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Event: 186

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Altered, Neuroanatomy

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Altered, Neuroanatomy

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
anatomical structure development nervous system abnormal

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
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


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

No help message More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

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.


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

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.