Relationship:747

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Hippocampal gene expression, Altered Hippocampal anatomy, Altered

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Directly Leads to Moderate Weak
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Directly Leads to Moderate Weak

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus sp. Rattus sp. Moderate NCBI

How Does This Key Event Relationship Work

The expression of thyroid hormone-responsive genes encode proteins that are important in modulating developmental events in the brain (e.g., neurogenesis, neuronal migration, myelination), though the exact developmental processes have not been fully elucidated (Zoeller, 2003, Zoeller and Crofton, 2005). Smaller brain size, reduced myelination, and disorganized cytoarchitecture in the cortex, cerebellum, and hippocampus have been described in models of severe hypothyroidism (Rami et al., 1986a, Madeira et al., 1988, Gravel and Hawkes, 1990, Madeira et al., 1991, Madeira et al., 1992, Powell et al., 2012). The interpretation of these findings in the context of thyroid hormone specific action however can be confounded by the very severe developmental delays and nutritional and other developmental compromise these animals suffer in such models.

Many studies measure serum TH and gene expression or serum TH and structural change. Alterations in the expression of a number of TH-responsive genes in the hippocampus are seen under conditions were hippocampal structure based on weight or volume is also reduced. Other studies reveal alterations in gene expression that are associated with more subtle changes in hippocampal structure such as changes in protein levels expressed in specific cell types (eg parvalbumin expression of inhibitory neurons). Other approaches demonstrate alterations in genes following TH insufficiency that are coupled with changes in specific structural components of neurons or synapses (ie protein levels of synapsin or postsynaptic density proteins, components of the synapse). Under conditions of TH insufficiency where gross measures of hippocampal weight or volume are not impacted, more subtle alterations in structure remain – i.e., if a specific cell type is underrepresented, if cells are not appropriately placed at the appropriate time, then structural integrity is compromised.

Under similar conditions of TH compromise, gene expression is altered and structural changes in hippocampal volume, cell number, cytoarchitecture have been reported. In several reports, these alterations were dose dependent, increasing in severity as the level of TH insufficiency increased. In other cases the effects were reversed by TH replacement. In most cases either gene expression or structural changes were the focus of the study, not as often were both addressed at the same time. It remains unknown exactly how alterations in TH-genes produced changes in hippocampal structure, but it is generally accepted that the primary means whereby TH insufficiencies negatively affect brain structures is through gene regulation.

Weight of Evidence

The weight of evidence for a direct linkage between perturbation of the expression of thyroid hormone-responsive genes in brain (and in hippocampus specifically) and neuroanatomical abnormalities is moderate. An increased number of reports of dose-responsive changes in genes specifically measured in the hippocampus and specific cytoarchitectural changes would make this relationship even stronger. Additional study information on the effect of subclinical hypothyroxinemia, hippocampal gene expression, and cytoarchitectural changes would be particularly useful in understanding this KER.

Biological Plausibility

It is well established that thyroid hormones influence growth and development in a number of organ systems, including the brain, by interacting with nuclear receptors that regulate gene transcription, directly or indirectly via transcription factor regulation.

Empirical Support for Linkage

Empirical Support for Linkage Gene Expression to Structural Change: Many studies have revealed alterations in gene/protein expression in the hippocampus and neocortex under conditions of TH insufficiency, while others have demonstrated changes in structure. Some examples exist where genes and structure have been simultaneously assessed. In most cases however, these associations of correlative, but strong correlations across these two KEs exist, especially with models of severe hypothyroidism.

Genes and Proteins are Altered: 1) Royland et al (2009) performed a microarray study on cortex and hippocampus harvested from neonatal rats born it dams exposed to graded levels of the TPO inhibitor, PTU. A number of TH-responsive genes whose altered expression was correlated with the dose of PTU and the level of TH reduction measured in the dams and the offspring at the time of sacrifice. Many of these genes were significantly altered at the lowest dose of PTU that produced only a state of hypothyroxinemia in the dam and the pup. These included gene probes involved in cell cycle (Gadd45a); cell growth (Hop, Cdc42), cytoskeleton (Csrp1); cell adhesion and neuronal migration (eg Col11a2, Itah3, Epha7), oligodendrocyte differentiation and myelination (eg Mal, Mag, Plp, Mbp), synaptic transmission (Grina3, Dpysl3) and plasticity (Ntf3, Camk1, Anxa6).

2) Shiraki et al (2014) also report multifocal brain region-specific microrarrays and included in their investigation the DG of the hippocampus in slightly older rats (PN21) than investigated by Royland et al. (2008) in response to a single high dose of PTU (10ppm) over the same time window from GD6-PN21. DG genes involved in cell differentiation, migration, axonogenesis, synaptogenesis were identified by gene ontology clusters. A subset of genes were further verified using qPCR. Expression of Ephrin signaling genes (Ephb2), glutamate receptors (Gria3), vimentin (Vim), paired box6 (Pax6), and reelin (Rln) was altered in hypothyroid pups.

3) Bastian et al (2012; 2013) using a dosing protocol similar Royland et al (2009) reported reductions in TH transcription factor, Hr, myelin genes Mpb abd Mopb, angiotensinogen, Agt, and the gene encoding the calcium-binding protein parvalbumin (Pvalb) in 3ppm but not 1ppm PTU exposed offspring on PN10. Increases in the expression of the TH transporter Mct8 were seen at 3ppm and in deiodinase 2 (Dio2) at 10ppm PTU. Parvalbumin is a protein only expressed in interneurons and reductions in gene expression were seen at the protein level using western blot (Gilbert et al., 2008; Bastian et al., 2013) and in immunohistochemical (Gilbert et al., 2008; Berbel et al., 1996) analyses.

3) Gilbert et al (2016) have reported dose-dependent reductions in mRNA for the neurotrophin, nerve growth factor (Ngf) in the hippocampus of PN14 neonate that persisted to adulthood in the low dose PTU model described above and implemented by Bastian et al. (2014). Selective dissection of DG from the rest of the hippocampal CA region in the adult offspring after full recovery of TH also revealed selective reductions in expression brain derived neurotrophic factor exon 4 (Bdnfiv), the TH-responsive transcription factor Klf9 (also known as Bteb), neurogranin, and Sox2. In in vitro studies of cortical neurons, T3 stimulation accelerates the formation of GABAergic boutons and alters the distribution of GABAergic axons among other neurons, possibly by modulating activity-dependent synaptic pruning. T3 may contribute to the establishment of emerging cortical networks by promoting activity-dependent stabilization of connections between GABAergic and synchronously active projection neurons (Westerholz et al., 2013). In this manner functionality of synaptic circuitry can impact structure and structure in the form of synaptic connectivity can modulate function.

Structure is Altered: 1) Using MRI, Hasegawa et al (2010) reported reductions in whole brain and hippocampal volumes in a severe model of congenital hypothyroidism. Pups born to rat dams exposed to 200ppm MMI from late gestation through lactation had smaller brains, and although hippocampal volumes were also decreased, the ratio of hippocampal/total brain volume was similar across control and treated rats.

2) Powell et al (2010) used more moderate dosing procedure and reported reductions in hippocampal and cortical volume in weanling and adult offspring of dams exposed to 10ppm PTU, but one which extended throughout gestation and lactation. Smaller brain size and reduced myelination were seen at weaning and persisted to adulthood. Although reductions were seen in cortex, hippocampal volumes however were not changed. Other structural abnormalities were seen.

3) Madiera et al. (1991; 1992; 1993) investigated subregions of the hippocampus in offspring of hypothyroid dams treated with PTU. No change in volume of the CA1 pyramidal cell layer was seen, but the neuronal volume and cell number were reduced in hypothyroid animals. In the neonatal brain, the pyramidal cells of Ammons horn show a gradation of progressive differentiation over time from area CA1 to CA4. Pyramidal neurons of hypothyroid animals have fewer synapses and an impoverished dendritic arbor, the extent of impairment dependent upon the position of the cells within the layer. Area CA3-4 pyramidal neurons are born later and were more affected than neurons within area CA1 (Rami, Patel et al. 1986; Madeira and Paula-Barbosa 1993). The apparent greater vulnerability of CA3-4 over CA1 neurons may be a function of timing of PTU initiation, exposure beginning late in gestation when pyramidal cells of CA1 had already differentiated. Some evidence of a blurring of cell layers was reported in area CA1 (Auso, Lavado-Autric et al. 2004) in response to brief episodes of maternal hypothyroxinemia in the mid to late gestational period.

4) The dentate gyrus is the other region within the hippocampus that is sensitive to hypothyroidism. PTU decreased the volume of the granule cell layer, the density of cells within the layer, and estimates of total granule cell number (Madeira et al., 1991). Migration of granule cells from the proliferative zone to the granule cell layer is retarded by thyroid deficiency as is dendritic arborization and synaptogenesis assessed by immunohistochemistry for the synaptic protein, synaptophysin (Rabie et al., 1980, Rami et al., 1986a, Rami et al., 1986b). Studies of this nature have not been performed in models other than severe neonatal hypothyroidism.

5) Gilbert et al (under review) reported no effects on hippocampus or brain weights in weanling-aged offspring of dams exposed to milder degrees of hypothyroidism induced by 3 and 10ppm PTU in the drinking water of pregnant rat dams. Using stereological techniques, volumes of striatum radiatum of CA1 and granule cell layer were reduced by the highest dose of PTU. These same findings were seen using linear morphometric assessments. In another study, volumes of dentate gyrus were also found in adult male offspring of 3ppm treated animals.

6) The hippocampus, specifically the dentate gyrus, is unique in its capacity to generate new neurons throughout the lifespan of the organism. TH deficiencies during adulthood interfere with this process of adult neurogenesis (Ambrogini et al., 2005, Montero-Pedrazuela et al., 2006, Kapoor et al., 2015). Neurotrophins, particularly BDNF, are critical to the survival of new granule cells, and the TH transcription factor Klf9 is selectively expressed in newly generated granule cells (Scobie et al., 2009). Moderate hypothyroidism induced by PTU during development reduces volume of the dentate gyrus, and the number of newborn cells in the adult hippocampus (Gilbert et al., under review).

Quantitative Understanding of the Linkage There are no data on the quantitative linkages between thyroid hormone-dependent gene expression change and altered hippocampal anatomy. Developmental window of exposure and duration of exposure can modulate response-response relationships.

Evidence Supporting Taxonomic Applicability Name Scientific Name Evidence Links

Uncertainties or Inconsistencies

Much of the data supporting this KER are correlative in nature. Much of the data supporting the relationship is bssed on single high dose models. However, similar correlations are supported in the more limited data available in which more modest hormone insufficiencies were induced by TPO-inhibitors and in cases were dose-response relationships were investigated.

Quantitative Understanding of the Linkage

There are no data on the quantitative linkages between thyroid hormone-dependent gene expression change and altered hippocampal anatomy. Developmental window of exposure and duration of exposure can modulate response-response relationships.

Evidence Supporting Taxonomic Applicability

References

  1. Ambrogini P, Cuppini R, Ferri P, Mancini C, Ciaroni S, Voci A, Gerdoni E, Gallo G (2005) Thyroid hormones affect neurogenesis in the dentate gyrus of adult rat. Neuroendocrinology 81:244-253.
  2. Auso E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escobar G, Berbel P (2004) A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 145:4037-4047.
  3. 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.
  4. 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.
  5. Berbel P, Marco P, Cerezo JR, DeFelipe J (1996) Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats. Neurosci Lett 204:65-68.
  6. Gilbert ME, Sanchez-Huerta K, Wood C (2016) Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.
  7. Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH (2007) Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 148:92-102.
  8. Gravel C, Hawkes R (1990) Maturation of the corpus callosum of the rat: I. Influence of thyroid hormones on the topography of callosal projections. J Comp Neurol 291:128-146.
  9. Hasegawa M, Kida I, Wada H (2010) A volumetric analysis of the brain and hippocampus of rats rendered perinatal hypothyroid. Neurosci Lett 479:240-244.
  10. Kapoor R, Fanibunda SE, Desouza LA, Guha SK, Vaidya VA (2015) Perspectives on thyroid hormone action in adult neurogenesis. J Neurochem 133:599-616.
  11. Madeira MD, Cadete-Leite A, Andrade JP, Paula-Barbosa MM (1991) Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 314:171-186.
  12. Madeira MD, Paula-Barbosa M, Cadete-Leite A, Tavares MA (1988) Unbiased estimate of cerebellar granule cell numbers in hypothyroid and in sex-age-matched control rats. J Hirnforsch 29:587-594.
  13. Madeira MD, Paula-Barbosa MM (1993) Reorganization of mossy fiber synapses in male and female hypothyroid rats: a stereological study. J Comp Neurol 337:334-352.
  14. Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A, Paula-Barbosa MM (1992) Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322:501-518.
  15. Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernandez-Lamo I, Garcia-Verdugo JM, Bernal J, Guadano-Ferraz A (2006) Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry 11:361-371.
  16. Powell MH, Nguyen HV, Gilbert M, Parekh M, Colon-Perez LM, Mareci TH, Montie E (2012) Magnetic resonance imaging and volumetric analysis: novel tools to study the effects of thyroid hormone disruption on white matter development. Neurotoxicology 33:1322-1329.
  17. Rabie A, Clavel MC, Legrand J (1980) Analysis of the mechanisms underlying increased histogenetic cell death in developing cerebellum of the hypothyroid rat: determination of the time required for granule cell death. Brain Res 190:409-414.
  18. Rami A, Patel AJ, Rabie A (1986a) Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience 19:1217-1226.
  19. Rami A, Rabie A, Patel AJ (1986b) Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus. Neuroscience 19:1207-1216.
  20. Royland JE, Parker JS, Gilbert ME (2008) A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain. J Neuroendocrinol 20:1319-1338.
  21. Scobie KN, Hall BJ, Wilke SA, Klemenhagen KC, Fujii-Kuriyama Y, Ghosh A, Hen R, Sahay A (2009) Kruppel-like factor 9 is necessary for late-phase neuronal maturation in the developing dentate gyrus and during adult hippocampal neurogenesis. J Neurosci 29:9875-9887.
  22. 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.
  23. Zoeller RT (2003) Challenges confronting risk analysis of potential thyroid toxicants. Risk Anal 23:143-162.
  24. Zoeller RT, Crofton KM (2005) Mode of action: developmental thyroid hormone insufficiency--neurological abnormalities resulting from exposure to propylthiouracil. Crit Rev Toxicol 35:771-781.