Upstream eventInhibition, Na+/I- symporter (NIS)
Impairment, Learning and memory
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment||non-adjacent||Moderate||Low|
Life Stage Applicability
|During brain development||Moderate|
Key Event Relationship Description
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 sever functional impairments including ataxia, spasticity, sever 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 Supporting this KER
The weight of evidence supporting an indirect linkage between the MIE, NIS inhibition, and the adverse outcome Impairment of learning and Memory is moderate.
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.
Some epidemiological and in vivo studies have indicated associations between NIS inhibition (e.g., as a consequence of exposure to perchlorate or other pollutants, such as BPA and BDE-47, NIS inhibitors) (Wu Y et al., 2016) and decreased cognition.
BPA exposure has been also associated with hypothyroidism (i.e., decreased of free T3 and free T4, increase of TSH plasma levels, perturbation of thyroid gland morphological structure and thyroid cell function) in humans (i.e., inverse relationships between urinary BPA and total T4 and TSH) (Meeker and Ferguson, 2011), in young rats breast-fed from mothers treated with BPA (Mahmoudi et al. 2018), and in pregnant ewes and their newborn lambs (i.e., decrease of total T4 in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease), and of plasma free T4 levels in the jugular blood of the newborns) (Viguié et al. 2013).
PBDEs and their hydroxylated metabolites (OH-PBDEs) can bind to the serum-binding proteins transthyretin and thyroxine-binding globulin, can affect deiodinases (DI 1, 2 and 3) activity, and alter TH metabolism and excretion, leading to hypothyroidism in experimental animals (Butt et al. 2011; Marchesini et al. 2008; Meerts et al. 2000; Szabo et al. 2009; Zhou et al. 2002). Human studies also observed PBDE-associated TH disruption during pregnancy (Chevrier et al. 2010; Herbstman et al. 2008; Lin et al. 2011; Stapleton et al. 2011; Zota et al. 2011). Therefore, thyroid disruption may be a critical underlying mechanism related to the developmental neurotoxicity of PBDEs and their metabolites (Dingemans et al. 2011; Costa et al. 2008; Chen et al. 2014).
- Wang et al., 2016: in this in vivo study, pregnant Sprague-Dawley female rats were orally treated with either vehicle or BPA (0.05, 0.5, 5 or 50 mg/kg BW/day) during days 9-20 of gestation. Male offspring were tested on PND 21 with the object recognition task. BPA-exposed male offspring underwent memory and cognitive impairments: they not only spent more time (~ 43% more, at 1.5 hr after training) in exploring the familiar object at the highest dose than the control, but also displayed a significant decrease in the object recognition index (at 50 mg/kg BW/day, ~ 54% lower short term memory measured 1.5 hr after training).
- Jang et al., 2012: In this in vivo study pregnant female C57BL/6 mice (F0) were exposed to BPA (0.1-10 mg/kg) from gestation day 6 to 17, and female offspring (F2) from F1 generation mice were analysed. High-dose BPA (10 mg/kg) caused neurocognitive deficit (i.e., reduced memory retention) as shown by passive avoidance testing (~ 33% decrease vs control) in F2 mice. These results suggest that BPA exposure (NIS inhibition) in pregnant mothers could decrease hippocampal neurogenesis and cognitive function in future generations.
- Taylor et al., 2014: In this historical cohort study of 21,846 women in Cardiff, United Kingdom, and Turin, Italy, who were pregnant from 2002 to 2006, levels of urinary perchlorate (a NIS inhibitor) in the highest 10% were associated with a higher risk for having children with IQ scores in the lowest decile at age three, as described in 487 mother–child pairs in mothers who were hypothyroid/hypothyroxinemic during pregnancy.
- Chen et al., 2014: In this prospective birth cohort, maternal serum concentrations of BDE-47 and other PBDE congeners were measured in 309 women at 16 weeks of gestation, and associated with neurodevelopment in children. Importantly, BDE-47 and other chemicals, such as triclosan, triclocarban and BPA, have been reported to disturb TH homeostasis by inhibiting NIS-mediated iodide uptake and altering the expression of genes involved in TH synthesis in rat thyroid follicular FRTL-5 cells (Wu Y et al., 2016). A 10-fold increase in prenatal BDE-47 exposure was associated with a 4.5-point decrease in Full-Scale IQ and a 3.3-point increase in the hyperactivity score at age 5 years in children.
- Roze et al., 2009: Similarly, this epidemiological study assessed the level of several compounds, including BDE-47 (i.e., 2,2'-bis-(4 chlorophenyl)-1,1'-dichloroethene, pentachlorophenol (PCP), PCB-153, 4OH-CB-107, 4OH-CB-146, 4OH-CB-187, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154, and hexabromocyclododecane), in 62 mothers during the 35th week of pregnancy, and possible associations with the neuropsychological level in their children at 5-6 years of age. THs were determined in umbilical cord blood. Brominated flame retardants correlated with worse fine manipulative abilities, worse attention, better coordination, better visual perception, and better behavior. Chlorinated OHCs correlated with less choreiform dyskinesia. Hydroxylated polychlorinated biphenyls correlated with worse fine manipulative abilities, better attention, and better visual perception. The wood protective agent (PCP) correlated with worse coordination, less sensory integrity, worse attention, and worse visuomotor integration.
- van Wijk et al., 2008: This in vivo study assessed the behavioural effects of perinatal and chronic hypothyroidism during development in both male and female offspring of hypothyroid rats. To induce hypothyroidism, dams and offspring were fed an iodide-poor diet and drinking water with 0.75% sodium perchlorate (NIS inhibitor). Treatment was started in dams 2 weeks prior to mating, and in pups either until the day of killing (i.e., chronic hypothyroidism) or only until weaning (i.e., perinatal hypothyroidism) to test for reversibility of the effects observed. Early neuromotor competence, as assessed in the grip test and balance beam test, was impaired by both chronic and perinatal hypothyroidism. The open field test, assessing locomotor activity, revealed hyperactive locomotor behavioural patterns in chronic hypothyroid animals only. The Morris water maze test, used to assess cognitive performance, showed that chronic hypothyroidism affected spatial memory in a negative manner. Perinatal hypothyroidism was found to impair spatial memory in female rats only. In general, the effects of chronic hypothyroidism on development were more pronounced than the effects of perinatal hypothyroidism. This suggests that the early effects of hypothyroidism on functional alterations of the developing brain may be partly reversible.
- Kosugi et al. 1998; Ferrandino et al. 2017: Three Japanese children inherited two NIS mutations (V59E and T354P) from their healthy mother and father, respectively. V59E NIS was reported to exhibit as much as 30% of the activity of wild-type NIS (Fujiwara et al. 2000). The T354P and V59E NIS mutant proteins, when expressed in COS7 cells, were both trafficked to the cell surface, but totally inactive. The three siblings displayed different degrees of mental retardation, including heavy learning and memory deficits. The oldest one was nursed for longer than the second oldest, and evinced a less severe cognitive deficit. The youngest was not nursed, and displayed a more severe cognitive deficit than either of her siblings. It was discovered that the mother was addicted to laminaria, an alga extremely rich in I− (Ferrandino et al. 2017). These studies will be also cited in support of Essentiality for KE (MIE).
- Babu et al. 2011: in this in vivo study 50-day-old female rats weighing 120–150 g were switched to a low iodine diet (LID) and given 1% KClO4 (NIS inhibitor) in drinking water for 10 days. Animals were then separated into an iodine sufficient groups (or euthyroid) and a low iodine diet (or hypothyroxinemic) group (0.005% KClO4) and kept on above diet regimen for 3 months. Based on the hormonal estimations and urinary iodine, female rats were further divided into euthyroid and hypothyroxinemic and were mated with normal males. In a separate group of age-matched female rats, hypothyroidism was induced in rats by giving MMI (0.025% wt/vol) in drinking water to the pregnant rats from gestational day 8 and continued thereafter until sacrifice of pups born to these dams (hypothyroid group).
Data showed a significant reduction in total serum T4 and T3 levels of rat pups administered with MMI compared to euthyroid controls (3-fold decrease of T3 vs ctr and 7-fold decrease of T4 at P16). Hypothyroxinemic pups (on low iodine diet and KClO4) showed a reduction in serum T4 (~ 70% decrease of T4 vs ctr) but not in T3, which was increased compared to euthyroid levels at P16 (~ 40% increase of T3 vs ctr). Even in the presence of elevated circulating T3 levels, hypothyroxinemic pups showed significantly impairment of TH responsiveness in developing rat neocortex.
Both hypothyroid (MMI) and hypothyroxinemic (KClO4) pups demonstrated a significant increase in D2 levels compared to controls (~ 11 fold in hypothyroidism, and ~ 4 fold in hypothyroxinemia). The expression of D3 mRNA was also decreased significantly (by ~ 3.3 fold in hypothyroidism and ~ 3 fold in hypothyroxinemic group compared to controls), whilst MCT8 and TH nuclear receptors α1 and β1 expression did not change. Additionally, myelin basic protein (MBP) protein levels and gene were decreased in both groups (for MBP gene: by ~ 60% and ~ 70% respectively in hypothyroidism and hypothyroxinemic groups vs Ctr). Moreover, increased number of apoptotic neurons was found evenly distributed in all the layers of the neocortex under both hypothyroxinemic and hypothyroid conditions. As stated in this study, altogether these data suggest that hypothyroxinemia induced by low iodine diet and KClO4 may lead to learning and memory impairment in this model. However, memory or cognitive tests were not assessed in this study.
- Buras et al. 2014: in this in vivo study 9-10 week old mice were administered with drinking water containing 0.05% MMI and 1% KClO4 for 4 weeks to render them hypothyroid. After 4 weeks, the hypothyroid group was further divided into 3 groups: the hypothyroid (0.05% MMI + 1% KCL04), T3 (0.05% MMI + 1% KCL04 + T3 (0.5 μg/ml) in drinking water) and T4 (0.05% MMI + 1% KCL04 + T4 (5 μg/ml) in drinking water) groups for weeks 5 and 6. T3 serum levels were decreased by ~ 40% in hypothyroid group vs Ctr, and T4 was totally depleted in hypothyroid group vs Ctr. Several tests were performed to evaluate fear-anxiety behaviour. In the elevated plus maze, the hypothyroid mice showed significantly lower distance and time in the open arms than the T3-treated group (~ 50% for both parameters) than the euthyroid controls. The hypothyroid group also showed greater distance and time in the closed arms (~ 10% and 20% more than Ctr respectively for distance and time scores) than the T3-treated group. Administration of T3 and T4 rescued these effects. Moreover, hypothyroid mice froze more than Ctr (~ 35% more) and T3 and T4 treatments reversed this effect.
- Navarro et al. 2015: in this in vivo study 0.02% MMI and 1% KClO4 were added to the drinking water in rats starting at embryonic day 10 (E10, developmental hypothyroidism) and E21 (early postnatal hypothyroidism) until day of sacrifice at PND 50. Behavior was studied using the acoustic prepulse inhibition (somatosensory attention) and the elevated plus-maze (anxiety-like assessment) tests. Total plasmatic T4 levels of both E10 (1.86 ng/ml) and E21 (1.08 ng/ml) pups were significantly lower than those of Ctr (36.29 ng/ml) pups. Total plasmatic T3 levels of E10 (0.10 ng/ml) and E21 (0.10 ng/ml) were significantly lower than in Ctr (0.45 ng/ml) pups. E10 and E21 treated pups showed abnormal laminar organization of the hippocampus, critical brain structure for learning and memory processes. The distribution, density and size of VGluT1 and VGAT boutons in the hippocampus and somatosensory cortex was abnormal in hypothyroid pups (in both groups) and these changes correlated with behavioral changes: prepulse inhibition of the startle response amplitude was reduced (23.3% in E10, 43.0% in E21 and 79.0% in Ctr pups), indicating severe pre-attention deficit in treated pups, while the percentage of time spent in open arms increased (57.0% time spent in open arms in E21 and 81.1% in E10 pups, vs 17.1% Ctr pups, indicative of increased anxiety).
- Vasilopoulou et al. 2016: this in vivo study investigated the effects of adult onset hypothyroidism (induced by administration of 1% w/v KClO4 in their drinking water for 8 weeks in adult male Balb/cJ mice) on acetylcholinesterase (AChE) activity and on related behavioral parameters. They found that adult onset hypothyroidism (TH levels were not measured in this study) caused decrease of memory and increased fear/anxiety (i.e., 51% decrease of time spent in open arms / [times spent in open + closed arms], 47% decrease of the number of entries into the open arms of the apparatus, and 42% decrease in the total number of arm entries), and activity of both isoforms of AChE was reduced in all examined brain regions.
Uncertainties and Inconsistencies
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 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).
Quantitative Understanding of the Linkage
Temporal concordance of insufficient iodide uptake (as a consequence of NIS inhibition occurring upon exposure to perchlorate or other pollutants, such as BPA and BDE-47) and decreased cognitive functions has been documented by some epidemiological studies (Taylor et al., 2014; Chen et al., 2014; Roze et al. 2009) and have demonstrated that there are critical exposure windows during gestation/development where permanent changes are triggered.
For example, different degrees of TH insufficiency have been produced in dams and pups by administering varying doses of NIS inhibitor (e.g., sodium perchlorate) (van Wijk et al., 2008) or TPO inhibitors and assessing the dose-dependency of the observed effects on a variety of measurements. In these low dose model studies, the absence of overt signs of maternal or neonatal toxicity is taken as evidence of the temporal concordance of hormone insufficiency and neurodevelopmental impairment and the specificity of the observed effects on brain development to be mediated by TH insufficiency (van Wijk et al., 2008; Gilbert and Sui, 2006; Sharlin et al., 2007; Axelstad et al., 2008; Sharlin et al., 2008; Babu et al., 2011; Gilbert, 2011; Powell et al., 2012; Gilbert et al., 2013; Bastian et al., 2014; Gilbert et al., 2014; Gilbert et al., 2016).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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.
Viguié C, Collet SH, Gayrard V, Picard-Hagen N, Puel S, Roques BB, Toutain PL, Lacroix MZ (2013). Maternal and fetal exposure to bisphenol a is associated with alterations of thyroid function in pregnant ewes and their newborn lambs. Endocrinology. Jan;154(1):521-8.
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.