To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1504

Relationship: 1504

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 BDNF, Reduced

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 Low Low Anna Price (send email) Open for citation & comment WPHA/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
mouse Mus musculus 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 Moderate

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

Several studies have shown that THs regulate BDNF expression in the brain (Koibuchi et al., 1999; Koibuchi and Chin, 2000; Sui and Li, 2010), with the subsequent neurodevelopmental consequences, as described in the direct KER. For example, during the early cortical network development TH has been shown to regulate the morphology and function of the GABAergic neurons (Westerholz et al., 2010) and BDNF is one of the mediators of this regulation (Binder and Scharfman, 2004; Gilbert and Lasley, 2013).

In view of the above evidence, it has been suggested that the thyroid insufficiency triggered by inhibition of TPO or NIS functions, resulting in decreased TH synthesis and subsequent lowered TH levels in serum and brain, may lead to reduction of the levels of BDNF mRNA or protein in the developmental brain.

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
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 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, even in the modest degree, 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). The levels of serum TH at birth are not always informative, as most of the neurological deficits are present despite the normal thyroid status of the newborn. That means that the cause of these impairments is rooted in the early stages of the neuronal development during the gestational period. The nature and the temporal occurrence of these defects suggest that TH may exert their effects through the neurotrophins, as they are the main regulators of neuronal system development (Lu and Figurov, 1997). Among them, BDNF represents the prime candidate because of its critical role in CNS development and its ability to regulate synaptic transmission, dendritic structure and synaptic plasticity in adulthood (Binder and Scharfman, 2004). Additionally, hippocampus and neocortex are two of the regions characterized by the highest BDNF expression (Kawamoto et al., 1996), and are also key brain areas for learning and memory functions.

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

Despite the fact that many in vivo studies have shown a correlation between hypothyroidism and decreased BDNF expression in the brain, no clear consensus can be reached by the overall evaluation of the existing data. There are numerous conflicting studies showing no significant alterations in BDNF mRNA or protein levels (Alvarez-Dolado et al., 1994; Bastian et al., 2010; 2012; Royland et al., 2008; Lasley and Gilbert, 2011). However, the results of these studies cannot exclude the possibility of temporal- or region-specific BDNF effects as a consequence of foetal hypothyroidism. A transient TH-dependent BDNF reduction in early postnatal life can be followed by a period of normal BDNF levels or, on the contrary, normal BDNF expression in the early developmental stages is not predictive of equally normal BDNF expression throughout development. Moreover, significant differences in study design, the assessed brain regions, the age and the method of assessment in the existing studies, further complicate result interpretation.

While PTU (TPO inhibitor) has been shown to decrease brain BDNF levels and expression in offspring born from PTU-treated rat dams (Shafiee et al. 2016; Chakraborty et al., 2012; Gilbert et al. 2016), in Cortés et al., 2012 study (in vivo), treatment of adult male Sprague-Dawley rats with PTU induced an increase in the amount of BDNF mRNA in the hippocampus, while the content of TrkB, the receptor for BDNF, resulted reduced at the postsynaptic density (PSD) of the CA3 region compared with controls. Treated rats presented also thinner PSD than control rats, and a reduced content of NMDAr subunits (NR1 and NR2A/B subunits) at the PSD in hypothyroid animals. These indicate differential effects elicited by PTU (i.e., TPO inhibition) on BDNF expression/regulation comparing the adult vs foetal brain. However, even though BDNF levels were increased, the decrease of BDNF receptor (TrkB) compromises the signalling pathway under BDNF control.

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

The connection between synthesis of TH and BDNF expression has been studied only in rodent models up to date.

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

Abedelhaffez AS, Hassan A. (2013). Brain derived neurotrophic factor and oxidative stress index in pups with developmental hypothyroidism: neuroprotective effects of selenium. Acta Physiol Hung. Jun;100(2):197-210.

Alvarez-Dolado M, Iglesias T, Rodrıguez-Pena A, Bernal J, Munoz A. (1994). Expression of neurotrophins and the trk family of neurotrophin receptors in normal and hypothyroid rat brain. Brain Res Mol Brain Res. 27:249–257.

Bastian TW, Prohaska JR, Georgieff MK, Anderson GW. (2010). Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations. Endocrinology 151:4055–4065.

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

Binder DK, Scharfman HE. (2004). Brain-derived neurotrophic factor. Growth Factors. 22(3):123–131

Blanco J, Mulero M, Heredia L, Pujol A, Domingo JL, Sanchez Dc. (2013). Perinatal exposure to BDE-99 causes learning disorders and decreases serum thyroid hormone levels and BDNF gene expression in hippocampus in rat offspring. Toxicol 308:122-128.

Chakraborty G, Magagna-Poveda A, Parratt C, Umans JG, MacLusky NJ, Scharfman HE. (2012). Reduced hippocampal brain-derived neurotrophic factor (BDNF) in neonatal rats after prenatal exposure to propylthiouracil (PTU). Endocrinology 153:1311–1316.

Cortés C, Eugenin E, Aliaga E, Carreño LJ, Bueno SM, Gonzalez PA, Gayol S, Naranjo D, Noches V, Marassi MP, Rosenthal D, Jadue C, Ibarra P, Keitel C, Wohllk N, Court F, Kalergis AM, Riedel CA. (2012). Hypothyroidism in the adult rat causes incremental changes in brain-derived neurotrophic factor, neuronal and astrocyte apoptosis, gliosis, and deterioration of postsynaptic density. Thyroid. Sep;22(9):951-63.

da Conceição RR, Laureano-Melo R, Oliveira KC, de Carvalho Melo MC, Kasamatsu TS, de Barros Maciel RM, de Souza JS, Giannocco G. (2016). Antidepressant behavior in thyroidectomized Wistar rats is induced by hippocampal hypothyroidism. Physiol Behav. Apr 1;157:158-64.

Gilbert ME, Lasley SM. (2013). Developmental thyroid hormone insufficiency and brain development: a role for brain-derived neurotrophic factor (BDNF)? Neurosci 239: 253-270.

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, Feb;157(2):774-87

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.

Jang YJ, Park HR, Kim TH, Yang WJ, Lee JJ, Choi SY, Oh SB, Lee E, Park JH, Kim HP, Kim HS, Lee J. (2012). High dose bisphenol A impairs hippocampal neurogenesis in female mice across generations. Toxicology. Jun 14;296(1-3):73-82.

Kawamoto Y, Nakamura S, Nakano S, Oka N, Akiguchi I, Kimura J. (1996). Immunohistochemical localization of brain-derived neurotrophic factor in adult rat brain. Neurosci 74(4):1209-1226.

Koibuchi N, Chin WW. (2000). Thyroid hormone action and brain development. Trends Endocrinol Metab. 11(4):123-128.

Koibuchi N, Yamaoka S, Chin WW. (2001). Effect of altered thyroid status on neurotrophin gene expression during postnatal development of the mouse cerebellum. Thyroid 11:205–210.

Koibuchi N, Fukuda H, Chin WW. (1999). Promoter-specific regulation of the brain-derived neurotrophic factor gene by thyroid hormone in the developing rat cerebellum. Endocrinol 140: 3955–3961.

Lasley SM, Gilbert ME. (2011). Developmental thyroid hormone insufficiency reduces expression of brain-derived neurotrophic factor (BDNF) in adults but not in neonates. Neurotoxicol Teratol 33:464–472.

Lu B, Figurov A. (1997). Role of neurotrophins in synapse development and plasticity. Rev Neurosci 8:1–12.

Neveu I, Arenas E. (1996.) Neurotrophins promote the survival and development of neurons in the cerebellum of hypothyroid rats in vivo. J Cell Biol 133:631–646.

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. Cerebral cortex. Jan;21:11-21.

Royland JE, Parker JS, Gilbert ME. (2008). A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. J Neuroendocrinol 20:1319–1338.

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.

Sinha RA, Pathak A, Kumar A, Tiwari M, Shrivastava A, Godbole MM. (2009). Enhanced neuronal loss under perinatal hypothyroidism involves impaired neurotrophic signaling and increased proteolysis of p75(NTR). Mol Cell Neurosci 40:354–364.

Sui L, Li BM. (2010). Effects of perinatal hypothyroidism on regulation of reelin and brain-derived neurotrophic factor gene expression in rat hippocampus: role of DNA methylation and histone acetylation. Steroids 75:988–997.

Westerholz S, deLima AD, Voigt T. (2010). Regulation of early spontaneous network activity and GABAergic neurons development by thyroid hormone. Neurosci 168:573–589.

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

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