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AOP: 271

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

Inhibition of thyroid peroxidase leading to impaired fertility in fish

Short name

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

TPO inhibition and impaired fertility

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 v2.0

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

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June-Woo Park, Korea Institute of Toxicology JRC-APT (Joint Research Center for Alternative and Predictive Toxicology)
Carlie LaLone, US EPA
Young Jun Kim, Environmental Safety Group, KIST Europe, JRC-APT
Chang-Beom Park, Korea Institute of Toxicology, JRC-APT

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

June-Woo Park (email point of contact)

Contributors

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June-Woo Park
Young Jun Kim
Carlie LaLone
Chang-Beom Park

Coaches

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Dan Villeneuve
Shihori Tanabe

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
1.59	Under Development

This AOP was last modified on June 07, 2023 05:33

Revision dates for related pages

Page	Revision Date/Time
Thyroperoxidase, Inhibition	November 04, 2022 09:24
Thyroid hormone synthesis, Decreased	November 04, 2022 09:25
Reduction, Plasma 17beta-estradiol concentrations	September 26, 2017 11:30
Reduction, Plasma vitellogenin concentrations	September 16, 2017 10:14
Reduction, Cumulative fecundity and spawning	March 20, 2017 17:52
Thyroperoxidase, Inhibition leads to TH synthesis, Decreased	November 04, 2022 09:27
TH synthesis, Decreased leads to Reduction, Plasma 17beta-estradiol concentrations	September 18, 2018 20:54
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations	October 18, 2018 11:02
Reduction, Plasma vitellogenin concentrations leads to Reduction, Cumulative fecundity and spawning	September 18, 2018 20:55
Propylthiouracil	November 29, 2016 18:42
Methimazole	November 29, 2016 18:42
Ethylene thiourea	November 29, 2016 18:42

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 links inhibition of thyroid peroxidase to reproductive toxicity in fish. This AOP describes one adverse outcome that may result from the inhibition of thyroid peroxidase (TPO). Thyroid peroxidase (TPO) is an enzyme for thyroid hormone (TH) synthesis. Chemical inhibition of TPO, the molecular-initiating event (MIE), results in decreased thyroid hormone (TH) synthesis. Reduction of TH induces the decline of E2 and VTG, which leads to decreased cumulative fecundity and spawning. Cumulative fertility is major endpoint for evaluation of reproductive toxicity caused by endocrine disruption. It is used as an endpoint for endocrine disruptor screening in OECD 229. Therefore, this AOP would be useful as a means to identify chemicals with known potential to adversely affect fish populations.

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

Acknowledgements: This research was supported by the National Research Council of Science & Technology(NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe)

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

MIE

279

Thyroperoxidase, Inhibition

KE	277	Thyroid hormone synthesis, Decreased	TH synthesis, Decreased
KE	219	Reduction, Plasma 17beta-estradiol concentrations	Reduction, Plasma 17beta-estradiol concentrations
KE	221	Reduction, Plasma vitellogenin concentrations	Reduction, Plasma vitellogenin concentrations

Reduction, Cumulative fecundity and spawning

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

Thyroperoxidase, Inhibition leads to TH synthesis, Decreased	adjacent	High	High
TH synthesis, Decreased leads to Reduction, Plasma 17beta-estradiol concentrations	adjacent
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations	adjacent	High	High
Reduction, Plasma vitellogenin concentrations leads to Reduction, Cumulative fecundity and spawning	adjacent	High	High

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

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

Name
Propylthiouracil
Methimazole
Ethylene thiourea

Life Stage Applicability

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

Life stage	Evidence
Adult, reproductively mature	High

Taxonomic Applicability

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Term	Scientific Term	Evidence	Link
fish	fish	High	NCBI

Sex Applicability

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

Sex	Evidence
Female	High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

MIE: Thyroperoxidase, Inhibition: The present MIE, an inhibition peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. Specifically as the TPO inhibited by MMI and PTU was reflected in the several thyroid hormone synthesis and release pathway genes (Alison et al., 2012).
KE 1: Thyroid hormone synthesis, Decrease: A lot of studies have a correlation between TPO activition leading to decrease of thyroid hormone. Many studies was exposed that TPO inhibition lead to a decreased or inactivate of thyroid hormones levels (Shaoying et al., 2011; Antonio et al., 2006; Tonacchera et al., 2004; De Groef et al., 2006; Waltz wt al., 2010).

Evidence Assessment

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Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

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

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

The continuous release of thyroid hormones into the bloodstream is integral to properly regulating these excretory systems. The thyroid gland produces a relatively inactive prohormone, thyroxine (T4), and an active hormone called triiodothyronine (T3). The levels of THs T4 and T3 and that of the thyroid-stimulating hormone (TSH) in vivo are representative assays for identifying thyroid disturbance factors during toxicity tests. The in vivo TH levels in response to thyroid-disrupting chemicals can be measured based on the test guidelines (TGs) of the Organization for Economic Cooperation and Development (OECD). The effects of the TS microspheres on the function and fate of 3D thyroid cells can be applied to this AOP. In addition, the zebrafish embryo evaluation model is validated with the proposed TS-microsphere integrated 3D cell aggregates in terms of sensitivity to chemical substances. It can be applied to the organization of tissue and organ level as quantitative AOP271,

References

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

Alison E.M. Vickers, Jason Heale, John R. Sinclair, Stephen Morris, Josh M. Rowe, Robyn L. Fisher. 2012. Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways. Toxicology and Applied Pharmacology, volume 260, Issue 1, PP. 81-88.

B. Jomaa, S.A.B. Hermsen, M.Y. Kessels, J.H.J. Van Den Berg, A.A.C.M. Peijnenburg, J.M.M.J.G. Aarts, A.H. Piersma, I.M.C.M. Rietjens. 2014. Developmental toxicity of thyroid-active compounds in a zebrafish embryotoxicity test. ALTEX 31, pp. 303-317.

De Groeg B, Decallonne BR, Van der Geyten S, Darras VM, Bouillon R. 2006. Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Europ J Endocr. 155:17-25.

Dietrich, J.W., Landgrafe, G. and Fotiadou, E.H. 2012. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res 2012, 351864.

E. Bagci, M. Heijlen, L. Vergauwen, A. Hagenaars, A.M. Houbrechts, C.V. Esguerra, R. Blust, V.M. Darras, D. Knapen. 2015. Deiodinase knockdown during early zebrafish development affects growth, development, energy metabolism, motility and phototransduction. PLoS One, p. e0123285.

Hadley, M.J.N.J. 1984. Endocrinology Prentice-Hall.

Jiang, J.Y., Umezu, M. and Sato, E. 2000. Improvement of follicular development rather than gonadotrophin secretion by thyroxine treatment in infertile immature hypothyroid rdw rats.

J Reprod Fertil 119, 193-199.

Kress, E., Samarut, J. and Plateroti, M. 2009. Thyroid hormones and the control of cell proliferation or cell differentiation: paradox or duality? Mol Cell Endocrinol 313, 36-49.

Medenica, S., Nedeljkovic, O., Radojevic, N., Stojkovic, M., Trbojevic, B. and Pajovic, B. 2015. Thyroid dysfunction and thyroid autoimmunity in euthyroid women in achieving fertility.

Eur Rev Med Pharmacol Sci 19, 977-987.

M. Heijlen, A.M. Houbrechts, E. Bagci, S.L.J. Van Herck, S. Kersseboom, C.V. Esguerra, R. Blust, T.J. Visser, D. Knapen, V.M. Darras. 2014. Knockdown of type 3 iodothyronine deiodinase severely perturbs both embryonic and early larval development in zebrafish. Endocrinology 155, pp. 1547-1559.

Mullur, R., Liu, Y.Y. and Brent, G.A. 2014. Thyroid hormone regulation of metabolism. Physiol Rev 94, 355-382.

Quesada-Garcia, A., Valdehita, A., Kropf, C., Casanova-Nakayama, A., Segner, H. and Navas, J.M. 2014. Thyroid signaling in immune organs and cells of the teleost fish rainbow trout (Oncorhynchus mykiss). Fish Shellfish Immunol 38, 166-174.

Ramprasad, M., Bhattacharyya, S.S. and Bhattacharyya, A. 2012. Thyroid disorders in pregnancy. Indian J Endocrinol Metab 16, S167-170.

Schreiber, G. and Richardson, S.J. 1997. The evolution of gene expression, structure and function of transthyretin. Comp Biochem Physiol B Biochem Mol Biol 116, 137-160.

Sharma, P. and Patino, R. 2013. Regulation of gonadal sex ratios and pubertal development by the thyroid endocrine system in zebrafish (Danio rerio). Gen Comp Endocrinol 184, 111-119.

Sharma, P., Tang, S., Mayer, G.D. and Patino, R. 2016. Effects of thyroid endocrine manipulation onsex-related gene expression and population sex ratios in Zebrafish. Gen Comp Endocrinol 235, 38-47.

Simonides, W.S. and van Hardeveld, C. 2008. Thyroid hormone as a determinant of metabolic and contractile phenotype of skeletal muscle. Thyroid 18, 205-216.

Thompson, C.C. and Potter, G.B. 2000. Thyroid hormone action in neural development. Cereb Cortex 10, 939-945.

Tonacchera M, Pinchera A, Dimida A, Ferrarini E, Agretti P, Vitti P, Santini F, Crump K, Gibbs J. 2004. Relative potencies and additivity or perchlorate, thiocyanate, nitrate, and iodide on the inhibition of radioative iodide uptake by the human sodium iodide symporter. Thyroid. 14: 1012-1019.

van der Ven, L.T., van den Brandhof, E.J., Vos, J.H., Power, D.M. and Wester, P.W. 2006. Effects of the antithyroid agent propylthiouracil in a partial life cycle assay with zebrafish. Environ Sci Technol 40, 74-81.

Waltz F, Pillette L, Ambroise Y. 2010. A nonradioactive iodide uptake assay for sodium iodide symporter function. Anal Biochem. 396:91-95.

I Jun, H Cho, Sebastian E. Amos, Y Choi, Y Choi, C Ryu, SA Lee, DW Han, H-S Han, J Yang, H Jeong, H Park, and Y.Kim,2023 Thyroid-friendly Soft Materials as Three-dimensional Cell Culture Tool for Stimulating Thyroid Cell Function Small 230023