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AOP: 605

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 Peroxidase Inhibition Leading to Reduced, Swimming Performance via Hypomyelination

Short name

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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

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

Authors

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_{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

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Ki-Tae Kim

Coaches

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OECD Information Table

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

This AOP was last modified on September 28, 2025 02:35

Revision dates for related pages

Page	Revision Date/Time
Thyroperoxidase, Inhibition	November 18, 2025 08:29
Thyroid hormone synthesis, Decreased	November 04, 2022 09:25
Thyroxine (T4) in serum, Decreased	October 10, 2022 08:52
Decreased, Triiodothyronine (T3)	October 07, 2022 08:26
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

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This AOP describes the sequence of events leading from thyroid peroxidase (TPO) inhibition to a decrease in population growth rate in vertebrates via hypomyelination. The sequence of events in this AOP has been validated in zebrafish embryos (Choi, 2025). Mechanistically, TPO inhibition reduces thyroid hormone (TH) synthesis, lowering circulating thyroxine (T4) and triiodothyronine (T3). TH signaling plays a pivotal role in central nervous system (CNS) development, including neuronal differentiation, synaptogenesis, and oligodendrocyte-mediated myelination (Naffaa et al., 2021). Consistent with this, zebrafish exposed to the prototypical TPO inhibitor propylthiouracil (PTU) exhibited reduced circulating TH levels. This reduction downregulated myelination-related genes, leading to a reduced number of oligodendrocytes and impaired myelin sheath formation in the CNS. The consequent hypomyelination compromised axonal signal transmission, disrupted neural circuit function, and manifested as reduced swimming performance in larval assays (Choi, 2025). Such behavioral impairment is expected to compromise prey capture and predator avoidance, thereby increasing mortality and decreasing population growth rate. Thus, this AOP delineates the pathway by which reduced synthesis or activity of TH leads to hypomyelination and population-level impacts, and it complements existing thyroid-axis AOPs (e.g., deficits in swim-bladder inflation and altered visual function), broadening the network linking thyroid function to neurodevelopmental toxicity.

AOP Development Strategy

Context

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Strategy

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Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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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

MIE

279

Thyroperoxidase, Inhibition

KE	277	Thyroid hormone synthesis, Decreased	TH synthesis, Decreased
KE	281	Thyroxine (T4) in serum, Decreased	T4 in serum, Decreased
KE	1003	Decreased, Triiodothyronine (T3)	Decreased, Triiodothyronine (T3)
KE	2106	Impaired, oligodendrocyte maturation	Impaired OL maturation
KE	2107	Hypomyelination	Hypomyelination
KE	1005	Reduced, Swimming performance	Reduced, Swimming performance

AO	351	Increased Mortality	Increased Mortality
AO	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

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Life Stage Applicability

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Life stage	Evidence
Embryo	High

Taxonomic Applicability

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Sex Applicability

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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

Choi Y-S, Kim K-T, 2025. Establishing an Adverse Outcome Pathway from Thyroid Peroxidase Inhibition to Mortality via Impaired Myelination in Zebrafish. SETAC North America 46th Annual Meeting; Portland, OR, USA.
Naffaa V, Laprévote O, Schang AL, 2021. Effects of endocrine disrupting chemicals on myelin development and diseases. Neurotoxicology 83, 51–68.