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TH synthesis, Decreased leads to Impairment, Learning and memory
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||non-adjacent||High||Moderate||Anna Price (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
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 Collection Strategy
Evidence Supporting this KER
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.
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
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.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Deficiencies in learning and memory following developmental hypothyroidism (TH synthesis inhibition) have been documented mainly in rodents and humans.
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.