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Relationship: 1388

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

T4 in serum, Decreased leads to Hippocampal anatomy, Altered

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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 TFHA/WNT Endorsed

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Male High
Female High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
During brain development High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. 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 Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. 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
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   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.  

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  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.   

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  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
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized 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 using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). 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