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Relationship: 444

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 neuronal tissue, Decreased leads to BDNF, Reduced

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 Na+/I- symporter (NIS) leads to learning and memory impairment adjacent Moderate Low Anna Price (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
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Birth to < 1 month High
Adult Moderate
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

It is widely accepted that the thyroid hormones (TH) have a prominent role in the development and function of the Central Nervous System (CNS) and their action has been closely linked to the cognitive function because of their importance in the neocortical development (Gilbert et al., 2012). During the early cortical network development TH has been shown to influence the number of cholinergic neurons and the degree of innervation of hippocampal CA3 and CA1 regions (Oh et al., 1991; Thompson and Potter 2000), and to regulate the morphology and function of GABAergic neurons (Westerholz et al., 2010).

One of the mediators of this regulation has been suggested to be the brain derived neurotrophic factor (BDNF), whose role in brain development and function has been very well-documented (Binder and Scharfman, 2004) and which function has been associated with TH levels in the brain (Gilbert and Lasley, 2013). Several studies have shown that TH can regulate BDNF expression in the brain (Koibuchi et al., 1999; Koibuchi and Chin, 2000; Sui and Li, 2010), with the subsequent neurodevelopmental consequences.

In view of the above evidence, it has been shown that the thyroid insufficiency (lower TH levels) results in reduction of BDNF levels (mRNA or protein) in the developmental brain.

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
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 importance of thyroid hormones (TH) in brain development has been recognised and investigated for many decades (Bernal, 2011). 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. Indeed, it has been shown that the thyroid insufficiency (lower TH levels) results in reduction of BDNF levels (mRNA or protein) in the developing brain, and the most likely affected brain regions are the hippocampus and cortex (Koromilas et al., 2010, Shafiee et al., 2016).  The hippocampus direct and indirect interactions with the THs provide crucial information on the neurobiological basis of the hypothyroidism-induced mental retardation and neurobehavioral dysfunction. TH deficiency during the foetal and/or the neonatal period produces deleterious effects for neural growth and development (such as reduced synaptic connectivity, delayed myelination, disturbed neuronal migration, deranged axonal projections, decreased synaptogenesis and alterations in neurotransmitters' levels), possibly through decreased BDNF levels (Koromilas et al., 2010; Shafiee et al., 2016).

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

Hypothyroidism (i.e., induced by chemicals known to inhibit TPO or NIS, or by thyroidectomy, leading to low TH serum levels) is generally associated with lower levels of BDNF in brain tissues. As described in Conceição et al., 2016, thyroidectomized adult rats, apart from showing reduced TH levels, also presented reduced hippocampal gene expression of MCT8, TRα1, DIO2 and BDNF, which support a link between hippocampal hypothyroidism and reduced BDNF levels.

However, despite the fact that many in vivo studies have shown a correlation between hypothyroidism and BDNF expression in the brain, there are no studies simultaneously measuring the levels of both TH and BDNF in the brain. Therefore, no clear consensus can be reached by the overall evaluation of the existing data. There are numerous conflicting studies showing no significant change in BDNF mRNA or protein levels under hypothyroid conditions (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 decreased 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.

- In Alvarez-Dolado et al. 1994, hypothyroid rats showed decreased trk (BDNF receptor) mRNA levels in the striatum on PND 5, PND 15 and in adults, increase of the low affinity neurotrophin receptor p75LNGFR mRNA in hypothyroid cerebellum on PND 5 and PND 15, decrease of nerve growth factor (NGF) mRNA in the cortex, hippocampus, and cerebellum of hypothyroid rats on neonatal hypothyroid rats on PND 15 and also after adult-onset hypothyroidism, whilst the relatively high expression of the two BDNF mRNAs did not change in any brain area.

- Bastian et al. (2010) assessed the effects Cu and Fe deficiencies on circulating and brain TH levels during development in pregnant rat dams rendered Cu deficient (CuD), Fe deficient (FeD), or TH deficient (by PTU treatment) from early gestation through weaning. Serum T4 and T3, and brain T3 levels were subsequently measured in PND 12 pups. Despite the remarkable decrease of serum TH and brain T3 induced by PTU treatment (and also by CuD and FeD), no significant changes of Bdnf IV mRNA levels were found. Authors commented that 'one explanation for this discrepancy is that many of the previous studies were performed using discrete brain regions, whereas this study was performed on whole-brain RNA'. Along the same line, in a follow up study, Bastian et al. (2012) could not find statistically significant reductions of Bdnf IV, Bdnf VI, and total Bdnf mRNA levels in hippocampus or cerebral cortex of Fe and TH deficient pups.

- Royland et al. (2008) assessed the effects of a PTU (TPO inhibitor) administration to pregnant rats from gestational day 6 until sacrifice of pups prior to weaning. However, PTU treatment did not change the expression of Bdnf at the mRNA level.

- In Lasley and Gilbert, 2011 study, different concentrations of PTU were administered to rat pregnant dams from gestational day 6 until weaning of the pups. Pups were sacrificed on PND 14, PND 21 and PND 100, analysis of TH serum levels was performed, along with analysis of hippocampal, cortical, and cerebellar levels of BDNF protein. While PTU caused a strong decrease of TH serum levels, no differences in BDNF protein were detected in the pre-weanling animals as a function of PTU exposure. On the contrary, dose-dependent decrease of BDNF levels emerged in adult males as a consequence of prenatal exposure despite the return to control TH levels. These findings reflect the potential for delayed impact of even modest TH reductions during critical periods of brain development on BDNF, a protein important for normal synaptic formation, as commented by the authors of this study.

It should also be considered that in severe models of TH deficiency, BDNF responsivity to TH is regulated in a promoter-, age-, and brain region-specific fashion (as described by Anderson and Mariash, 2002), and even modest differences of these parameters in study design may explain inconsistencies in study results.

The absence of significant changes in BDNF levels in the above cited studies could be also due to different sensitivity of analythical tools, experimental design and statistical processing of the results.

While PTU (TPO inhibitor) has been shown to decrease serum TH levels and brain BDNF protein levels and mRNA 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, 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. While these data indicate differential effects elicited by PTU (i.e., TPO inhibition) on BDNF expression/regulation comparing the adult vs foetal brain, downregulation of TrkB receptors still leads to decrease signalling pathways regulated by BDNF.

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
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

The connection between TH levels and BDNF expression has been studied only in rodent models up to date (see above studies).

References

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

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.

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.

Anderson GW, Mariash CN. 2002. Molecular aspects of thyroid hormone-regulated behavior. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, editors. , eds. Hormones, brain and behavior. San Diego: Academic Press; 539–566.

Blanco J, Mulero M, Heredia L, Pujol A, Domingo JL, Sánchez DJ (2013). Perinatal exposure to BDE-99 causes learning disorders and decreases serum thyroid hormone levels and BDNF gene expression in hippocampus in rat offspring. Toxicology. Jun 7;308:122-8.

Bastian TW, Anderson JA, Fretham SJ, Prohaska JR, Georgieff MK, Anderson GW. (2012). Fetal and neonatal iron deficiency reduces thyroid hormone-responsive gene mRNA levels in the neonatal rat hippocampus and cerebral cortex. Endocrinology 153: 5668–5680.

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

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, 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, 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.

Kawahori K, Hashimoto K, Yuan X, Tsujimoto K, Hanzawa N, Hamaguchi M, Kase S, Fujita K, Tagawa K, Okazawa H, Nakajima Y, Shibusawa N, Yamada M, Ogawa Y (2018). Mild Maternal Hypothyroxinemia During Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring. Thyroid. Mar;28(3):395-406.

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.

Koromilas C1, Liapi C, Schulpis KH, Kalafatakis K, Zarros A, Tsakiris S. (2010). Structural and functional alterations in the hippocampus due to hypothyroidism. Metab Brain Dis 25(3):339-54.

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.

Liu D, Teng W, Shan Z, Yu X, Gao Y, Wang S, Fan C, Wang H, Zhang H. (2010). The effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring. Thyroid 20:909–915.

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

Mokhtari T, Akbari M, Malek F, Kashani IR, Rastegar T, Noorbakhsh F, Ghazi-Khansari M, Attari F, Hassanzadeh G (2017). Improvement of memory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. Daru. Feb 15;25(1):4.

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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.

Oh JD, Butcher LL, Woolf NJ (1991). Thyroid hormone modulates the development of cholingergic terminal fields in the rat forebrain: relation to nerve growth factor receptor. Devl Brain Res  59:133–142.

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Remaud S, Gothié JD, Morvan-Dubois G, Demeneix BA (2014). Thyroid hrmone signaling and adult neurogenesis in mammals. Front. Endocrinol., 5, p. 40

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.

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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, 329, pp. 151-161.

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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.

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Wang S, Teng W, Gao Y, Fan C, Zhang H, Shan Z. (2012). Early levothyroxine treatment on maternal subclinical hypothyroidism improves spatial learning of offspring in rats. J Neuroendocrinol 24:841–848.

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

Wu Y, Beland FA1, Fang JL. (2016). Effect of triclosan, triclocarban, 2,2',4,4'-tetrabromodiphenyl ether, and bisphenol A on the iodide uptake, thyroid peroxidase activity, and expression of genes involved in thyroid hormone synthesis. Toxicol In Vitro. Apr;32:310-9.

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