To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1387
T4 in serum, 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||non-adjacent||High||Low||Evgeniia Kazymova (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
Many of the physiological effects of thyroid hormones (THs) are mediated through regulation of gene expression by zinc finger nuclear receptor proteins that are encoded by thyroid hormone genes alpha (Thra) and beta (Thrb). It is widely accepted that TH regulates gene transcription during brain development (Bernal, 2007; Anderson et al., 2003). The sole source of TH to the brain is from the circulating levels of the prohormone, thyroxine (T4). Once taken up from the serum to reach the brain, T4 is converted to triiodothyronine (T3) which binds to TH nuclear receptors (TRα and TRβ). On binding, and in the presence of regulatory cofactors, transcription of certain genes is either up- or down-regulated (Oppenheimer, 1983). However, only a small number of genes have been shown to be directly influenced by TH receptor binding, and of these, most are transcription factors (Quignodon et al., 2008; Thompson and Potter, 2000; Horn and Heuer, 2010). In this manner, THs do influence a wide variety of genes.
Evidence Collection Strategy
Evidence Supporting this KER
The weight of evidence for this indirect relationship is strong. It is well established that serum TH is the primary source of brain T4 from which neuronal T3, the active hormone, is locally generated and presented to the receptors in the nucleus of neurons to control gene transcription.
The biological plausibility of this KER is rated as strong. This is consistent with the known biology of the relationship between serum TH concentrations and brain TH concentrations, and the known action of TH to mediate gene transcription in brain and many other tissues.
Uncertainties and Inconsistencies
There are no inconsistencies in this KER, but there are some uncertainties. It is widely accepted that changes in serum THs will result in alterations in hippocampal gene expression. Several different animal models have been used to manipulate serum TH concentrations that also measure gene expression changes. Varying windows of exposure to TH disruption and developmental sample time and region examined have also varied across studies. However, dose-response data is lacking. Most investigations of hippocampal gene expression have employed treatments that induce severe hormone reductions induced by PTU or MMI, or by thyroidectomy. In addition, few reports have studied the genes in the hippocampus, the cortex being more accessible in young animals. Finally, when the hippocampus is the target, different genes at different ages are reported, making it difficult to compare findings.
Known modulating factors
There are no quantitative models that predict the degree of serum TH reduction that is required to alter hippocampal gene transcription. Most investigations for hippocampus have been conducted in the neonate after severe hormone reductions. Only four publications have reported dose-dependent effects on gene expression in at less than maximal hormone depletion (Bastian et al., 2012; 2014; O'Shaughnessy et al., 2018; Royland et al., 2008). O'Shaughnessy et al (2018) demostrates dose-response relationships between cortical T4 and T3 concentrations and changes in a variety of neocortical 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.
In addition, there is very little known about whether compensatory processes are available in the developing hippocampus that may modulate the impact of serum levels on hippocampal gene transcription. These available data suggest that a 40-50% decrement in serum T4 in the pup, is sufficient to observe changes in hippocampal gene expression. This is similar to finding for loss of hearing function in rats following postnatal chemical-induced hypothyroxinemia (Crofton, 2004).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most of the data available has come from rodent models.
Alvarez-Dolado M, Ruiz M, Del Rio JA, Alcantara S, Burgaya F, Sheldon M, Nakajima K, Bernal J, Howell BW, Curran T, Soriano E, Munoz A (1999) Thyroid hormone regulates reelin and dab1 expression during brain development. J Neurosci 19:6979-6993.
Anderson GW, Schoonover CM, Jones SA (2003) Control of thyroid hormone action in the developing rat brain. Thyroid 13:1039-56.
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. Nature clinical practice Endocrinology & metabolism. 3:249-259.
Cayrou C, Denver RJ, Puymirat J. Suppression of the basic transcription element-binding protein in brain neuronal cultures inhibits thyroid hormone-induced neurite branching. Endocrinology. 2002 Jun;143(6):2242-9.
Crofton KM. Developmental disruption of thyroid hormone: correlations with hearing dysfunction in rats. Risk Anal. 2004 Dec;24(6):1665-71.
Denver RJ, Ouellet L, Furling D, Kobayashi A, Fujii-Kuriyama Y, Puymirat J. Basic transcription element binding protein (BTEB) is a thyroid hormone-regulated gene in the developing central nervous system. Evidence for a role in neurite outgrowth. J Biol Chem. 1999 Aug 13;274(33):23128-34.
Denver RJ, Williamson KE (2009) Identification of a thyroid hormone response element in the mouse Kruppel-like factor 9 gene to explain its postnatal expression in the brain. Endocrinology 150:3935-3943.
Dong J, Liu W, Wang Y, Xi Q, Chen J. 2010. Hypothyroidism following developmental iodine deficiency reduces hippocampal neurogranin, CaMK II and calmodulin and elevates calcineurin in lactational rats. International journal of developmental neuroscience 28:589-596.
Dong H, You SH, Williams A, Wade MG, Yauk CL, Thomas Zoeller R (2015) Transient Maternal Hypothyroxinemia Potentiates the Transcriptional Response to Exogenous Thyroid Hormone in the Fetal Cerebral Cortex Before the Onset of Fetal Thyroid Function: A Messenger and MicroRNA Profiling Study. Cereb Cortex 25:1735-1745.
Dowling AL, Zoeller RT. Thyroid hormone of maternal origin regulates the expression of RC3/neurogranin mRNA in the fetal rat brain. Brain research Molecular brain research. 2000. 82:126-132.
Gil-Ibanez P, Garcia-Garcia F, Dopazo J, Bernal J, Morte B. 2015. Global Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types. Cerebral cortex. Nov 2.
Horn S. and Heuer H. Thyroid hormone action during brain development: more questions than answers. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):19-26.
Ibarrola N, Rodriguez-Pena A (1997) Hypothyroidism coordinately and transiently affects myelin protein gene expression in most rat brain regions during postnatal development. Brain Res 752:285-293.
Iñiguez MA, Rodriguez-Peña A, Ibarrola N, Aguilera M, Muñoz A, Bernal J. Thyroid hormone regulation of RC3, a brain-specific gene encoding a protein kinase-C substrate. Endocrinology. 1993 Aug;133(2):467-73.
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) 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 2010a. 151:810-820.
Morte B, Ceballos A, Diez D, Grijota-Martinez C, Dumitrescu AM, Di Cosmo C, Galton VA, Refetoff S, Bernal J. 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. 2010b. 151:2381-2387.
Navarro D, Alvarado M, Morte B, Berbel D, Sesma J, Pacheco P, Morreale de Escobar G, Bernal J, Berbel P. Late Maternal Hypothyroidism Alters the Expression of Camk4 in Neocortical Subplate Neurons: A Comparison with Nurr1 Labeling. Cereb Cortex 2014. 10:2694-2706.
Oppenheimer J. The nuclear-receptor-triiodothyronine complex: Relationship to thyroid hormone distribution, metabolism, and biological action, In: Samuels HH, eds: Molecular Basis of Thyroid Hormone Action. Academic Press: New York. 1983: 1-34.
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. Cereb Cortex 21:11-21.
Quignodon L, et al. Thyroid hormone signaling is highly heterogeneous during pre- and postnatal brain development. J Mol Endocrinol 2004, 33(2), 467-476.
Royland JE, Parker JS, Gilbert ME. A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. J Neuroendocrinol. 2008 Dec;20(12):1319-38.
Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PM, Kavlock R, Kimmel G, Klaunig J, Meek ME, Preston RJ, Slikker W Jr, Tabacova S, Williams GM, Wiltse J, Zoeller RT, Fenner-Crisp P, Patton DE. Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol. 2005 35:664-72.
Shiraki A, Saito F, Akane H, Takeyoshi M, Imatanaka N, Itahashi M, Yoshida T, Shibutani M (2014) Expression alterations of genes on both neuronal and glial development in rats after developmental exposure to 6-propyl-2-thiouracil. Toxicol Lett 228:225-234.
Thompson CC, Potter GB. Thyroid hormone action in neural development. Cereb Cortex 2000, 10(10), 939-945.