Upstream eventT4 in serum, Decreased
T4 in neuronal tissue, Decreased
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low|
|XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low|
|Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||High||Low|
|Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment||adjacent||Moderate||Low|
Life Stage Applicability
|During brain development||High|
|All life stages||Moderate|
Key Event Relationship Description
In mammals, thyroxine (T4) in brain tissue is derived almost entirely from the circulating pool of T4 in blood. Transfer of free T4 (and to a lesser extent, T3) from serum binding proteins (thyroid binding globulin (TBG), transthyretin (TTR) and albumin; see McLean et al., 2017, for a recent review) into the brain requires transport across the blood brain barrier (BBB) and/or indirect transport from the cerebral spinal fluid (CSF) into the brain through the blood-CSF-barrier. The blood vessels in rodents and humans express the main T4 transporter, MCT8, (Roberts et al. 2008), as does the choroid plexus which also expresses TTR and secretes the protein into the CSF (Alshehri et al. 2015).
T4 entering the brain through the BBB is taken up into astrocytes via cell membrane iodothyronine transporters (e.g., organic anion-transporting polypeptides) (Visser et al., 2011). In astrocytes, T4 is then deiodinated by Type II deiodinase to triiodothyronine (T3) (St Germain and Galton, 1997), which is then transported via other iodothyronine transporters (e.g., monocarboxylate transporter) into neurons (Visser et al., 2011). While some circulating T3 may be taken up into brain tissue directly from blood (Dratman et al., 1991), the majority of neuronal T3 comes from deiodination of T4 in astrocytes. Decreases in circulating T4 will result in decreased brain T3 tissue concentrations. It is also known that Type II deiodinase can be up-regulated in response to decreased T4 concentrations to maintain tissue concentrations of T3 (Pedraza et al., 2007; Lavado-Autric et al., 2013; Morse et al., 1986), except in tanycytes of the paraventricular nucleus (Fekete and Lechan, 2014).
T4 and T3 are synthesized by NIS and TPO in the thyroid gland as iodinated thyroglobulin (Tg) and stored in the colloid of thyroid follicles. Secretion from the follicle into serum is a multi-step process. The first involves thyroid stimulating hormone (TSH) stimulation of the separation of the peptide linkage between Tg and TH. The next steps involve endocytosis of colloid, fusion of the endosome with the basolateral membrane of the thyrocyte, and finally release of TH into the blood. More detailed descriptions of this process can be found in reviews by Braverman 2012, Utiger 2006, and Zoeller et al., 2007.
Monocarboxylate transporter 8 (MCT8) is a specific human transporter for the T4 and T3 that allows their entry in the brain and other organs. Mutations in MCT8 (Allan-Herndon-Dudley syndrome, AHDS) lead to a severe form of X-linked truncal hypotonia, spasticity, mental retardation (or 'cretinism'), and are characterised by normal to high TSH, elevated plasma T3, low T4, and decreased TH signaling in discrete brain areas (McAninch and Bianco, 2014; Anık et al., 2014; López-Espíndola et al., 2014).
Other in vivo studies have proven direct associations between levels of serum T4 and the levels of TH-dependent signalling in the brain (i.e., brain TH levels). For instance, mice characterized by single MCT8 deficiency showed low serum T4, elevated serum TSH and T3, and decreased T3-dependent gene expression in both the hypothalamus and the cortex (Stohn et al., 2016). Analogously, another study reported that MCT8 knock-out mice were characterized by high serum T3, low serum T4, and decreased forebrain TH content (Müller et al., 2014). The hippocampus seems to be one of the brain regions mostly affected by low TH levels, as shown in thyroidectomized Wistar rats, which resulted affected by hippocampal hypothyroidism (da Conceição et al., 2016). These data altogether support direct associations between levels of serum T4 and levels of TH-dependent signalling in the brain (i.e., brain TH levels).
Evidence Supporting this KER
The weight of evidence linking reductions in circulating serum TH and reduced brain concentrations of TH is moderate. Many studies support this basic linkage. However, there are compensatory mechanisms (e.g., upregulation of deiodinases, transporters) that may alter the relationship between hormones in the periphery and hormone concentrations in the brain. There is limited information available on the quantitative relationship between circulating levels of TH, these compensatory processes, and neuronal T4 concentrations, especially during development. Furthermore, in certain conditions, such as iodine deficiency, the decreases in circulating hormone might have greater impacts on tissue levels of TH (see for instance, Escobar del Rey, et al., 1989).
The biological relationship between these two KEs is strong as it is well accepted dogma within the scientific community. There is no doubt that decreased circulating T4 leads to declines in tissue concentrations of T4 and T3 in a variety of tissues, including brain. However, compensatory mechanisms (e.g., increased expression of Type 2 deiodinase) may differ during different life stages and across different tissues, especially in different brain regions. Similarly, the degree to which serum TH must drop to overwhelm these compensatory responses has not been established.
Several studies have shown that tissue levels (including the brain) of TH are proportional to serum hormone level (Oppenheimer, 1983; Morreale de Escobar et al., 1987; 1990; Calvo et al., 1992; Porterfield and Hendrich, 1992, 1993; Broedel et al., 2003). In thyroidectomized rats, brain concentrations of T4 were decreased and Type II deiodinase (DII) activity was increased. Both brain T3 and T4 as well as DII activity returned to normal following infusion of T4 (Escobar-Morreale et al., 1995; 1997). Animals treated with PTU, MMI, or iodine deficiency during development demonstrate both lower serum and lower brain TH concentrations (Escobar-Morreale et al 1995; 1997; Taylor et al., 2008; Bastian et al., 2012; 2014; Gilbert et al., 2013).
Temporal Evidence: For the current AOP the temporal nature of this KER is described in the context of different developmental stages (Seed et al., 2005). While all brain regions will be impacted by changes in serum hormones, brain concentrations will be a function of development stage and brain region. Data are available from thyroid hormone replacement studies that demonstrate recovery of fetal brain T3 and T4 levels (following low iodine diets or MMI exposure) to control levels after maternal thyroid hormone replacement or iodine supplementation (e.g., Calvo et al.,1990; Obregon et al., 1991). For example, Calvo et al. (1990) carried out a detailed study of the effects of TPO inhibition on serum and tissues levels of TH in gestating rats. Clear dose-dependent effects of T4 replacement, but not T3 replacement were seen in all maternal tissues. However, for fetal tissues, neither T4 nor T3, at any dose, could completely restore tissue TH levels to control levels.
Dose-Response Evidence: There is good evidence, albeit from a limited number of studies of the correlative relationship between circulating thyroid hormone concentrations and brain tissue concentrations during fetal and early postnatal development following maternal iodine deficient diets or chemical treatments that depress serum THs (c.f., Calvo et al., 1990; Obregon et al., 1991; Morse et al.,1996)
Empirical support for the linkage comes from pathological analyses of human brain tissues and in vivo studies on MCT8 knock-out mice and thyroidectomized rats.
Four male patients affected by AHDS from two unrelated Turkish families (age from 1.5 to 11 years) presented high plasma T3, low plasma T4 and rT3, and normal/mildly elevated TSH levels. Functional analysis of a novel missense MCT8 mutation (p.G495A) revealed lowered TH transport (from 20 to 85%) depending on the cell/tissue context. Phenotypically, patients were characterized by severe psychomotor retardation, axial hypotonia, lack of speech, diminished muscle mass, increased muscle tone, hyperreflexia, myopathic facies (Anık et al., 2014).
Another study analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy in comparison with brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy, as controls. The MCT8-deficient fetal cerebral cortex showed 50% reduction of TH (i.e., T4, T3, and rT3), while T3 and T4 levels were normal in the liver. This TH deficiency in the brain produced an expected increase in type 2 deiodinase and decrease in type 3 deiodinase mRNA expression. Also, MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy displayed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression (López-Espíndola et al., 2014).
Several in vivo studies have proven direct associations between levels of serum T4 and the levels of TH-dependent signalling in the brain (i.e., brain TH levels). For instance, mice characterized by single MCT8 deficiency showed low serum T4, elevated serum TSH and T3, and decreased T3-dependent gene expression in both the hypothalamus and the cortex (Stohn et al., 2016).
Analogously, another study reported that MCT8 knock-out mice were characterized by high serum T3, low serum T4, and decreased forebrain TH content, while TH concentrations in the liver, kidneys, and thyroid gland resulted increased (Müller et al., 2014).
The hippocampus, critical brain structure for cognitive, learning and memory processes, seems to be one of the brain regions mostly affected by low TH levels, as shown in thyroidectomized Wistar rats, which resulted affected by hippocampal hypothyroidism. Thyroidectomized rats were characterized by increased serum TSH, decreased T4 and T3 serum levels, and a reduced hippocampal expression of MCT8, thyroid hormone receptor alfa, deiodinase type 2, ectonucleotide pyrophosphatase/phosphodiesterase 2 and brain-derived neurotrophic factor (BDNF) genes (da Conceição et al., 2016). These data altogether support direct associations between levels of serum T4 and levels of TH-dependent signalling in the brain (i.e., brain TH levels).
Uncertainties and Inconsistencies
The ability of the developing brain to compensate for TH insufficiency is not well known. Limited data is available that demonstrates that the developing brain can compensate for chemical-induced alterations in TH concentrations (e.g., Calvo et al., 1990; Morse et al., 1996; Sharlin et al., 2010). There are likely different quantitative relationships between these two KEs depending on the compensatory ability based on both developmental stage and specific brain region (Sharlin et al., 2010). For these reasons, the empirical support for this linkage is rated as moderate. In addition, future work on transport mechanisms and deiodinase activity may add additional KEs and KERs to this AOP.
Quantitative Understanding of the Linkage
While it is well established that decreased in serum TH levels result in decreased brain TH concentrations, particularly fetal brain concentrations, a major gap is the lack of empirical data that allow direct quantification of this relationship.
There may also be different quantitative relationships between these two KEs depending on the compensatory ability of different developing brain regions (Sharlin et al., 2010).
- Fisher et al., (2013) recently published a quantitative biologically-based dose-response model (BBDR) for iodine deficiency in the rat. In particular, HPT axis adaptations to dietary iodide intake in euthyroid (4.1-39 µg iodide/day) and iodide-deficient (0.31 and 1.2 µg iodide/day) conditions were evaluated. In rat pups that were iodide deficient during gestation and lactation, decreases in serum T4 levels were associated with declines in TH levels in the fetal brain and a suppression of synaptic responses in the hippocampal region of the brain of the adult offspring (Gilbert et al., 2013).
- Anık et al., 2014 Four males with AHDS from two unrelated Turkish families (age from 1.5 to 11 years) presented high plasma T3, low plasma T4 and rT3, and normal/mildly elevated TSH levels. Functional analysis of a novel missense MCT8 mutation (p.G495A) revealed lowered TH transport to organs (including the brain) (from 20 to 85%) depending on the cell/tissue context.
- López-Espíndola et al., 2014 This study analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy in comparison with brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy, as controls. The MCT8-deficient fetal cerebral cortex showed 50% reduction of TH (i.e., T4, T3, and rT3), while T3 and T4 levels were normal in the liver. This TH deficiency in the brain produced an expected increase in type 2 deiodinase and decrease in type 3 deiodinase mRNA expression.
- Stohn et al., 2016 In this study, mice characterized by single MCT8 deficiency showed low serum T4 (~ 47% decrease vs control mice, at age P21), elevated serum TSH (~ 125% increase vs control mice, at age P21) and T3 (~ 33% increase vs control mice, at age P21), and decreased T3-dependent gene expression in both the hypothalamus (~ 57% decrease vs control mice, at age P21) and the cortex (~ 40% decrease vs control mice, at age P21), as indicated by the lower expression of the rat hairless (hr) gene, which is highly up-regulated by TH in the developing CNS.
- Müller et al., 2014 This study reported that MCT8 knock-out mice were characterized by high serum T3 (~ 100% increase at P21, and ~ 300% increase at 2.5 months of age, compared to control mice), low serum T4 (~ 62% decrease at P21, and ~ 50% decrease at 2.5 months of age, compared to control mice), and decreased TH content in the forebrain (~ 43% decrease for both T3 and T4, at 2.5 months of age, compared to control mice), while TH concentrations in the liver, kidneys, and thyroid gland resulted increased.
- da Conceição et al., 2016 Thyroidectomized Wistar rats resulted affected by hippocampal hypothyroidism. Thyroidectomized rats were characterized by increased serum TSH (~ 750% increase vs control rats), decreased T4 (~ 80% decrease vs control rats) and T3 (~ 45% decrease vs control rats) serum levels, and a reduced hippocampal expression of MCT8 (~ 83% decrease vs control rats), thyroid hormone receptor alfa (Trα1, ~ 77% decrease vs control rats), deiodinase type 2 (Dio2, ~ 90% decrease vs control rats), ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2, ~ 80% decrease vs control rats) and brain-derived neurotrophic factor (BDNF, ~ 75% decrease vs control rats) mRNAs.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The majority of the information on this KER comes from in vivo studies with rodents (mainly MCT8 knock-out mice and thyroidectomized rats) and histopathological analyses of human brain tissues derived from patients affected by AHDS (Allan-Herndon-Dudley syndrome). The evolutionary conservation of the transport of TH from circulation to the developing brain suggests, with some uncertainty, that this KER is also applicable to other taxa, including birds, fish and frogs (Van Herck et al., 2013; Denver, 1998; Power et al., 2001).
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