AOP: 608

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Thyroid Hormone Excess Leading to Reduced, Swimming Performance via Hypomyelination

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

TH excess–mediated reduced swimming via hypomyelination

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.7

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

_{Ki-Tae Kim, Cong Minh Tran, Jiyun Kang, Yoonseo Choi}

_{Affiliation: Seoul National University of Science and Technology, Seoul, South Korea}

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Ki-Tae Kim (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Ki-Tae Kim

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on October 01, 2025 04:21

Revision dates for related pages

Page	Revision Date/Time
Oxidative Stress	November 15, 2024 10:33
Increase, Reactive oxygen species	June 12, 2025 01:27
Impaired, oligodendrocyte maturation	February 21, 2023 10:42
Hypomyelination	February 21, 2023 10:48
Reduced, Swimming performance	September 08, 2021 06:12
Increased Mortality	July 08, 2022 07:32
Decrease, Population growth rate	January 03, 2023 09:09

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP describes the sequence of events leading from developmental excess of thyroid hormone (TH) to a decrease in population growth rate in vertebrates. The sequence of events in this AOP has been validated in zebrafish embryos (Tran, 2024). TH signaling, mediated predominantly by triiodothyronine (T3) and thyroxine (T4), plays a pivotal role in central nervous system (CNS) development, including neuronal differentiation, synaptogenesis, and oligodendrocyte-mediated myelination (Naffaa et al., 2021). While prior thyroid-related neurodevelopmental AOPs emphasize TH deficiency, recent clinical literature indicates that both TH deficiency and excess are associated with adverse cognitive and behavioral outcomes in children (Mulder et al., 2025). In rodents, hyperthyroidism increased reactive oxygen species (ROS) in the brain, supporting a link between TH excess and oxidative stress (Mogulkoc et al., 2006). Elevated circulating THs are expected to promote oxidative stress in the CNS and increase ROS that compromise oligodendrocyte progenitor cell maturation. Consistent with this, zebrafish embryos exposed to excess THs (T3 and T4) showed upregulation of apoptosis-related genes, leading to suppression of myelination-related genes and disruption of myelin sheath architecture indicative of demyelination-like processes (Tran, 2024). These molecular and cellular alterations converge on hypomyelination. The consequent hypomyelination impaired axonal signal transmission and manifested as reduced swimming performance in zebrafish larval assays (e.g., light–dark transitions). Reduced swimming performance is expected to compromise prey capture and predator avoidance, thereby increasing mortality and reducing population growth rate. This AOP complements AOP 488 and is novel in explicitly incorporating the thyroid axis and validating the pathway in a non-mammalian vertebrate model (zebrafish embryos).

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

KE	1392	Oxidative Stress	Oxidative Stress
KE	1115	Increase, Reactive oxygen species	Increase, ROS
KE	2106	Impaired, oligodendrocyte maturation	Impaired OL maturation
KE	2107	Hypomyelination	Hypomyelination
KE	1005	Reduced, Swimming performance	Reduced, Swimming performance
KE	351	Increased Mortality	Increased Mortality
KE	360	Decrease, Population growth rate	Decrease, Population growth rate

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

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Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Known Modulating Factors

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Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

List of the literature that was cited for this AOP. More help

Tran CM, 2024. Thyroid and neurological disruption of several organophosphate esters, degradation products, and mixtures in embryo-larval zebrafish and their potential crosstalk. Ph.D. dissertation, Seoul National University of Science and Technology, Seoul, Korea.
Naffaa V, Laprévote O, Schang AL, 2021. Effects of endocrine disrupting chemicals on myelin development and diseases. Neurotoxicology 83, 51–68.
Mulder TA, Muetzel RL, Peeters RP, Tiemeier H, Korevaar TIM, 2025. Maternal thyroid function during pregnancy and early adolescent regional differences in cerebral gray matter morphology. The Journal of Clinical Endocrinology & Metabolism, dgaf349.
Mogulkoc R, Baltaci AK, Oztekin E, Sivrikaya A, Aydin L, 2006. Effects of hyperthyroidism induced by L-thyroxin administration on lipid peroxidation in various rat tissues. Acta Biologica Hungarica 57(2), 157–163.