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Alexandra Rolaki, Francesca Pistollato, Sharon Munn and Anna Bal-Price* (*corresponding author: firstname.lastname@example.org)
European Commission Joint Research Centre, Directorate F - Health, Consumers and Reference Materials, Ispra, Italy
Point of Contact
Anna Price (email point of contact)
- Anna Price
|Author status||OECD status||OECD project||SAAOP status|
|Open for comment. Do not cite||EAGMST Approved||1.28||Included in OECD Work Plan|
This AOP was last modified on January 28, 2019 10:54
|Decrease of Thyroidal iodide||September 16, 2017 10:17|
|Thyroxine (T4) in neuronal tissue, Decreased||August 11, 2018 09:20|
|Reduced levels of BDNF||June 13, 2018 08:31|
|Decrease of synaptogenesis||September 16, 2017 10:14|
|Impairment, Learning and memory||June 13, 2018 08:45|
|Thyroxine (T4) in serum, Decreased||August 10, 2018 19:43|
|Decrease of GABAergic interneurons||September 16, 2017 10:15|
|Inhibition, Na+/I- symporter (NIS)||May 29, 2018 06:25|
|Decrease of neuronal network function||May 28, 2018 11:36|
|Thyroid hormone synthesis, Decreased||August 11, 2018 13:21|
|Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, Decreased||May 29, 2018 07:24|
|Thyroidal Iodide, Decreased leads to TH synthesis, Decreased||June 04, 2018 06:11|
|TH synthesis, Decreased leads to T4 in serum, Decreased||August 11, 2018 19:01|
|T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased||August 11, 2018 19:02|
|T4 in neuronal tissue, Decreased leads to BDNF, Reduced||May 30, 2018 12:28|
|BDNF, Reduced leads to GABAergic interneurons, Decreased||January 19, 2018 06:23|
|GABAergic interneurons, Decreased leads to Synaptogenesis, Decreased||January 19, 2018 06:27|
|Synaptogenesis, Decreased leads to Neuronal network function, Decreased||May 25, 2018 10:14|
|Neuronal network function, Decreased leads to Impairment, Learning and memory||January 26, 2018 10:32|
|Inhibition, Na+/I- symporter (NIS) leads to Impairment, Learning and memory||May 29, 2018 06:14|
|TH synthesis, Decreased leads to Impairment, Learning and memory||May 29, 2018 09:54|
|TH synthesis, Decreased leads to BDNF, Reduced||May 29, 2018 09:59|
|TH synthesis, Decreased leads to GABAergic interneurons, Decreased||May 29, 2018 10:11|
|BDNF, Reduced leads to Synaptogenesis, Decreased||May 29, 2018 12:43|
|BDNF, Reduced leads to Impairment, Learning and memory||May 29, 2018 05:55|
|Perchlorate||November 29, 2016 18:42|
|Nitrate||November 29, 2016 18:42|
|Thiocyanate||November 29, 2016 18:42|
|Dysidenin||November 29, 2016 18:42|
|Aryltrifluoroborates||November 29, 2016 18:42|
The thyroid hormones (TH) are essential for brain development, maturation, and function as they regulate the early key developmental processes such as neurogenesis, cell migration, proliferation, myelination and neuronal and glial differentiation. Normal human brain development and cognitive function relays on sufficient production of TH during the perinatal period. The function of Na+/I- symporter (NIS) is critical for the physiological production of TH levels in the serum, as it is a membrane bound glycoprotein that mediates the transport of iodide form the bloodstream into the thyroid cells, and this constitutes the initial step for TH synthesis. NIS is a well-studied target of chemicals, and its inhibition results in decreased TH synthesis and its secretion into blood leading to subsequent TH insufficiency in the brain with detrimental effects in neurocognitive function in children. The present AOP describes causative links between inhibition of NIS function (the molecular initiating event) leading to the decreased levels of TH in the blood and consequently in the brain, causing learning and memory deficit in children (Adverse outcome). Learning and memory depend upon the coordinated action of different brain regions and neurotransmitter systems creating functionally integrated neural networks. Hippocampus and cortex are the most critical brain structures involved in the process of cognitive functions in rodents and primates, including man. The overall weight of evidence for this AOP is strong. The function of NIS and its essentiality for TH synthesis is well known across species, however, quantitative information of KERs is limited.
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||424||Inhibition, Na+/I- symporter (NIS)||Inhibition, Na+/I- symporter (NIS)|
|2||KE||425||Decrease of Thyroidal iodide||Thyroidal Iodide, Decreased|
|3||KE||277||Thyroid hormone synthesis, Decreased||TH synthesis, Decreased|
|4||KE||281||Thyroxine (T4) in serum, Decreased||T4 in serum, Decreased|
|5||KE||280||Thyroxine (T4) in neuronal tissue, Decreased||T4 in neuronal tissue, Decreased|
|6||KE||381||Reduced levels of BDNF||BDNF, Reduced|
|7||KE||851||Decrease of GABAergic interneurons||GABAergic interneurons, Decreased|
|8||KE||385||Decrease of synaptogenesis||Synaptogenesis, Decreased|
|9||KE||386||Decrease of neuronal network function||Neuronal network function, Decreased|
|10||AO||341||Impairment, Learning and memory||Impairment, Learning and memory|
Relationships Between Two Key Events
(Including MIEs and AOs)
|Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, Decreased||adjacent||High||High|
|Thyroidal Iodide, Decreased leads to TH synthesis, Decreased||adjacent||High||High|
|TH synthesis, Decreased leads to T4 in serum, Decreased||adjacent||High||Moderate|
|T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased||adjacent||Moderate||Low|
|T4 in neuronal tissue, Decreased leads to BDNF, Reduced||adjacent||Moderate||Low|
|BDNF, Reduced leads to GABAergic interneurons, Decreased||adjacent||Moderate||Low|
|GABAergic interneurons, Decreased leads to Synaptogenesis, Decreased||adjacent||Moderate||Low|
|Synaptogenesis, Decreased leads to Neuronal network function, Decreased||adjacent||Low||Low|
|Neuronal network function, Decreased leads to Impairment, Learning and memory||adjacent||High||Low|
|Inhibition, Na+/I- symporter (NIS) leads to Impairment, Learning and memory||non-adjacent||Moderate||Low|
|TH synthesis, Decreased leads to Impairment, Learning and memory||non-adjacent||High||Moderate|
|TH synthesis, Decreased leads to BDNF, Reduced||non-adjacent||Low||Low|
|TH synthesis, Decreased leads to GABAergic interneurons, Decreased||non-adjacent||Low||Low|
|BDNF, Reduced leads to Synaptogenesis, Decreased||non-adjacent||Moderate||Low|
|BDNF, Reduced leads to Impairment, Learning and memory||non-adjacent||Moderate||Moderate|
Life Stage Applicability
|During brain development||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Rattus sp.||Rattus sp.||High||NCBI|
Overall Assessment of the AOP
This AOP refers mainly to humans and rodent species (principally rat) with regard to taxa. All the KEs are applicable to either sex ("mixed", as indicated under description of individual KEs and KERs), and the life-stage, for all the KEs, is defined as "during brain development", encompassing foetal and perinatal stage, continuing also during childhood and youth.
Biological Plausibility: The functional relationship between NIS and thyroidal iodide uptake is well established. In the human, NIS mutations are associated with congenital iodide transport defect, a condition characterized by low iodide uptake, hypothyroidism and goiter (Bizhanova and Kopp, 2009; De La Vieja et al., 2000; Pohlenz and Refetoff, 1999). The same is true for the relationship between iodide uptake and serum TH concentration, as it is known that Iodide Deficient (ID) suffer also by low thyroid levels in the blood (Wolff, 1998; DeLange, 2000). The correlation of serum and brain concentrations of TH are supported by a smaller amount of quantitative data but the biological plausibility of this connection is mainly based on the number of studies that show that the brain TH is proportional to the serum TH (Broedel et al., 2003). BDNF is thought to underlie the effects of developmental hypothyroidism but this notion is based mainly on their common physiological role during brain development rather than on solid experimental evidence (Gilbert and Lasley, 2013). On the other hand, the role of BDNF on the GABAergic interneurons development and function is well established, as many experimental data have been produced the last decades in support to this relationship (Woo and Lu, 2006; Palizvan et al., 2004; Patz et al., 2004). It is also widely accepted that the GABAergic signalling and therefore the proper function of GABAergic interneurons is fundamental for the normal synapse formation, which in turn controls the neuronal network formation, maturation and function. Numerous studies have shown that the depolarizing GABA signalling is controlled by the intracellular Cl- concentration in the postsynaptic cells and is the first drive for synapse formation (Wang and Kriegstein, 2008; Cancedda et al., 2007; Ge et al., 2006; Chudotvorova et al., 2005; Akerman and Cline, 2006). This early synaptogenesis period is critical for the establishment of the basic neuronal circuitry, despite the fact that synaptogenesis is a continuous process throughout life (Rodier, 1995). Neonatal hypothyroidism results in altered neuronal structure and function, including reduction in neurite outgrowth, synaptogenesis and dendritic elaborations. RC3/neurogranin is a gene directly regulated by thyroid hormone whose expression is consistent with a role in synapse formation and/or function (Munoz et al., 1991). The specific alterations in dendritic morphology have been identified in several cell types, including pyramidal cells in the cerebral cortex (decrease in dendritic spine number) (Schwartz, 1983), pyramidal cells in the visual cortex (reduced number and altered distribution of dendritic spines) (Morreale de Escobar et al., 1983), cholinergic basal forebrain neurons (decreased number of primary dendrites and number of dendritic branchpoints) (Gould and Butcher, 1989), Purkinje cells (decreased number and size of dendritic spines) (Nicholson and Altman, 1972; Legrand, 1979) and granule and pyramidal cells in the hippocampus (decreased branching of apical and basal dendrites) (Rami et al., 1986). Thus, TH influences the size, packing density and dendritic morphology of neurons throughout the brain, including myelination. Indeed, a striking phenotype in the hypothyroid neonatal brain is the reduction in myelin-protein gene expression (Farsetti et al., 1992; Pombo et al., 1999). However it should be noted that TH role during brain development is complex and still not fully understood.
Dose-response concordance: Multiple events were considered together in only limited number of studies. There is overwhelming evidence that supports the concordance of NIS inhibition with the decrease of thyroidal iodide uptake or the lower levels of serum TH but these two events have rarely been tested together. However, in the few cases that the levels of thyroidal iodide and the serum TH levels are measured in the same study the results are mostly conflicting, mainly due to the well-developed compensatory mechanisms that exist to maintain the TH levels in the body. That means that the effects of NIS inhibitors might not be detectable in short-term or low-dose experiments. Perchlorate is a well-described NIS inhibitor and the interpretation of related studies is straightforward because thyroid is considered the critical effect organ of perchlorate toxicity (National Research Council 2005); thus, any effects of perchlorate on the nervous system are necessarily interpreted to be subsequent to inhibition of iodide uptake by the thyroid gland and to a reduction in serum THs. Indeed, the use of potassium or sodium perchlorate has contributed to the identification of a dose-response relationships between NIS inhibition and thyroidal iodide uptake (Greer et al., 2002; Tonacchera et al., 2004; Cianchetta et al., 2010; Waltz et al., 2010; Lecat-Guillet et al., 2007; 2008) but the respective concordance with serum TH was not shown in most of these studies. On the other hand, in the human and animal studies that revealed a strong dose-dependent association between perchlorate exposure and circulating levels of TH (Blount et al., 2006; Cao et al., 2010; Suh et al., 2013; Steinmaus et al., 2007; Steinmaus et al., 2013; Siglin et al., 2000; Caldwell et al., 1995; Argus research laboratories 2001; York et al., 2003; York et al., 2004), the decrease of thyroidal iodide was not investigated. The downstream effects of TH insufficiency are better understood and documented but the majority of the dose-response data are derived from hypothyroid rodents after exposure with propylthiouracil (PTU) and methimazole (MMI), which is the most common used chemicals for the production of hypothyroid state to animals. Those types of experiments give information on the mechanisms through which TH insufficiency leads to neurodevelopmental deficits, but this pathway cannot be connected with NIS inhibition as data on specific NIS inhibitors is still lacking. In regards to the downstream events in the pathway, there is a strong correlation between each KE but the majority of the studies have been performed under severe hypothyroid conditions (high doses of PTU and/or MMI, thyroidectomies); therefore it is difficult to establish the dose-response relationships in each one of them. The association between serum TH levels and BDNF protein in the brain is very well documented but with the exception of few cases (Chakraborty et al., 2012; Blanco et al., 2013) no dose-response experiments are available. The same problem is also encountered in the relationship between BDNF levels and the GABAergic function, as there is only one recent study (Westerholz et al., 2013) that describes a correlation between these two events, but the results are described on the basis of T3 presence or complete absence in the cultures, which does not allow the establishment of dose-response evaluation. However, a dose-response relationship has been shown in earlier studies between the T3 hormone and the density of synapses in cortical cultures, an effect which was paralleled with the electrical activity of the network (Westerholz et al., 2010; Hosoda et al., 2003). More recently, a model of low level TH disruption has been developed, in which different concentrations of PTU have been tested and the subsequent dose-response relationships with GABAergic interneurons expression, synaptogenesis and learning and memory deficits were established (Sui and Gilbert, 2003; Gilbert and Sui, 2006; Gilbert, 2011; Gilbert et al, 2006, 2012; Berbel et al., 1996). Additionally, results from animal studies with perchlorate have also shown a dose-dependent reduction in excitatory and inhibitory synaptic function leading to learning and memory impairments (Gilbert and Sui, 2008). In contrast, there is only limited data in support to the correlation between TH insufficiency and the neuronal network function, and no dose-response relationship can be established.
Temporal concordance: In regards to temporality, the concordance between the KEs from the NIS inhibition until the TH levels in the brain is well-established. It is widely accepted that the most important role of iodine is the formation of the thyroid hormones (T4 and T3) and that iodine deficiency early in development can cause severe hypothyroidism leading to irreversible neurocognitive impairments (DeLange, 2000; Zimmermann et al., 2006). The majority of the data on TH insufficiency is derived from studies performed in different developmental stages and this study design facilitates the establishment of temporal concordance between the downstream KEs in the AOP. In general, TH insufficiency during the prenatal and early post-natal period is correlated with deficits in GABAergic morphology and function, especially of PV-positive interneurons (Berbel et al., 1996; Gilbert et al., 2007; Westerholz et al., 2010; 2013), with the decrease of active synapses and of synchronized electrical activity in cortical networks (Westerholz et al., 2010; Hosoda et al., 2003). This developmental window is known to be critical for the brain development and therefore TH deficits during this period has been correlated with mental retardation and other neurological impairments in children, which in some cases are irreversible (Mirabella et al., 2000; Porterfield and Hendrich, 1993). In at least two studies multiple KEs have been considered together and provide important information on the temporality of the AOP. Westerholz et al., 2010 and 2013 have shown that TH insufficiency during the first two postnatal weeks may cause alterations in the morphology and function of PV-positive GABAergic interneurons, with subsequent effects on the number of active synapses and the electrical activity of the neuronal network. During the same period the inhibition of BDNF function was shown to be also involved in the formation of synaptic connections (Westerholz et al., 2013). Further investigation of the mediating mechanisms revealed that a critical function in the above mentioned cascade was the timely shift of GABA signalling from depolarization to hyperpolarization, a milestone in brain development. The GABA switch takes place at the end of the second postnatal week in rodents, and thus we can conclude that all the KEs are performed during the perinatal period up to 14 days postnatal, which fits in the overall AOP, as this is the critical period for synaptogenesis and subsequently for the proper development of learning and memory functions.
Domain of Applicability
This AOP refers mainly to humans and rodent species (principally rat) with regard to taxa. All the KEs are applicable to either sex ("mixed", as indicated under description of individual KEs and KERs), and the life-stage, for all the KEs, is defined as "during brain development", encompassing foetal and perinatal stage, continuing also during childhood and youth.
Essentiality of the Key Events
No or contradictory experimental evidence
Weight of evidence for essentiality of MIE resulting in KE1 Decreased Thyroidal iodine and other KEs downstream is high. A number of studies have demonstrated that cessation of exposure to NIS inhibitors results in a return to normal iodine uptake (e.g. Greer et al., 2002, Russet et al., 2015), TH synthesis is recovered and TH levels return to their baseline values. For instance a recovery period of 15-30 days after the exposure to NIS inhibitor (perchlorate) showed that the inhibitory effects were eliminated almost completely, as the measurements of iodide uptake (Greer et al., 2002) and serum TH levels (Siglin et al., 2000) were indistinguishable from their respective baseline values. Also, the use of cells that did not endogenously express the NIS transfer protein prevented completely iodide uptake that was reversed by hNIS transfection (Cianchetta et al., 2010).
Three Japanese children inherited two NIS mutations (V59E and T354P) from their healthy mother and father, respectively (Kosugi et al. 1998; Ferrandino et al. 2017). 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).
Iodine deficiency is regulated by an addition of iodine to salt and other dietary products. Increased iodine levels in diet compensates decreased TH synthesis and TH levels in blood (Rousset et al., 2015. Dun 1998, 2002; International Council for Control of Iodine Deficiency Disorders. Current Iodine Deficiency Disorders Status Database. http://www.iccidd.org .
In pregnant women mild hypothyroxinemia due to iodine deficiency leads to altered neurocognitive performance (AO of this AOP) of the progeny. This hypothyroxinemia was corrected with iodine supplements during the first trimester (La Gamma et al., 2006).
In vitro study using thyroid follicular FRTL-5 cells, showed that incubation with hydrogen peroxide decreased NIS-mediated I- transport, and this effect as reverted by adding ROS scavengers (Arriagada et al., 2015).
Thyroid hormone synthesis, Decreased
Several studies have proven that NIS inhibitors lead to a decrease of thyroidal iodide uptake resulting in a reduction of TH synthesis (e.g. Jones et al., 1996; Tonacchera et al., 2004; De Groef et al., 2006; Waltz et al., 2010). Removing exposure to NIS inhibitors reverses decreased TH synthesis (as described above). Similar studies are published for decreased TH synthesis induced by TPO inhibitors.
Thyroid gland T4 concentrations as well as serum TH are decreased in response to thyroidectomy where TH synthesis takes place, and recovered when in-vitro derived follicles are grafted in athyroid mice (Antonica et al., 2012).
T4 in serum,
There is strong evidence that decreased Thyroxine (T4) synthesis in the thyroid gland results in decreased T4 concentration in serum ((Dong et al., 2017; Calil-Silveira et al., 2016; Tang et al., 2013; Liu et al., 2012; Pearce et al., 2012). Recovery experiments (cessation an exposure to NIS or TPO inhibitors) demonstrate recovery of serum T4 concentrations (Dong et al., 2017; Calil-Silveira et al., 2016; Tang et al., 2013; Liu et al., 2012; Pearce et al., 2012; Steinmaus, 2016a, 2016b; Wu Y et al., 2016).
T4 or T3 treatment during critical developmental windows, was shown to restore (or reduce) structural alterations in brain (Goodman and Gilbert, 2007; Auso et al., 2004; Lavado-Autric et al., 2003; Berbel et al., 2010; Koibuchi and Chin, 2000). For instance, Auso et al., 2004 showed that infusion of dams with T4 between E13 and E15 prevented alterations of the cytoarchitecture and the radial distribution of BrdU+ neurons in the somatosensory cortex and hippocampus (Auso et al., 2004).
T3 or T4 were administered to wild-type (WT) and to Mct8KO mice previously made hypothyroid. The Mct8KO mice only responded to T4 which reached the brain in the Mct8-deficient mice through Oatp1c1 transporter. D2 activity was responsible for normal expression of most brain TH-regulated functions that was compromised in the absence of Mct8 (Morte et al., 2010; Bernal, 2015).
Calvo et al. (1990) showed that T4 and T3 administration restored both serum and tissue levels of TH in gestating hypothyroid rats.
Vara et al., 2002 showed that T3 administration in hypothyroid rats recovered neuronal network function, as shown by analysis of Ca(2+)-dependent neurotransmitter release.
Sawano et al., 2013 showed that GAD65 protein (GABAergic marker) was reduced by more than 50% of control in the hippocampus of hypothyroid rats, but daily T4 replacement after birth recovered GAD65 protein to control levels.
In humans, hormone insufficiency that occurs in mid-pregnancy due to maternal drops in serum hormone, and that which occurs in late pregnancy due to disruptions in the fetal thyroid gland lead to different patterns of cognitive impairment (Zoeller and Rovet, 2004). In animal models, deficits in hippocampal-dependent cognitive tasks result from developmental, but not adult hormone deprivation (Gilbert and Sui, 2006; Gilbert et al., 2016; Axelstad et al, 2009; Gilbert, 2011; Opazo et al., 2008). Replacement studies have demonstrated that varying adverse neurobehavioral outcomes, including learning and memory impairment, can be reduced or eliminated if T4 (and/or T3) treatment is given during the critical windows (e.g., Kawada et al., 1988; Reid et al., 2007).
While T4 and T3 administration restored both serum and tissue levels of TH in gestating hypothyroid rats, recovery of TH levels (in serum and tissues) occurred only partially in fetal tissues (Calvo et al., 1990).
Wang et al., 2012 have shown that L-T4 treatment (at GD10 and GD13) ameliorated the adverse effect of maternal subclinical hypothyroidism on spatial learning and memory (AO) in the offspring.
Wang et al., 2012 also showed that T4 treatment ameliorated BDNF expression changes in the progeny of rats with subclinical hypothyroidism.
Pathak et al, 2011 showed that TH administration (at E13-15 in MMI-treated rat dams) recovered the number and length of radial glia, the loss of neuronal bipolarity, and the impaired neuronal migration (indicative of decreased synaptogenesis) observed in hypothyroid offspring.
Di Liegro et al. (1995) showed that in primary cultures T3 treatment induces the expression of synapsin I (increased synaptogenesis).
Infusion of dams with T4 after E18 did not prevent alterations of somatosensory cortex and hippocampus cytoarchitecture (Auso et al., 2004).
Wang et al., 2012 also showed that T4 treatment at GD17 had only minimal effects on spatial learning in the offspring.
Gilbert et al., 2007 showed that PV+ cells (GABAergic) were diminished in the hippocampus and neocortex of hypothyroid offspring. Return of TH to control levels in adulthood was not associated with higher PV+ cell numbers.
T4 in neuronal tissue
Several studies have demonstrated that fetal brain TH levels, previously decreased by maternal exposure to TH synthesis inhibitors or thyroidectomy, recovered following maternal supply of T4 (e.g., Calvo et al., 1990). However, there are no studies with direct infusion of T4 or T3 directly into brain.
The upregulation of deiodinase has been shown to compensate for some loss of neuronal T3 (Escobar-Morreale et al., 1995; 1997).
Indirect evidence shows that T4 replacement that brings circulating T4 concentration back to physiological levels normal, leads to recovery of brain TH and prevents downstream effects including alterations in cell morphology, differentiation and function.
BDNF release, Reduced
It is well known fact that BDNF is critical for neuronal differentiation and maturation, including synaptic integrity and neuronal plasticity in hippocampus and cortex, two brain structures that are essential for learning and memory processes in animals and humans. Limited data from studies in BDNF knockout animals demonstrate that deficits in hippocampal synaptic transmission and plasticity, and downstream key events can be rescued with recombinant BDNF (Aarse et al., 2016; Andero et al., 2014). Afew examples are briefly described below.
In in vivo studies on hypothyroid rat models, exposed to TPO inhibitors (MMI, PTU), and/or NIS inhibitor (perchlorate) offspring showed reductions in BDNF mRNA and protein levels, and the most affected brain regions were two brain structures critical for learning and memory processes, such as hippocampus and cortex, and the cerebellum (Koibuchi et al., 1999; 2001; Sinha et al., 2009; Neveu and Arenas, 1996; Gilbert and Lasley, 2013). Following a T4 dosing regimen in rats an increased BDNF mRNA and protein expression was observed (e.g. Camboni et al., 2003; Lüesse et al., 1998). Inhibition of BDNF by K252a (a TrK antagonist) in cultures containing T3 resulted in decreased number of synaptic boutons, (critical for synaptogenesis) as in the T3-deprived cultures (Westerholz et al., 2013). T3-deficient rat cultures of cortical PV+ GABA interneurons, found that the number of synaptic boutons was reduced but exogenous BDNF application abolished this effect (Westerholz et al., (2013).
Limited data from studies in BDNF knockout animals demonstrate that deficits in hippocampal synaptic transmission and plasticity, and downstream behaviors can be rescued with recombinant BDNF (Aarse et al., 2016; Andero et al., 2014).
Aguado et al., 2003 showed that BDNF overexpression in transgenic embryos increased the number of synapses (increased synaptogenesis), and increased spontaneous neuronal activity (increased neuronal network function), and increased the number of GABAergic interneurons, indicating that BDNF is essential to control both GABAergic pre- and postsynaptic sites.
Neveu and Arenas, 1996 found that early hypothyroidism (by PTU administration to rat dams) decreased the expression of neurotrophin 3 (NT-3) and BDNF mRNA. Grafting of P3 hypothyroid rats with cell lines overexpressing BDNF (or NT-3) prevented hypothyroidism-induced cell death in neurons of the internal granule cell layer at P15.
BDNF application elicits presynaptic changes in GABAergic interneurons, as several presynaptic proteins were up-regulated after BDNF application (Yamada et al., 2002; Berghuis et al., 2004). Increase of GABAA receptor density was observed in cultured hippocampus-derived neurons after treatment with BDNF (Yamada et al., 2002).
Westerholz et al., (2013), by using rat T3-deficient cultures of cortical PV+ interneurons, found that the number of synaptic boutons (critical for synaptogenesis) was reduced but exogenous BDNF application abolished this effect.
In this in vivo study, the protein synthesis inhibitor anisomycin (Ani; 80 μg/0.8 μl per side) was injected in the dorsal hippocampus of Male Wistar rats (2.5 months) 12 h after inhibitory avoidance (IA) training (i.e., using a strong foot shock, which generates a persistent LTM), which causes a selective deficit in memory retention 7 days, but not 2 days, after training. Human recombinant BDNF (hrBDNF, 0.25 μg/0.8 μl per side) or vehicle (Veh) was delivered 15 min after Ani infusion into the hippocampus. hrBDNF completely rescued long-term memories (LTM) at 7 days after training caused by Ani given at 12 h after training. Additionally, infusion of BDNF antisense oligonucleotides (i.e., BDNF ASO, which blocks the expression of BDNF 12 h after training) into the dorsal hippocampus 10 h after training, was found to impair persistence (a characteristic feature of LTM), but not formation of IA LTM (as compared with BDNF missense oligonucleotide). This indicates that BDNF during the late posttraining critical time period is not only required but sufficient for persistence of LTM storage (Bekinschtein et al. 2008).
In this study the role of BDNF in both short and long term memories (STM and LTM) formation of a hippocampal-dependent one-trial fear-motivated learning task was examined in male Wistar rats (2–3 months). IA training was found associated with a rapid and transient increase in BDNF mRNA expression (by 90%, 1 hr after IA training) in the hippocampus. Bilateral infusions of function-blocking anti-BDNF antibody (0.5 µg/side) into the CA1 region of the dorsal hippocampus decreased ERK2 activation, and blocked STM formation. On the contrary, intrahippocampal administration of rhBDNF (0.25 µg/side) increased ERK1/2 activation and facilitated STM. These results strongly indicate that endogenous BDNF is required for both STM and LTM formation of an IA learning (Alonso et al. 2002).
Beta-estradiol (E2) induced synaptogenesis by enhancing BDNF release from dentate gyrus (DG) granule cells measuered by increased the expression of PSD95, a postsynaptic marker. E2 effects were completely inhibited by blocking the BDNF receptor (TrkB) with K252a or by using a function-blocking antibody to BDNF, which inhibited the expression of PSD95. Both K252a and the antibody anti-BDNF elicited a decrease of spine density (presynaptic sites) (Sato et al., 2007).
Intrahippocampal microinfusion of BDNF modulated the ability of the hippocampal mossy fiber pathway to produce long-term potentiation (LTP) by high frequency stimulation. On the opposite, administration of the TrkB inhibitor K252a, in combination with BDNF, blocked the functional and morphological effects produced by BDNF (Schjetnan and Escobar, 2012). These data confirm the role of BDNF in the regulation of synaptic plasticity and Neuronal Network Function (KE downstream)
In heterozygous BDNF knockout (BDNF+/-) mice, a decrease of NMDAR-independent mossy fiber LTP occurred. Inhibition of TrkB/BDNF signalling with K252a, or with the selective BDNF scavenger TrkB-Fc inhibited mossy fiber LTP to the same extent as observed in BDNF+/- mice Schildt et al., (2013), supporting an important role of BDNF in Neuronal Network Function (KE downstream).
Exogenous application of BDNF in developing neocortical and hippocampal GABAergic interneurons has demonstrated an enhanced dendritic elongation and branching in cultures (synaptogenesis) (Jin et al., 2003; Vicario-Abejon et al., 1998; Marty et al., 2000).
Endogenous BDNF promotes interneuron differentiation (Kohara et al., 2003).
KE6 GABAergic interneurons, Decreased
There are limited studies in a support of this KE.
Prenatal exposure to TPO inhibitors (PTU or MMI, to induce hypothyroidism), decreased number of the GABAergic interneurons (parvalbumin (PV)+ cells) and glutamic acid decarboxylase 65 (GAD65)+ cells (e.g. Sawano et al., 2013; Shiraki et al., 2012; Gilbert et al., 2007).
Bisphenol-A (BPA), inhibitor of NIS (Wu Y et al., 2016) decreased KCC2 mRNA expression and attenuated [Cl−]i shift in migrating cortical inhibitory precursor neurons, as observed in primary rat and human cortical neurons (Yeo et al., 2013).
Transcriptional repression of KCC2 (responsible for neuronal Cl− homeostasis) delays the GABAergic switch (Yeo et al., 2009). The absence of T3 in cultures of cortical GABAergic interneurons also delays the developmental KCC2 up-regulation and subsequently the GABA shift, with a profound decrease in the number of synapses (Westerholz et al., 2010; 2013), proving that early synapto-genesis network activity is under control of TH mediated through Gabaergic inetrneurons.
The connectivity and functionality of neural networks depends on where and when synapses are formed (synaptogenesis). Therefore, the decreased synapse formation during the process of synaptogenesis is detrimental and leads to decrease of neural network formation and function. The neuronal electrical activity dependence on synapse formation and is critical for proper neuronal communication. Alterations in synaptic connectivity lead to refinement of neuronal networks during development (Cline and Haas, 2008). It is well established fact that hypothyroidism decreases synaptogenesis resulting in synaptic transmission and plasticity impairments (Vara et al., 2002, Sui and Gilbert, 2003, Gilbert, 2004, Dong et al., 2005, Sui et al., 2005; Gilbert and Paczkowski, 2003, Gilbert and Sui, 2006, Gilbert, 2011, Gilbert et al., 2013). Indeed, pyramidal neurons of hypothyroid animals have fewer synapses and an impoverished dendritic arbor (Rami et al., 1986, Madeira et al., 1992). It has been demonstrated that the decreased expression of genes critical for synaptogenesis (e.g. Srg1, RC3/neurogranin, a Hairless Homolog) in hypothyroidism rats can be reversed by an administration of TH (Thompson, 1996; Potter et al., 2001; Thompson and Potter, 2000). For example Srg1 (Synaptotagmin-related gene 1) mRNA expression is reduced ~3-fold in rat hypothyroid cerebellum. Injection of thyroid hormone causes a very rapid induction of Srg1 (in 2 hrs) (Thompson, 1996; Potter et al., 2001) suggesting that this gene is a direct target of thyroid hormone action.
In mutant mice lacking PSD-95, it has been recorded increase of NMDA-dependent LTP, at different frequencies of synaptic stimulation that cause severe impaired spatial learning, without thought affecting the synaptic NMDA receptor currents, subunit expression, localization and synaptic morphology (Migaud et al., 1998). Furthermore, recent genetic screening in human subjects and neurobehavioural studies in transgenic mice have suggested that loss of synaptophysin plays important role in mental retardation and/or learning deficits (Schmitt et al., 2009; Tarpey et al., 2009).
It is well understood and documented that the ability of neurons to communicate with each other is based on neural network formation that relies on functional synapse establishment (Colón-Ramos, 2009). Indeed, decreased neuronal network function in developing brain (dysfunction of synaptic connectivity, transmission and plasticity) contribute to the impairment of learning and memory. A number of studies have linked exposure to TPO inhibitors (e.g., PTU, MMI), as well as iodine deficient diets, to changes in serum TH levels, which result in alterations in both synaptic function within neuronal networks and cognitive behaviors (Akaike et al., 1991; Vara et al., 2002; Gilbert and Sui, 2006; Axelstad et al., 2008; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). It is well documented that hippocampal regions (i.e., area CA1 and dentate gyrus) exhibit alterations in network function of excitatory and inhibitory synaptic transmission following reductions in serum TH in the pre and early postnatal period (Vara et al., 2002; Sui and Gilbert, 2003; Sui et al., 2005; Gilbert and Sui, 2006; Taylor et al., 2008; Gilbert, 2011; Gilbert et al., 2016). These deficits persist into adulthood, long after recovery to euthyroid status, suggesting that they might be only partially reversible.
Learning and memory,
The essentiality of the relationship between decreased TH levels and learning and memory deficit is well-documented based on the existing literature. TH plays a critical role for normal nervous system development and function, including learning and memory processes (e.g. Williams, 2008; Bernal, 2015). This includes particularly development of the hippocampus and cortex, two brain regions that play a major role in spatial, temporal, and contextual memory. Indeed, most developed countries check for childhood hypothyroidism at birth to immediately begin replacement therapy. This has been shown to alleviate most adverse impacts of hypothyroidism in congenitally hypothyroid children (Derksen-Lubsen and Verkerk 1996; Zoeller and Rovet, 2004). Similar results are also produced in animal studies showing that T4 treatment reverses spatial learning deficits induced by maternal hypothyroidism in rats (e.g. Wang et al., 2012). In the context of NIS inhibitors Taylor and co-workers found that levels of urinary perchlorate assessed in a cohort study of 21,846 women, were positively associated with a higher risk for children having lower IQ scores at 3 years of age (Taylor et al., 2014).
Some semi-quantitative data are available for the described KERs; however, further experimental work is needed to define thresholds suitable to assess when a given KE-downstream will be triggered by the KE-upstream.
Considerations for Potential Applications of the AOP (optional)
The US EPA and OECD Developmental Neurotoxicity (DNT) Test Guidelines (OCSPP 870.6300 and OECD 426, respectively) require testing of learning and memory. These DNT guidelines are based entirely on in vivo experiments, which are costly, time consuming, and unsuitable for testing a larger number of chemicals. At the same time the published data strongly suggest that environmental chemicals contribute to the recent observed increase of neurodevelopmental disorders in children such as lowered IQ, learning disabilities, attention deficit hyperactivity disorder (ADHD) and, in particular, autism. This highlights the pressing need for standardised alternative methodologies that can more rapidly and cost-effectively screen large numbers of chemicals for their potential to cause cognitive deficit in children.
This AOP can encourage the development of new in vitro test battery anchored to the KEs identified in the AOP. The majority of KEs in this AOP has strong essentiality to induce the AO (impairment of learning and memory) and established indirect relationship with the AO that would allow not only the development of testing methods that address these specific KEs but also the understanding of the relationship between the measured KEs and the AO.
Therefore, this AOP can potentially provide the basis for development of a mechanistically informed Integrated Approaches and Testing Assessment (IATA) to identify chemicals with potential to cause impairment of learning and memory. It should be noted that it not necessary to quantify all the intermediate KEs defined in an AOP pathway to enable computational modelling to proceed to a quantitative model that would predict cognitive outcomes from in vitro data.
This AOP stimulated recent efforts to develop screening radioactive (Dohan et al., 2003; Riesco-Eizaguirre and Santisteban, 2006) and non-radioactive (Waltz et al., 210) in vitro assays to detect potential NIS inhibitors that could inform quantitative structure activity relationships, read-across models, and/or systems biology models to prioritize chemicals for further testing (Waltz et al., 2010).
Finally, this AOP could provide the opportunity to group chemicals based not only on their physical- chemical properties but also their biological activity (biological grouping) referring to the triggered key events.
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