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Key Event Title
|Level of Biological Organization|
Key Event Components
|anatomical structure development||nervous system||abnormal|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|NIS and Neurodevelopment||KeyEvent||Kevin Crofton (send email)||Not under active development|
Key Event Description
TH signalling controls a number of major anatomical processes in development that if altered will lead to permanently abnormal brain morphology. These processes include differentiation of neurons and glia from progenitor cells, neuronal migration, and myelination of axonal processes. The evidence supporting a role of TH in these neurodevelopmental 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 studies, have provided ample evidence of TH control of these processes (Gilbert and Zoeller, 2010). Below are brief descriptions of the impact of TH insufficiency on two of these processes.
Altered Neuronal Migration: Effects of TH insufficiency on specific developmental events are reflected in alterations in brain structure. 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. 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 Axonal 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 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. Many of methods applied to reveal anatomical abnormalities are routine neurohistopatholgical procedures similar to those recommended in EPA and OECD developmental neurotoxicity guidelines. Subtle changes in cytoarchitecure such as seen in the neocortex depend on more specialized birth dating procedures and staining techniques. Some alterations in brain structure are transient in nature and depend on appropriate timing for detection.
Domain of Applicability
The majority of the evidence supporting this KE comes from rodent studies. However, amphibians display vast structural remodelling during metamorphosis that is TH-dependent and share common TH signaling pathways with rat brain development.
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.
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.
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.
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.
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.
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.