Upstream eventT4 in neuronal tissue, Decreased
Hippocampal gene expression, Altered
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|
|Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
Many cellular and biochemical effects of thyroid hormones (TH) are mediated through regulation of gene expression (Oppenheimer, 1983; Bernal, 2007). Thyroxine (T4) is transferred from the serum to the brain (see KER: Thyroxine (T4) in Serum, Decreased leads to Thyroxine (T4) in Neuronal Tissue, Decreased), where it converted to triiodothyronine (T3), the level of which is highly controlled by deiodinases. T3 binds to thyroid receptors (TR) in the nucleus of neuronal and glial cells to control gene expression. It is generally accepted that the modulation of TR gene expression in the hippocampus, or any other brain region, must therefore depend on the presence of hormone in these tissues.
Evidence Supporting this KER
The weight of evidence is moderate for TH concentrations affecting gene expression in the developing brain is (Oppenheimer and Schwartz, 1997; Oppenheimer, 1983; Bernal, 2007; Morte et al., 2010a; 2010b; Williams, 2008). Direct measurement of TH in brain tissue, and in hippocampus in particular, has shown correlations with gene expression. Therefore, it is assumed that reductions in TH-responsive genes in the hippocampus stem from reduced availability of hormone in the brain from the serum. However, studies in which there are simultaneous assessments of hippocampal concentrations of thyroid hormone and hippocampal gene expression is limited.
The biological relationship between these two KEs is strong. It is a generally accepted fact that TH produce their actions on brain development by binding to nuclear receptors to affect gene transcription. See KER (1387): "T4 in serum, Decreased leads (non-adjacently) to Hippocampal gene expression, Altered" for more information on TR regulated genes. As the primary means whereby TH promotes its action is by binding to TR in brain, TH must be present in brain to affect this action. Circulating levels of T4 represent the primary source of T4 in the brain, which is then converted to the active hormone T3 by deiodinases within neuronal tissue.
The empirical support for this KER is moderate. Many in vitro studies have demonstrated a relationship between hormone concentraionsTH and the induction of gene expression in brain cells, including hippocampal neurons in culture (Gil-Ibanez et al., 2015; Morte et al., 2010b). However, there are a limited number of studies investigating TH concentrations in the hippocampus and hippocampal gene expression. This is the case because thyroid hormone is difficult to measure in hippocampus and TH-induced gene expression changes can be subtle. We are aware of only four in vivo studies in which both thyroid hormones in the brain and gene expression in brain were simultaneously measured (Bastian et al., 2012; 2014; Hernandez et al., 2010; Sharlin et al., 2008). Only two of these reports, stemming from the same laboratory, specifically assessed thyroid hormone and gene expression in hippocampus. In these studies, Bastian et al., (2012; 2014) measured decrements in hippocampal T3 using RIA and correlated these reductions with alterations in the expression of myelin associated genes (Mbp, Plp), the neurotrophin, Ngf, the calcium binding protein Parv, a TH-dependent transcription factor, Hr, and Agt.
Temporal Evidence: The temporal nature of this KER on TH dependent gene regulation is developmental (Seed et al., 2005). The impact of brain TH concentrations on regulation of TR regulated genes is age-dependent for a number of genes critical for normal hippocampal development. It is widely accepted that different genes are altered dependent upon the window of exposure in the fetal, neonatal or adult brain (c.f., Pathak et al, 2011; Mohan et al., 2012; Quignodon et al., 2004; Williams, 2008). Thyroid hormone supplementation has been shown to reverse some of the effects on gene expression (Mohan et al., 2012; Liu et al., 2010; Pathak et al., 2011).
Dose-Response Evidence: Dose-response data exists but is limited to a small number of studies and a small number of genes (Bastian et al., 2012; 2014; Sharlin et al., 2008).
Uncertainties and Inconsistencies
There are no inconsistencies in this KER, but there are uncertainties. Uncertainties remain in the relationship of neuronal TH concentrations and gene expression in the brain because of the lack of studies simultaneously examining brain hormone and gene expression in the same study. This stems from the technological challenges associated with measuring brain hormone and the sometimes-subtle changes in brain gene expression induced by manipulations of the thyroid system. In addition, there are also some physiological actions of T4 that are mediated non-genomically at the cell membrane (Davis et al., 2016). However, the exact role for the non-genomic effects is not well accepted or understood (Galton, 2017).
Quantitative Understanding of the Linkage
There is only one study available to date that provides empirical data on both TH concentrations and measures of gene expression changes in brain. O'Shaughnessy et al (2018) demostrates dose-response relationships between brain T4 and T3 concentrations and changes in a variety of genes (e.g., Parv, Col11a2, Hr, Ngf) that were "statistically significant at doses that decreased brain t4 and/or T3". There was no quantitation of this relationship reported.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most of the data available has come from rodent models. The evolutionary conservation of thyroid receptors (Holzer et al., 2017) coupled with their role in TR regulated gene transcription in neurodevelopment, suggests that this KER may also be applicable to other species (see text above).
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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.
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Quignodon L, Legrand C, Allioli N, Guadano-Ferraz A, Bernal J, Samarut J, Flamant F (2004) Thyroid hormone signaling is highly heterogeneous during pre- and postnatal brain development. J Mol Endocrinol 33:467-476.
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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.
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