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Relationship: 312
Title
T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased
Upstream event
Downstream event
AOPs Referencing Relationship
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Male | Moderate |
| Female | Moderate |
Life Stage Applicability
| Term | Evidence |
|---|---|
| During brain development | High |
| All life stages | Moderate |
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 expresses 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 OATP), monocarboxylate transporter 8 (MCT8) (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 (MCT8) 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 eventually 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).
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
The fact that decreased serum TH results in lower brain TH concentrations is well accepted. However, the ability of the developing brain to compensate for insuffiencies in serum TH has not been well studied. Limited data is available that demonstrates that changes in local deiodination in 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). And, 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
The role of cellular transporters represents an additional uncertainly. In addition, future work on cellular transport mechanisms and deiodinase activity is likley to inform addition of new KEs and KERs between serum and brain T4.
Response-response Relationship
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 (Hassan et al., 2018). Recently, serum TH and brain TH were measured in fetal cortex and postnatal day 14 offspring following graded degrees of hypothyroidism induced by PTU (O’Shaughnessy et al., 2018). Results showed that brain levels TH levels at both ages were quantitatively related to serum T4 levels. Additional dose-response information is necessary to confirm these findings, and standardization of analysis for the measurements in these distinct matrices is crucial to allow comparisons to be made between independent experiments.
Time-scale
Known Feedforward/Feedback loops influencing this KER
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 evoluationary conservation of the transport of TH from circulation to the developing brain suggests, with some uncertainty, that this KER is also applicable to other mammalian species.