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Relationship: 1506

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

TH synthesis, Decreased leads to Impairment, Learning and memory

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 Na+/I- symporter (NIS) leads to learning and memory impairment non-adjacent High Moderate Arthur Author (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 Moderate NCBI
human Homo sapiens Moderate 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
Unspecific Moderate

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

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 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 supporting the relationship between decreased TH synthesis and learning and memory impairments (occurring as a consequence of altered neuronal network and synaptic function) is strong (Vara et al., 2002; Sui and Gilbert, 2003,  2004, 2011;Dong et al., 2005; Sui et al., 2005). This is consistent with the well understood and documented relationship between TH synthesis that is responsible for TH concentrations in serum, and consequently in brain. TH controls brain development and function, including learning and memory processes, in humans and animals.

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 importance of thyroid hormones (TH) in brain development has been recognised and investigated for many decades (Bernal, 2011; Williams 2008). Several human studies have shown that low levels of circulating maternal TH (as a consequence of a decrease of TH synthesis) can lead to neurophysiological deficits in the offspring, including learning and memory deficits, or even cretinism in most severe cases (Zoeller and Rovet, 2004; Henrichs et al., 2010).

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

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.

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
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

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

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

Akaike M, Kato, N., Ohno, H., Kobayashi, T. (1991). Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol Teratol 13:317-322.

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.

Axelstad M, Hansen PR, Boberg J, Bonnichsen M, Nellemann C, Lund SP, Hougaard KS, U H. (2008). Developmental neurotoxicity of Propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes. Toxicol Appl Pharmacol 232:1-13.

Berbel P, Navarro D, Auso E, Varea E, Rodriguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM. (2010). Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity. Cereb Cortex 20:1462-1475.

Bernal J. (2011). Thyroid hormone transport in developing brain. Curr Opin Endocrinol Diab Obes 18:295–299.

Davenport JW, Dorcey TP. (1972). Hypothyroidism: learning deficit induced in rats by early exposure to thiouracil. Horm Behav 3:97-112.

de Escobar GM, Obregon MJ, del Rey FE. (2007). Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutr.10(12A):1554–1570.

de Escobar GM, Ares S, Berbel P, Obregon MJ, del Rey FE. (2008). The changing role of maternal thyroid hormone in fetal brain development. Semin Perinatol. 32(6):380–386.

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

Gilbert ME. (2004). Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Brain Res Dev Brain Res 148:11-18.

Gilbert ME, Sui L. (2006). Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.

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

Gilbert ME, Rovet J, Chen Z, Koibuchi N. (2012). Developmental thyroid hormone disruption: prevalence, environmental contaminants and neurodevelopmental consequences. Neurotoxicology 33(4):842-852.

Gilbert ME, Sanchez-Huerta K, Wood C. (2016). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.

Goodman JH, Gilbert ME. (2007). Modest thyroid hormone insufficiency during development induces a cellular malformation in the corpus callosum: a model of cortical dysplasia. Endocrinology. 2007 Jun;148(6):2593-7.

Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer-Schrama SM, Hofman A, Jaddoe VV, Visser W, Steegers EA, Verhulst FC, de Rijke YB, Tiemeier H. (2010). Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 95:4227–4234.

Horn S, Heuer H. (2010). Thyroid hormone action during brain development: more questions than answers. Mol Cell Endocrinol. 315(1–2):19–26.

Koibuchi N, Chin WW. (2000). Thyroid hormone action and brain development. Trends Endocrinol Metab 11:123-128.

Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G. (2003). Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111:1073-1082.

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.

Melse-Boonstra A, Jaiswal N. (2010). Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Pract Res Clin Endocrinol Metab. 24(1):29–38.

Oerbeck B, Sundet K, Kase BF, Heyerdahl S. (2003). Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults. Pediatrics 112:923-930.

Pesce L, Kopp P. (2014). Iodide transport: implications for health and disease. Int J Pediatr Endocrinol. 2014(1):8.

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.

Shafiee SM, Vafaei AA, Rashidy-Pour A. (2016). Effects of maternal hypothyroidism during pregnancy on learning, memory and hippocampal BDNF in rat pups: Beneficial effects of exercise. Neuroscience. Aug 4;329:151-61.

Sui L, Anderson WL, Gilbert ME. (2005). 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 85:647-656.

Sui L, Gilbert ME. (2003). Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology 144:4195-4203.

Tamasy V, Meisami E, Vallerga A, Timiras PS. (1986). Rehabilitation from neonatal hypothyroidism: spontaneous motor activity, exploratory behavior, avoidance learning and responses of pituitary--thyroid axis to stress in male rats. Psychoneuroendocrinology 11:91-103.

Taylor MA, Swant J, Wagner JJ, Fisher JW, Ferguson DC. (2008). Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology. Endocrinology 149:3521-3530.

Vara H, Martinez B, Santos A, Colino A. (2002). Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 110:19-28.

Wheeler SM, McAndrews MP, Sheard ED, Rovet J. (2012). Visuospatial associative memory and hippocampal functioning in congenital hypothyroidism. J Int Neuropsychol Soc 18:49-56.

Wheeler SM, McLelland VC, Sheard E, McAndrews MP, Rovet JF. (2015). Hippocampal Functioning and Verbal Associative Memory in Adolescents with Congenital Hypothyroidism. Front Endocrinol (Lausanne) 6:163.

Wheeler SM, Willoughby KA, McAndrews MP, Rovet JF. (2011). Hippocampal size and memory functioning in children and adolescents with congenital hypothyroidism. J Clin Endocrinol Metab 96:E1427-1434.

Williams GR. (2008). Neurodevelopmental and Neurophysiological Actions of Thyroid Hormone. Journal of Neuroendocrinology ,  20,  784–794.

Willoughby KA, McAndrews MP, Rovet J. (2013). Effects of early thyroid hormone deficiency on children's autobiographical memory performance. J Int Neuropsychol Soc 19:419-429.

Willoughby KA, McAndrews MP, Rovet JF. (2014). Effects of maternal hypothyroidism on offspring hippocampus and memory. Thyroid 24:576-584.

Zimmermann MB. (2007). The adverse effects of mild-to-moderate iodine deficiency during pregnancy and childhood: a review. Thyroid. 17(9):829–835.

Zimmermann MB. (2012). The effects of iodine deficiency in pregnancy and infancy. Paediatr Perinat Epidemiol. 26(Suppl 1):108–117.

Zoeller RT, Rovet J. (2004). Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J Neuroendocrinol 16:809–818.