Event:595

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Event Title

Thyroid hormone-related neuroanatomy, Altered
Thyroid hormone-related neuroanatomy, Altered

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Xenobiotic Induced Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals KE Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Strong NCBI
rat Rattus sp. Strong NCBI

Level of Biological Organization

Biological Organization
Organ

How this Key Event works

Disruption of major anatomical processes during development will lead to permanent changes in brain morphology. These processes include differentiation of neuron and glia from progenitor cells, migration, and myelination. The evidence for TH controls of these processes is strong.

Evidence from human is primarily from studies of iodine-deficient children and children with congenital hypothyroidism (CH)(Zoeller and Rovet, 2004). Animal models using rats and mice, as well as in vitro cell culture studies, have provided a plethora of support for the TH control of these processes (Gilbert and Zoeller, 2010). A large number of in vitro model systems have demonstrated TH-dependent induction, by direct or indirect means, on cell migration, neuronal differentiation neurite outgrowth, dendritic arborization, synapse formation, when T3 is added to the culture media (Dezonne et al., 2013; Heuer and Mason, 2003). The demonstration of such profound action on some of these critical developmental processes using in vivo model systems has been documented, but is largely limited to very severe hormone restrictions (e.g., Koibuchi and Chin, 2000; Madiera et al., 1991; Gravel and Hawkes, 1990; Rami and Rabie. 1997). The type of neuroanatomical change observed is also dependent on the timing over which the deficiency occurs - different brain regions being dependent on TH at different times during the pre and postnatal period (Williams et al., 2008). Recently, reports of moderate reductions in TH during more restricted developmental windows have appeared.

Below are brief descriptions of the impact of TH insufficiency on two of these processes - neuronal migration and myelination.

Altered Migration: Altered lamination and cellular morphology in cerebellum (Koibuchi and Chin,2000; Morte et al., 2004; Farwell and Dubord-Tomasetti, 1999), hippocampus (Madeira et al., 1991), and the neocortex (Auso et al., 2003; Cuevas et al., 2005) have been documented under conditions of hypothyroidism. In addition presence of aberrantly placed neuronal cells in the corpus callosum have been described (Gilbert et al., 2014, Powell et al., 2012; Shibutani et al., 2009).

Altered Myelination: Nerve conduction is accelerated by the insulation formed by oligodendrocytes of the myelin sheath that surround axons of many nerve fibers. Reduced size and altered composition of the white matter tracts throughout the brain, the most prominent of which is the corpus callosusm, are hallmarks of severe developmental hypothyroidism (Berbel et al., 1993, 1994; Ferreira et al., 2004; Gravel and Hawkes, 1990; Ibarrola and Rodriguez-Pena, 1997; Schnoover et al., 2005). In addition, more subtle abnormalities have also been described in white matter tracks including corpus callosum and anterior commissure following more modest reductions in circulating levels of TH in the neonatal period (Sharlin et al., 2008).

How it is Measured or Detected

Data in support of this key event have been collected using a wide variety of standard biochemical, histological and anatomical methods (eg., morphometrics,immunohistochemical staining, in situ hybridation)and imaging procedures (Hoffman et al., 2008). Many of methods applied to reveal anatomical anormalities are routine neurohistopatholgical procedures similar to those recommended in EPA and OECD developmental neurotoxicity guidelines (US EPA, 1998; OECD, 2007). Subtle changes in cytoarchitecure such as seen in the neocortex depend on more specialized birth dating procedures and staining techniques (Auso et al., 2003). Some alterations in brain structure are transient in nature and depend on appropriate timing for detection (Morte et al., 2004).

Evidence Supporting Taxonomic Applicability

The majority of the evidence supporting this KE comes from rodent studies. However, amphibians display vast structural remodelling in that share common thyroid hormone dependent signaling pathways.

References

Auso E, et al. A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 2004, 145(9), 4037-4047.

Berbel, P., A. Guadano-Ferraz, et al. (1994). Role of thyroid hormones in the maturation of interhemispheric connections in rats. Behav Brain Res 64(1-2): 9-14.

Berbel, P., A. Guadano-Ferraz, et al. (1993). Organization of auditory callosal connections in hypothyroid adult rats. Eur J Neurosci 5(11): 1465-78.

Cuevas E, et al. Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of medial ganglionic eminence-derived neurons. Eur J Neurosci 2005, 22(3), 541-551.

ADD DeSonne et al Front 2013 paper on astrocytes T3 neurite outgrown/synaptogenesis

Farwell AP, Dubord-Tomasetti SA. Thyroid hormone regulates the extracellular organization of laminin on astrocytes. Endocrinology 1999, 140(11), 5014-5021.

Ferreira, A. A., J. C. Nazario, et al. (2004). Effects of experimental hypothyroidism on myelin sheath structural organization. J Neurocytol 33(2): 225-31.

Gilbert ME, Ramos RL, McCloskey DP, Goodman JH. Subcortical band heterotopia in rat offspring following maternal hypothyroxinaemia: structural and functional characteristics. J Neuroendocrinol. 2014 Aug;26(8):528-41.

Gilbert M, Zoeller R. Thyroid hormone - impact on the developing brain: Possible mechanisms of neurotoxicity. In: Harry GJ T, HA ed. Neurotoxicology, 3rd edition Vol 3. New York: Informa Healthcare USA, Inc; 2010:79-111.

Gravel C Hawkes R. Maturation of the corpus callosum of the rat: I. Influence of thyroid hormones on the topography of callosal projections. J Comp Neurol 1990, 291(1), 128-146.

ADD Heuer and Mason 2003 JNS paper on purkinje cells in vitro

Ibarrola, N. and A. Rodriguez-Pena (1997). "Hypothyroidism coordinately and transiently affects myelin protein gene expression in most rat brain regions during postnatal development." Brain Res 752(1-2): 285- 93.

Koibuchi N, Chin WW. Thyroid hormone action and brain development. Trends Endocrinol Metab 2000, 11(4), 123-128.

Madeira, MD, et al. Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 1991, 314(1), 171-186.

Morte B, et al. Aberrant maturation of astrocytes in thyroid hormone receptor alpha 1 knockout mice reveals an interplay between thyroid hormone receptor isoforms. Endocrinology 2004, 145(3), 1386-1391.

OECD/OCDE 426. OECD Guideline for the Testing of Chemicals, Developmental Neurotoxicity Study, 2007.

Powell MH, Nguyen HV, Gilbert M, Parekh M, Colon-Perez LM, Mareci TH, Montie E. Magnetic resonance imaging and volumetric analysis: novel tools to study the effects of thyroid hormone disruption on white matter development. Neurotoxicology. 2012 Oct;33(5):1322-9.

ADD Rami and Rabie 1997 DG morphology paper

Schoonover, C. M., M. M. Seibel, et al. (2004). Thyroid hormone regulates oligodendrocyte accumulation in developing rat brain white matter tracts. Endocrinology 145(11): 5013-20.

Sharlin DS, et al. The balance between oligodendrocyte and astrocyte production in major white matter tracts is linearly related to serum total thyroxine. Endocrinology 2008, 149(5), 2527-2536.

Shibutani M, Woo GH, Fujimoto H, Saegusa Y, Takahashi M, Inoue K, Hirose M, Nishikawa A. Assessment of developmental effects of hypothyroidism in rats from in utero and lactation exposure to anti-thyroid agents. Reproductive toxicology (Elmsford, NY). 2009;28(3):297-307.

U.S.EPA, Health Effects Guidelines OPPTS 870.6300, Developmental Neurotoxicity Study, 1998.

ADD Wiliams et al 2008 JNE review

Zoeller, R. T. and. Rovet, J. Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J Neuroendocrinol, 2004; 16(10): 809-18.