription that influences hippocampal structural development and subsequent physiological function.

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 weight of evidence for this indirect relationship is moderate. A wide variety studies have been performed in several labs in which thyroid hormone reductions in serum induced by chemicals/treatments, acting at a variety of target sites to disrupt hormonal status, is coincident with altered hippocampal physiology and/or plasticity. These include inhibition of TPO, NIS, dietary insufficiencies of iodine, and upregulation of liver catabolism, NIS inhibition, or dietary manipulation of iodine. Most of the data available is from the model TPO inhibitors, PTU and MMI, and this data documents enduring hippocampal physiological impairments in adult offspring following a period of transient serum TH insufficiencies in the pre- and post-natal period. Serum hormones are reported for the neonate and the dam at the termination of exposure, and recovery of hormonal status in the adult has been demonstrated in a number of studies despite the persistence of the hippocampal deficit. A few laboratories have reported dose-dependent effects at less than maximal hormone depletion.

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

The biological plausibility of this KER is rated as strong. The relationship is consistent with the known biology of how TH control development of hippocampal physiology.

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 some remaining uncertainties. It is widely accepted that changes in serum THs during development will result in alterations in behavior controlled by the hippocampus. This has been repeatedly demonstrated in animal models and in humans. However, most studies have been performed under conditions of severe hypothyroidism induced primarily by TPO-inhibitors MMI and PTU, or severe iodine deficiency. In addition, it is also known that there is an interaction between physiological and anatomical development, where anatomy develops first, and can be ‘reshaped’ by the ongoing maturation of physiological function (e.g., Kutsarova et al., 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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Insufficient data exist to date that could be used to develop a quantitative predictive model of neurophysiological in hippocampus from serum TH concentrations. The dynamic range over which neurophysiological endpoints can vary is small complicating the development of quantitative relationships between degree of TH insufficiency and magnitude of neurophysiological impairment.

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 to support this KER are derived from rodent studies.


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

Anderson GW, Schoonover CM, Jones SA (2003) Control of thyroid hormone action in the developing rat brain. Thyroid 13:1039-56.

Bernal J. 2007. Thyroid hormone receptors in brain development and function. Nature clinical practice Endocrinology & metabolism. 3:249-259.

Dong J, Yin H, Liu W, Wang P, Jiang Y, Chen J. Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicol 2005; 26:417-426.

Gilbert ME. Perinatal exposure to polychlorinated biphenyls alters excitatory synaptic transmission and short-term plasticity in the hippocampus of the adult rat. Neurotoxicology. 2003 Dec;24(6):851-60.

Gilbert ME. Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Brain Res Dev 2004 Jan 31;148(1):11-8

Gilbert ME. Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci. 2011;124(2):432-445.

Gilbert ME, Hedge JM, Valentín-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW. An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci. 2013 Mar;132(1):177-95.

Gilbert ME, Paczkowski C. Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus. Brain Res Dev Brain Res. 2003 Oct 10;145(1):19-29

Gilbert ME, Sanchez-Huerta K, Wood C. Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology. 2016 Feb;157(2):774-87.

Gilbert ME, Sui L. Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res. 2006 Jan 19;1069(1):10-2

Gilbert ME, Sui L. Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat. Environ Health Perspect. 2008 Jun;116(6):752-60.

Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH. Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology. 2007 Jan;148(1):92-102. PubMed PMID: 17008398.

Kozorovitskiy Y, Saunders A, Johnson CA, Lowell BB, Sabatini BL. Recurrent network activity drives striatal synaptogenesis. Nature. 2012 May 13;485(7400):646-50.

Sánchez-Huerta K, Pacheco-Rosado J, Gilbert ME. Adult onset-hypothyroidism: alterations in hippocampal field potentials in the dentate gyrus are largely associated with anaesthesia-induced hypothermia. J Neuroendocrinol. 2015 Jan;27(1):8-19.

Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PM, Kavlock R, Kimmel G, Klaunig J, Meek ME, Preston RJ, Slikker W Jr, Tabacova S, Williams GM, Wiltse J, Zoeller RT, Fenner-Crisp P, Patton DE.  Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol. 2005 35:664-72.

Sui L, Anderson WL, Gilbert ME. Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci. 2005 May;85(1):647-56.

Sui L, Gilbert ME. Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology. 2003 Sep;144(9):4195-203.

Taylor MA, Swant J, Wagner JJ, Fisher JW, Ferguson DC. Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology. Endocrinology. 2008 Jul;149(7):3521-30. doi: 10.1210/en.2008-0020. PubMed PMID: 18372327.

Vara H, Muñoz-Cuevas J, Colino A. Age-dependent alterations of long-term synaptic plasticityin thyroid-deficient rats. Hippocampus. 2003;13(7):816-25.

Westerholz S, de Lima AD, Voigt T. Thyroid hormone-dependent development of early cortical networks: temporal specificity and the contribution of trkB and mTOR pathways. Front Cell Neurosci. 2013 Aug 6;7:121.

Westerholz S, de Lima AD, Voigt T. Regulation of early spontaneous network activity and GABAergic neurons development by thyroid hormone. Neuroscience. 2010Jun 30;168(2):573-89.