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T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low||Kevin Crofton (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low||Mary Gilbert (send email)||Under Development: Contributions and Comments Welcome|
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.
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).
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).
Bastian TW, Anderson JA, Fretham SJ, Prohaska JR, Georgieff MK, Anderson GW (2012), Fetal and neonatal iron deficiency reduces thyroid hormone-responsive gene mRNA levels in the neonatal rat hippocampus and cerebral cortex. Endocrinology 153:5668-5680.
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.
Bernal J (2007) Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 3:249-259.
Davis, P.J., Goglia, F., Leonard, J.L., 2016. Nongenomic actions of thyroid hormone. Nat. Rev. Endocrinol. 12, 111-121.
Galton VA. The ups and downs of the thyroxine pro-hormone hypothesis. Mol Cell Endocrinol. 2017 Jan 24. pii: S0303-7207(17)30042-4. doi: 10.1016/j.mce.2017.01.029.
Gil-Ibañez P, García-García F, Dopazo J, Bernal J, Morte B. Global Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types. Cereb Cortex. 2017 Jan 1;27(1):706-717.
Hernandez A, Quignodon L, Martinez ME, Flamant F, St Germain DL (2010), Type 3 deiodinase deficiency causes spatial and temporal alterations in brain T3 signaling that are dissociated from serum thyroid hormone levels. Endocrinology 151:5550-5558.
Holzer G, Roux N, Laudet V. Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling. Mol Cell Endocrinol. 2017 Mar 22. pii: S0303-7207(17)30191-0. doi: 10.1016/j.mce.2017.03.021.
Liu D, Teng W, Shan Z, Yu X, Gao Y, Wang S, Fan C, Wang H, Zhang H. The effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring. Thyroid. 2010 Aug;20(8):909-15.
Mohan V, Sinha RA, Pathak A, Rastogi L, Kumar P, Pal A, Godbole MM (2012) Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis. Exp Neurol 237:477-488.
Morte B, Diez D, Auso E, Belinchon MM, Gil-Ibanez P, Grijota-Martinez C, Navarro D, de Escobar GM, Berbel P, Bernal J (2010a) Thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex: prominent role of the Ca2+/calmodulin-dependent protein kinase IV pathway. Endocrinology 151:810-820.
Morte B, Ceballos A, Diez D, Grijota-Martínez C, Dumitrescu AM, Di Cosmo C, Galton VA, Refetoff S, Bernal J. (2010b) Thyroid hormone-regulated mouse cerebral cortex genes are differentially dependent on the source of the hormone: a study in monocarboxylate transporter-8- and deiodinase-2-deficient mice. Endocrinology. 2010 May;151(5):2381-7
Oppenheimer, J. (1983). The nuclear-receptor-triiodothyronine complex: Relationship to thyroid hormone distribution, metabolism, and biological action. Molecular Basis of Thyroid Hormone Action. J. O. a. H. Samuels. New York, Academic Press: 1-34.
Oppenheimer, J. H. and H. L. Schwartz (1997). "Molecular basis of thyroid hormone-dependent brain development." Endocr Rev 18(4): 462-75.
O'Shaughnessy KL, Wood, C, Ford RL, Kosian, PA, Hotchkiss, MG, Degitz SJ, Gilbert ME. Thyroid hormone disruption in the fetal and neonatal rat: Predictive hormone measures and bioindicators of hormone action in the developing cortex. Toxicol Sci. 2018 Aug 6. doi: 10.1093/toxsci/kfy190. [Epub ahead of print]
Pathak A, Sinha RA, Mohan V, Mitra K, Godbole MM. 2011. Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration. Cerebral cortex. 21:11-21.
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.
Williams GR (2008), Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol. 2008 Jun;20(6):784-94