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T4 in neuronal tissue, Decreased leads to BDNF, Reduced
Key Event Relationship Overview
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|
Life Stage Applicability
|Birth to < 1 month||High|
|During brain development||High|
Key Event Relationship Description
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 Supporting this KER
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
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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The connection between TH levels and BDNF expression has been studied only in rodent models up to date (see above studies).
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.
Morte B, Diez D, Auso E, Belinchon MM, Gil-Ibanez P, Grijota-Martinez C, Navarro D, de Escobar GM, Berbel P, Bernal J (2010a) Thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex: prominent role of the Ca2+/calmodulin-dependent protein kinase IV pathway. Endocrinology 151:810-820.
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.
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.
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.
Schwartz HL, Strait KA, Ling NC, Oppenheimer JH (1992). Quantitation of rat-tissue thyroid-hormone binding-receptor isoforms by immunoprecipitation of nuclear triiodothyronine binding-capacity. J. Biol. Chem., 267 (17), pp. 11794–11799.
Sabbaghziarani F, Mortezaee K, Akbari M, Kashani IR, Soleimani M, Hassanzadeh G, Zendedel A (2017). Stimulation of neurotrophic factors and inhibition of proinflammatory cytokines by exogenous application of triiodothyronine in the rat model of ischemic stroke. Cell Biochem Funct. Jan;35(1):50-55.
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.
Shi R, Xie X, Gao Y, Zhou YJ, Zhang Y, Chen LM, Tian Y (2017). [The effects of prenatal exposure to brominated diphenyl ethers-209 to the influence of male offspring rats hippocampus BDNF potein expression and its mechanism of action]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. Sep 20;35(9):652-655.
Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A (1998). Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20:727–740
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.
Sui L, Ren WW, Li BM (2010). Administration of thyroid hormone increases reelin and brain-derived neurotrophic factor expression in rat hippocampus in vivo. Brain Res. Feb 8;1313:9-24.
Thompson CC, Potter GB. (2000). Thyroid hormone action in neural development. Cereb Cortex. Oct;10(10):939-45.
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.
Zoeller RT, Rovet J. (2004). Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J Neuroendocrinol 16:809–818.