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Relationship: 1503


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

Inhibition, Na+/I- symporter (NIS) leads to Impairment, Learning and memory

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 non-adjacent Moderate Low Arthur Author (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 Moderate NCBI
mouse Mus musculus Low NCBI
human Homo sapiens Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
During brain development Moderate

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

NIS is a membrane protein responsible for iodide transport into the follicular cells of the thyroid, which is the first and most critical step leading to T4 biosynthesis (Dohan et al., 2000). TH synthesis is dramatically suppressed in case of NIS dysfunction or inhibition (Spitzweg and Morris, 2010; Jones et al., 1996; Tonacchera et al., 2004; De Groef et al., 2006), resulting in the decreased TH levels in the serum and consequently in the brain. Hypothyroid brain development results in severe functional impairments including ataxia, spasticity, severe mental retardation, including impairment of learning and memory.

NIS inhibition occurring as a consequence of exposure to certain pollutants has been associated with learning and memory deficits in rodents and humans (Wang et al, 2016; Jang et al, 2012; Taylor et al., 2014; Chen et al., 2014; Roze et al., 2009; van Wijk et al., 2008; Wu Y et al., 2016).

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

The weight of evidence supporting an indirect linkage between the MIE, NIS inhibition, and the adverse outcome Impairment of learning and Memory is moderate.

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
NIS inhibition occurring as a consequence of exposure to certain pollutants has been associated with learning and memory deficits in rodents and humans (Wang et al, 2016; Jang et al, 2012; Taylor et al., 2014; Chen et al., 2014; Roze et al., 2009; van Wijk et al., 2008).

During pre- and perinatal development, disruption of TH signaling leads to a multitude of neurological deficits. Multiple studies have shown that TH deprivation leads to defects in learning processes (for a comprehensive review, see Raymaekers and Darras, 2017). Congenital hypothyroidism has been shown to cause selective visuocognitive malfunctions, a lower IQ even in young adults (Oerbeck et al., 2003; Simic et al., 2013; Wheeler et al., 2012; Willoughby et al., 2014). On the other hand, adult-onset hyperthyroidism has been associated with a decrease in signal activity between the hippocampus and other cortical regions (Zhang et al., 2014), hyperactivity, attention deficits and changes in anxiety state (Raymaekers and Darras, 2017), which could impact learning potential.

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

Single NIS mutations, causing decreased thyroidal iodide uptake, may not necessarily lead to cognitive disorders. In this regard, Nicola and coworkers (Nicola et al., 2015) recently identified a new NIS mutation (V270E) in a patient (full-term girl born to healthy, non-consanguineous Jamaican parents), who resulted to be heterozygous for this NIS mutation (R124H/V270E). The presence of the mutation V270E markedly reduces iodide uptake (5.4% 24 hours after the oral administration of 100 μCi 123I− (normal range, 10–40%)) via a pronounced (but not total) impairment of the protein's plasma membrane targeting. However, the retaining of a minimal iodide uptake was enough to enable sufficient TH biosynthesis and prevent cognitive impairment.

It should be noted that the van Wijk et al. 2008  study was performed with only one dose group exposed to perchlorate during development, and the behavioural assessments were performed using a limited group size of 5-8, possibly reducing the reliability of this study. In general, chronic hypothyroidism effects on development were more pronounced than the effects of perinatal hypothyroidism, suggesting that functional alterations occurring as a consequence of hypothyroidism may be partly reversible depending on developmental stage of the deficiency.

Opposite, other in vivo studies do not support associations between perinatal perchlorate exposure and neurobehavioural effects. For example, York et al. (2004) could not observe meaningful behavioral effects in rat offspring exposed as high as 10.0 mg/kg/day, as evaluated by passive avoidance, swimming water maze, motor activity, and auditory startle. In their re-evaluation of the data (York et al. 2005), authors concluded that rat pups exposed to perchlorate both during pregnancy and after 10 days of lactation, despite showing alterations of neurohistopathological features, did not show altered development of gross motor movements. Moreover, Gilbert and Sui (2008) found that adult male offspring born from rat dams exposed to 0, 30, 300, or 1,000 ppm perchlorate in drinking water from gestational day 6 until weaning, underwent reduction of T3 (10–14% reduction) and T4 (~ 9–20% reduction) reduction on postnatal day 21 (at the highest perchlorate dose), significant reductions in baseline synaptic transmission (~ 20% increase in excitatory postsynaptic potential slope amplitude), but without changes of motor activity, spatial learning, or fear conditioning.

Taylor et al. 2004 (CATS study) identified 1050 pregnant women with hypothyroidism or hypothyroxinemia; half were in the immediate T4 treatment group, and half were in the group tested and treated after pregnancy. 487 (46.4%) mother-child pairs completed psychological testing and urinary iodine and perchlorate measurements. Therefore, the 487 women-child pairs represent approximately two-thirds of those reported in the study of T4 treatment effects on cognitive outcome. Taking this into account, the absence of a direct effect of perchlorate on maternal thyroid function (Pearce et al. 2010), suggests that developmental effects of perchlorate may not necessarily be linked to maternal thyroid hormone levels, as commented in (Brent, 2014).

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
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

As described in the Empirical Support section, the association between NIS inhibition and learning and memory impairment has been studied only in rodent models and in humans.


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

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.

Babu S, Sinha RA, Mohan V, Rao G, Pal A, Pathak A, Singh M, Godbole MM (2011). Effect of hypothyroxinemia on thyroid hormone responsiveness and action during rat postnatal neocortical development. Exp Neurol. Mar;228(1):91-8.

Bastian TW, Prohaska JR, Georgieff MK, Anderson GW. (2014). Fetal and neonatal iron deficiency exacerbates mild thyroid hormone insufficiency effects on male thyroid hormone levels and brain thyroid hormone-responsive gene expression. Endocrinology 155:1157-1167.

Brent GA (2014). Perchlorate Exposure in Pregnancy and Cognitive Outcomes in Children: It's Not Your Mother's Thyroid. J Clin Endocrinol Metab. Nov; 99(11): 4066–4068.

Buras A, Battle L, Landers E, Nguyen T, Vasudevan N (2014). Thyroid hormones regulate anxiety in the male mouse. Horm Behav. Feb;65(2):88-96.

Butt CM, Wang D, Stapleton HM (2011). Halogenated phenolic contaminants inhibit the in vitro activity of the thyroid-regulating deiodinases in human liver. Toxicol Sci. Dec; 124(2):339-47.

Chen A, Yolton K, Rauch SA, Webster GM, Hornung R, Sjödin A, Dietrich KN, Lanphear BP. (2014). Prenatal polybrominated diphenyl ether exposures and neurodevelopment in U.S. children through 5 years of age: the HOME study. Environ Health Perspect. Aug;122(8):856-62.

Chevrier J, Harley KG, Bradman A, Gharbi M, Sjödin A, Eskenazi B (2010). Polybrominated diphenyl ether (PBDE) flame retardants and thyroid hormone during pregnancy. Environ Health Perspect. Oct; 118(10):1444-9.

Costa LG, Giordano G, Tagliaferri S, Caglieri A, Mutti A (2008). Polybrominated diphenyl ether (PBDE) flame retardants: environmental contamination, human body burden and potential adverse health effects. Acta Biomed. Dec;79(3):172-83.

De Groef B, Decallonne BR, Van der Geyten S, Darras VM, Bouillon R. (2006). Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Europ J Endocr. 155:17-25.

Dingemans MM, van den Berg M, Westerink RH (2011). Neurotoxicity of brominated flame retardants: (in)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system. Environ Health Perspect. Jul; 119(7):900-7.

Dohan O, De la Vieja A, Carrasco N. (2000) Molecular study of the sodium-iodide symporter (NIS): a new field in thyroidology. Trends Endocrinol Metab. Apr;11(3):99-105.

Ferrandino G, Kaspari RR, Reyna-Neyra A, Boutagy NE, Sinusas AJ, Carrasco N (2017). An extremely high dietary iodide supply forestalls severe hypothyroidism in Na+/I- symporter (NIS) knockout mice. Sci Rep. 2017 Jul 13;7(1):5329.

Fujiwara H, Tatsumi K, Tanaka S, Kimura M, Nose O, Amino N (2000). A novel hV59E missense mutation in the sodium iodide symporter gene in a family with iodide transport defect. Thyroid 10:471–474.

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, Hedge JM, Valentin-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW. (2013). An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci 132:177-195.

Gilbert ME, Ramos RL, McCloskey DP, Goodman JH. (2014). Subcortical band heterotopia in rat offspring following maternal hypothyroxinaemia: structural and functional characteristics. J Neuroendocrinol 26:528-541.

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.

Gilbert ME, Sui L (2008). Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat. Environ Health Perspect. Jun;116(6):752-60.

Herbstman JB, Sjödin A, Apelberg BJ, Witter FR, Halden RU, Patterson DG, Panny SR, Needham LL, Goldman LR (2008). Birth delivery mode modifies the associations between prenatal polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) and neonatal thyroid hormone levels. Environ Health Perspect. Oct; 116(10):1376-82.

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.

Jones PA, Pendlington RU, Earl LK, Sharma RK, Barrat MD. (1996). In vitro investigations of the direct effects of complex anions on thyroidal iodide uptake: identification of novel inhibitors. Toxicol. In Vitro. 10: 149-160.

Kosugi S, Inoue S, Matsuda A, Jhiang SM (1998). Novel, missense and loss-of-function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients. J Clin Endocrinol Metab. Sep;83(9):3373-6.

Lin SM, Chen FA, Huang YF, Hsing LL, Chen LL, Wu LS, Liu TS, Chang-Chien GP, Chen KC, Chao HR (2011). Negative associations between PBDE levels and thyroid hormones in cord blood. Int J Hyg Environ Health. Mar; 214(2):115-20.

Mahmoudi A, Ghorbel H, Feki I, Bouallagui Z, Guermazi F, Ayadi L, Sayadi S (2018). Oleuropein and hydroxytyrosol protect rats' pups against bisphenol A induced hypothyroidism. Biomed Pharmacother. Apr 27;103:1115-1126.

Marchesini GR, Meimaridou A, Haasnoot W, Meulenberg E, Albertus F, Mizuguchi M, Takeuchi M, Irth H, Murk AJ (2008). Biosensor discovery of thyroxine transport disrupting chemicals. Toxicol Appl Pharmacol. Oct 1; 232(1):150-60.

Meeker JD, Ferguson KK (2011). Relationship between urinary phthalate and bisphenol A concentrations and serum thyroid measures in U.S. adults and adolescents from the National Health and Nutrition Examination Survey (NHANES) 2007-2008. Environ Health Perspect. Oct;119(10):1396-402.

Meerts IA, van Zanden JJ, Luijks EA, van Leeuwen-Bol I, Marsh G, Jakobsson E, Bergman A, Brouwer A (2000). Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro. Toxicol Sci. Jul; 56(1):95-104.

Navarro D, Alvarado M, Navarrete F, Giner M, Obregon MJ, Manzanares J, Berbel P (2015). Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats. Front Neuroanat. Feb 17;9:9.

Nicola JP, Reyna-Neyra A, Saenger P, Rodriguez-Buritica DF, Gamez Godoy JD, Muzumdar R, Amzel LM, Carrasco N. (2015). Sodium/Iodide Symporter Mutant V270E Causes Stunted Growth but No Cognitive Deficiency. J Clin Endocrinol Metab. Oct;100(10):E1353-61.

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, pp. 923-930.

Pearce EN, Lazarus JH, Smyth PP, et al. Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women. (2010). J Clin Endocrinol Metab. 95:3207–3215.

Powell MH, Nguyen HV, Gilbert M, Parekh M, Colon-Perez LM, Mareci TH, Montie E. (2012). Magnetic resonance imaging and volumetric analysis: novel tools to study the effects of thyroid hormone disruption on white matter development. Neurotoxicology 33:1322-1329.

Raymaekers SR, Darras VM (2017). Thyroid hormones and learning-associated neuroplasticity. Gen Comp Endocrinol. Jun 1;247:26-33.

Roze E, Meijer L, Bakker A, Van Braeckel KN, Sauer PJ, Bos AF. (2009). Prenatal exposure to organohalogens, including brominated flame retardants, influences motor, cognitive, and behavioral performance at school age. Environ Health Perspect. Dec;117(12):1953-8.

Sharlin DS TD, Bansal R, Gilbert ME, and Zoeller RT. (2007). The Thyroid Hormone Transporter, MCT8, Selectively Responds to Thyroid Hormone Insufficiency in the Developing Rat Brain. In: Endocrinology.

Sharlin DS, Tighe D, Gilbert ME, Zoeller RT. (2008). The balance between oligodendrocyte and astrocyte production in major white matter tracts is linearly related to serum total thyroxine. Endocrinology 149:2527-2536.

Simic N, Khan S, Rovet J (2013). Visuospatial, visuoperceptual, and visuoconstructive abilities in congenital hypothyroidism. J. Int. Neuropsychol. Soc., 19, pp. 1119-1127.

Spitzweg C, Morris JC. (2010). Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Mol Cell Endocrinol. Jun 30;322(1-2):56-63.

Stapleton HM, Eagle S, Anthopolos R, Wolkin A, Miranda ML (2011). Associations between polybrominated diphenyl ether (PBDE) flame retardants, phenolic metabolites, and thyroid hormones during pregnancy. Environ Health Perspect. Oct; 119(10):1454-9.

Szabo DT, Richardson VM, Ross DG, Diliberto JJ, Kodavanti PR, Birnbaum LS (2009). Effects of perinatal PBDE exposure on hepatic phase I, phase II, phase III, and deiodinase 1 gene expression involved in thyroid hormone metabolism in male rat pups. Toxicol Sci. 2009 Jan; 107(1):27-39.

Taylor PN, Okosieme OE, Murphy R, Hales C, Chiusano E, Maina A, Joomun M, Bestwick JP, Smyth P, Paradice R, Channon S, Braverman LE, Dayan CM, Lazarus JH, Pearce EN. (2014). Maternal perchlorate levels in women with borderline thyroid function during pregnancy and the cognitive development of their offspring: data from the Controlled Antenatal Thyroid Study.J Clin Endocrinol Metab. Nov; 99(11):4291-8.

Tonacchera M, Agretti P, de Marco G, Elisei R, Perri A, Ambrogini E, De Servi M, Ceccarelli C, Viacava P, Refetoff S, Panunzi C, Bitti ML, Vitti P, Chiovato L, Pinchera A. (2003). Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein. Clin Endocrinol. 59: 500–506.

van Wijk N1, Rijntjes E, van de Heijning BJ. (2008). Perinatal and chronic hypothyroidism impair behavioural development in male and female rats. Exp Physiol. Nov;93(11):1199-209.

Vasilopoulou CG, Constantinou C, Giannakopoulou D, Giompres P, Margarity M. (2016). Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice. Physiol Behav. Oct 1;164(Pt A):284-91.

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Wang C, Li Z, Han H, Luo G, Zhou B, Wang S, Wang J. (2016). Impairment of object recognition memory by maternal bisphenol A exposure is associated with inhibition of Akt and ERK/CREB/BDNF pathway in the male offspring hippocampus. Toxicology. Feb 3;341-343:56-64.

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

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

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.

York RG, Barnett J Jr, Brown WR, Garman RH, Mattie DR, Dodd D (2004). A rat neurodevelopmental evaluation of offspring, including evaluation of adult and neonatal thyroid, from mothers treated with ammonium perchlorate in drinking water. Int J Toxicol. May-Jun;23(3):191-214.

York RG, Barnett J, Girard MF, Mattie DR, Bekkedal MV, Garman RH, Strawson JS (2005). Refining the effects observed in a developmental neurobehavioral study of ammonium perchlorate administered orally in drinking water to rats. II. Behavioral and neurodevelopment effects. Int J Toxicol. Nov-Dec;24(6):451-67.

Zhang W, Liu X, Zhang Y, Song L, Hou J, Chen B, He M, Cai P, Lii H (2014). Disrupted functional connectivity of the hippocampus in patients with hyperthyroidism: evidence from resting-state fMRI. Eur. J. Radiol., 83, pp. 1907-1913.

Zhou T, Taylor MM, DeVito MJ, Crofton KM (2002). Developmental exposure to brominated diphenyl ethers results in thyroid hormone disruption. Toxicol Sci. Mar; 66(1):105-16.

Zota AR, Park JS, Wang Y, Petreas M, Zoeller RT, Woodruff TJ (2011). Polybrominated diphenyl ethers, hydroxylated polybrominated diphenyl ethers, and measures of thyroid function in second trimester pregnant women in California. Environ Sci Technol. Sep 15; 45(18):7896-905.