API

Relationship: 1387

Title

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T4 in serum, Decreased leads to Hippocampal gene expression, Altered

Upstream event

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T4 in serum, Decreased

Downstream event

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Hippocampal gene expression, Altered

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals non-adjacent High Low

Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Sex Applicability

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Sex Evidence
Male High
Female High

Life Stage Applicability

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Term Evidence
During brain development High

Key Event Relationship Description

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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 Supporting this KER

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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.

Biological Plausibility

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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.

Empirical Evidence

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The empirical support for this KER is strong. A global transcriptome analysis of primary cerebrocoritical cells was recently published in which a number of genes regulated by T3 were identified (Gil-Ibanez et al., 2015). Although the bulk of literature in which serum TH reductions have been associated with gene expression changes in the brain have been focused on the cortex, several reports in hippocampus are available. Genes directly regulated by TH include the transcription factors Hr and Klf9 (Bteb) (Thompson and Potter, 2000; Cayrou et al., 2002; Denver and Williamson, 2009). The expression of a number of genes modulated by TH are expressed in the hippocampus. Many of genes that regulate processes involved in hippocampal development are also present in the developing cortex. Thus, Table 1 lists TH responsive genes whose expression in either area are altered by TH reduction. This list is not meant to be exhaustive, just exemplary.

 

Gene Name

Tissue

Model

Age

Reference

FETAL

Klf9 (Bteb)

Rat- Cortex

MMI+CLO4

Fetus-GD17

Dong et al., 2015

Nurr1

Mouse-cortex

Thyroidectomy, MMI + ClO4

Fetal GD17; PN90

Navarro et al., 2014

Bdnf

Rat- Cortex

MMI

Fetus GD14-18

Pathak et al., 2011

Trkb

Rat- Cortex

MMI

Fetus GD14-18

Pathak et al., 2011

MCT8

Rat- Cortex

MMI

Fetus GD14-18

Mohan et al, 2012

Dio2

Rat -Cortex

MMI

Fetus GD14-18

Mohan et al, 2012

CyclinD1

Rat- Cortex

MMI

Fetus GD14-18

Mohan et al, 2012

Cyclin D2

Rat- Cortex

MMi

Fetus GD14-18

Mohan et al, 2012

Pax6

Rat- Cortex

MMI

Fetus GD14

Mohan et al, 2012

Hr

Mouse- cortex

MMI + ClO4

Fetal GD17

Morte et al., 2010

Sema7a

Mouse- Cortex

MMI + ClO4

Fetal GD17

Morte et al., 2010

RC3 (Neurogranin)

Rat- Hippocampus,

Cortex

MMI

Fetus-GD16

Dowling and Zoeller, 2001

Camk4

Mouse-cortex

Thyroidectomy,  MMI + ClO4

Fetal GD17; PN90

Morte et al., 2010; Navarro et al., 2014

NEONATAL

Klf9 (Bteb)

Rat, Mouse- Cortex

PTU

Neonate-PN14

Royland et al., 2008; Bastian et al., 2012; Denver and Williamson, 2009; Denver et al., 1999

Hr

Rat-  Cortex, Hippocampus, Cerebellum

PTU, MMI

Neonate-PN14

Royland et al., 2008; Bastian et al., 2012; Thompson and Potter, 2000; Morte et al., 2010

Parv

Rat- cortex

PTU

Neonate-PN14/21

Royland et al., 2008; Bastian et al., 2012; 2014, Shiraki et al., 2014

Ngf

Rat- Hippocampus, cortex

PTU

Neonate-PN14, PN90

Royland et al., 2008; Bastian et al., 2012; Gilbert et al., 2016

Agt

Rat- Cortex

PTU

Neonate, PN14

Royland et al., 2008; Bastian et al., 2012; 2014

Col11a2

Rat- Cortex

PTU

Neonate, PN14

Royland et al., 2008

Itih2

Rat- Cortex

PTU

Neonate, PN14

Royland et al., 2008

Sema7a

Rat- Cortex

PTU

Neonate-PN14

Royland et al., 2008

Reelin

Rat- Hippocampus, cortex, cerebellum

Thyroidectomy, PTU

 

Alvarez-Dolado et al. 1999; Shiraki et al., 2014

Mbp

Rat- Hippocampus, Cortex, Cerebellum

PTU, MMI

Neonate- PN14/21

Ibarrola et al., 1997; Royland et al., 2008; Bastian et al., 2012; 2014, Shiraki et al, 2014

Plp2

Hippocampus, Cortex

PTU, MMI

 

Royland et al., 2008; Bastian et al., 2012

Camk4

Rat/Mouse- cortex

PTU

Neonate-PN14

Royland et al., 2008

RC3 (Neurogranin)

Rat-hippocampus

Thyroidectomy + MMI

Neonate-PN5, PN21

Iniquez et al., 1993; Dong et al., 2010

Temporal Evidence:  The temporal nature of this KER is developmental (Seed et al., 2005). It is a well-recognized fact that there are critical developmental windows for disruption of the serum THs that result in altered gene expression in the developing brain, including the hippocampus. Rescue experiments for this endpoint of gene expression in hypothyroid models are limited. In one, a combination of T3 and T4 treatment delivered on the last day of a 3-day gestational MMI hypothyroxinemia mouse model altered the pattern of gene expression observed in the cortex of offspring relative to euthyroid controls and MMI alone (Dong et al., 2015).

Dose-Response Evidence: There are a limited number of studies that have reported on the dose-dependent nature of the correlation between serum THs and hippocampal gene expression (Bastian et al., 2012; 2014; Royland et al., 2008).

Uncertainties and Inconsistencies

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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.

Quantitative Understanding of the Linkage

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Response-response Relationship

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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).

Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Most of the data available has come from rodent models.

References

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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.