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Relationship: 1388

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 serum, Decreased leads to Hippocampal anatomy, Altered

Upstream event

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

T4 in serum, Decreased

Downstream event

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

Hippocampal anatomy, 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	non-adjacent	High	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

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

The vast majority of brain thyroxine (T4) is from the serum. Once taken up from the serum, T4 is converted to triiodothyronine (T3) which binds to the nuclear receptors (TRα and TRβ) to control thyroid-mediated gene expression (Oppenheimer, 1983). It is well established that TH regulates genes critical for brain development (Bernal, 2007; Anderson et al., 2003). As such, the structural development of the hippocampus is modulated by TR-mediated gene transcription, and alterations in serum TH can adversely impact hippocampal neuroanatomy.

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 strong. There is a vast amount of literature that supports this KER in multiple species.

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 the regulation of serum TH concentrations, brain TH concentrations, and the known action of TH to modulate genes critical for developmental processes that control structural development of the brain in general, including the hippocampus.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The empirical support for this KER is strong. In humans, untreated congenital hypothyroidism and severe iodine deficiency are accompanied by reductions in circulating levels of TH, and result in severe structural alterations in brain size, including hippocampus (Wheeler et al., 2011). The tie to serum TH has been amply demonstrated in clinical therapy of hypothyroidism during pregnancy and in congenitaly hypothyroid children born to euthroid mothers. In addition, there is a vast amount of data from animal studies that support this relationship. Gross structural changes in the hippocampus following severe TH insufficiency are widely reported (Hasegawa et al., 2010; Powell et al.,2010; Madiera et al., 1991; 1992; Rami et al. 1986a 1986b; Madeira and Paula-Barbosa 1993; Rabie et al., 1980; Berbel et al., 1996). Other studies reveal more subtle changes in hippocampal structure such as reductions in a specific subregions of the hippocampus or of a cell type (eg. parvalbumin expressing inhibitory neurons) or synaptic component (ie synapsin, postsynaptic density proteins) or misplacement of cells within the hippocampal cell layers (Berbel et al., 1997; 2010; Gilbert et al., 2007; Auso et al., 2003; Gilbert et al., 2016; Cattani et al., 2013). These observations at the histological level are correlated with reductions in serum T4. The most profound structural impairments are typically seen with severe reductions in both hormones.

Additional evidence for a relationship between serum TH and hippocampal anatomy comes from the study of adult neurogenesis. The propensity of the hippocampus to generate new neurons throughout the lifetime of the organism occurs in only two brain regions, the olfactory bulb and the hippocampus. Severe reductions in circulating levels of TH in adulthood reduces both neuroprogenitor cell proliferation and survival of newly generated neurons in the neurogenic niche of the hippocampal dentate gyrus (Ambrogini et al., 2005, Montero-Pedrazuela et al., 2006, Kapoor et al., 2015). These same effects on neurogenesis also occur during development. However, the impact of developmental TH disruption on neurogenesis in adult offspring shows that the developing brain is more sensitive to these persistent effects. For example, a reduction in the capacity for neurogenesis was recently demonstrated in adult euthyroid offspring of developmentally TH compromised dams (Gilbert et al., 2016). These data indicate a permanent deficit in the capacity for neurogenesis, a process that controls dentate gyrus volume and cell number, following moderate reductions in serum TH in the fetus/neonate.

Finally, from in vitro studies, T3 stimulation accelerates the formation of GABAergic boutons and alters the distribution of GABAergic axons among growing neurons in culture. This growth is dependent on both activity within the network and the presence of T3. It can be blocked by the T3 nuclear receptor antagonist, 1-850, or pharmacological block of synaptic activity (Westerholz et al., 2010; 2013). T3 is believed to have this effect by it action on synaptic pruning. This example reveals the dynamic interplay between synaptic activity and neuroanatomy in the developing nervous system (Kozorovitskiy 2012).

Temporal Evidence: The temporal nature of this KER is developmental (Seed et al., 2005). It is a well-recognized fact that there are critical developmental windows for disruption of the serum THs that result in altered hippocampal anatomy. Reductions in serum TH in the neonate produced alterations in hippocampal parvalbumin-expressing neurons while the same treatment in adulthood is without effect (Gilbert et al., 2007). In a rodent model of prenatal TH deficiency, decreased length and number of radial glial cells which are critical for neuronal migration was reversed by hormone replacement treatment to the dam (Pathak et al., 2011). Reversibility of cortical layering defects with thyroxine treatment have also been reported in models of maternal hypothyroidism (Pathak et al., 2011; Berbel et al., 2010; Mohan et al., 2012). In in vitro studies, temporal specificity of the influence of T3 on GABAergic synapses and synaptic pruning has also been demonstrated (Westerholz et al., 2013). In addition, clinical therapy of hypothyroidism during pregnancy, and in congenitally hypothyroid children born to euthroid mothers ameliorates most of the adverse impacts on the developing human brain.

Dose-Response Evidence: There are limited data available to inform the dose-dependent nature of the correlation between serum THs and changes in hippocampal anatomy. Gilbert et al (2007) demonstrated dose-dependent declines in the expression of protein marker inhibitory neurons in both hippocampus and neocortex with graded exposures to PTU and resultant serum T4. Shiraki et al. (2014; 2016) report dose-dependent alterations in the expression patterns of several neuronal and glial protein markers in the hippocampus after developmental exposure to different doses of PTU or MMI. Gilbert et al. (2016) report dose-dependent reductions in linear morphometry and volume of hippocampal subfields following developmental exposure to the PTU.

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

This has been repeatedly demonstrated. However, with some studies noted above, most investigations have been conducted in the neonate after severe hormone reductions induced by PTU, MMI or thyroidectomy. These severe changes alter a wide variety of general growth and developmental processes. In one of the few dose-response studies assessing hippocampal anatomy, alterations in simple guidenline metrics of linear morphometry and volume of hippocampal subfields following developmental exposure to the PTU were largely restricted to the high dose group, despite alterations in downstream KEs of hippocampal physiology and cognitive function. This may result from inadequacy of the assessment tools or the timing of the observations. Similarly, in chemically induced serum hormone reductions of comparable magnitude as those induced by PTU or MMI, observations of hippocampal morphology are not always seen (PTU vs ETU or mancozeb, European Commission, 2017). Consideration of the sensitivity of neuroanatomical and neurobehavioral method used, as well as chemical kinetics that drive the reduction of maternal, fetal, or neonatal TH reduction, may be key to understanding these discrepancies. More data is needed that link more limited decrements in serum TH to specific hippocampal anatomical changes. The role of direct fetal TPO inhibition contribution to fetal TH and subsequent changes to hippocampal structure and subsequent downstream KEs in humans is a knowledge gap.

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

Most investigations for hippocampal anatomy have been conducted in the neonate after severe hormone reductions. There is currently insufficient data for quantitative analysis of serum T4 and hippocampal neuroanatomy.

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 available data has come from rodent models. Human clinincal studies have documented changes in hippocampal volume in children with congenital hypothyroidism (Wheeler et al., 2011).

References

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

Ambrogini P, Cuppini R, Ferri P, Mancini C, Ciaroni S, Voci A, Gerdoni E, Gallo G (2005) Thyroid hormones affect neurogenesis in the dentate gyrus of adult rat. Neuroendocrinology 81:244-253.

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

Auso E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escobar G, Berbel P (2004) A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 145:4037-4047.

Berbel P, Marco P, Cerezo JR, DeFelipe J (1996) Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats. Neurosci Lett 204:65-68.

Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM. Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity. Cereb Cortex. 2010 Jun;20(6):1462-75.

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

Cattani D, Goulart PB, Cavalli VL, Winkelmann-Duarte E, Dos Santos AQ,

Pierozan P, de Souza DF, Woehl VM, Fernandes MC, Silva FR, Gonçalves CA, Pessoa-Pureur R, Zamoner A. Congenital hypothyroidism alters the oxidative status, enzyme activities and morphological parameters in the hippocampus of developing rats. Mol Cell Endocrinol. 2013 Aug 15;375(1-2):14-26.

Gilbert ME, Goodman JH, Gomez J, Johnstone AF, Ramos RL. Adult hippocampal neurogenesis is impaired by transient and moderate developmental thyroid hormone disruption. Neurotoxicology. 2016. 59:9-21.

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

Hasegawa M, Kida I, Wada H (2010) A volumetric analysis of the brain and hippocampus of rats rendered perinatal hypothyroid. Neurosci Lett 479:240-244.

Kapoor R, Fanibunda SE, Desouza LA, Guha SK, Vaidya VA (2015) Perspectives on thyroid hormone action in adult neurogenesis. J Neurochem 133:599-616.

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

Madeira MD, Cadete-Leite A, Andrade JP, Paula-Barbosa MM (1991) Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 314:171-186.

Madeira MD, Paula-Barbosa MM (1993) Reorganization of mossy fiber synapses in male and female hypothyroid rats: a stereological study. J Comp Neurol 337:334-352.

Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A, Paula-Barbosa MM (1992) Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322:501-518.

Mohan V, Sinha RA, Pathak A, Rastogi L, Kumar P, Pal A, Godbole MM (2012) Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis. Exp Neurol 237:477-488.

Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernandez-Lamo I, Garcia-Verdugo JM, Bernal J, Guadano-Ferraz A (2006) Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry 11:361-371.

Oppenheimer J. The nuclear-receptor-triiodothyronine complex: Relationship to thyroid hormone distribution, metabolism, and biological action, In: Samuels HH, eds: Molecular Basis of Thyroid Hormone Action. Academic Press: New York. 1983: 1-34.

Pathak A, Sinha RA, Mohan V, Mitra K, Godbole MM (2011) Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration. Cereb Cortex 21:11-21.

Powell MH, Nguyen HV, Gilbert M, Parekh M, Colon-Perez LM, Mareci TH, Montie E (2012) Magnetic resonance imaging and volumetric analysis: novel tools to study the effects of thyroid hormone disruption on white matter development. Neurotoxicology 33:1322-1329.

Rabie A, Clavel MC, Legrand J (1980) Analysis of the mechanisms underlying increased histogenetic cell death in developing cerebellum of the hypothyroid rat: determination of the time required for granule cell death. Brain Res 190:409-414.

Rami A, Patel AJ, Rabie A (1986a) Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience 19:1217-1226.

Rami A, Rabie A, Patel AJ (1986b) Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus. Neuroscience 19:1207-1216.

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.

Shiraki A, Saito F, Akane H, Takeyoshi M, Imatanaka N, Itahashi M, Yoshida T, Shibutani M (2014) Expression alterations of genes on both neuronal and glial development in rats after developmental exposure to 6-propyl-2-thiouracil. Toxicol Lett 228:225-234.

Shiraki A, Saito F, Akane H, Akahori Y, Imatanaka N, Itahashi M, Yoshida T, Shibutani M. Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism. J Appl Toxicol. 2016 Jan;36(1):24-34.

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. 7:121.

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

Wheeler SM, Willoughby KA, McAndrews MP, Rovet JF. Hippocampal size and memory functioning in children and adolescents with congenital hypothyroidism. J Clin Endocrinol Metab. 2011. 96(9):E1427-34