Aop: 190

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

Type II iodothyronine deiodinase (DIO2) inhibition leading to altered amphibian metamorphosis

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
DIO2 inhib alters metamorphosis

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
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Authors

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

Jonathan T. Haselman, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <haselman.jon@epa.gov>

Sigmund J. Degitz, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <degitz.sigmund@epa.gov>

Michael W. Hornung, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <hornung.michael@epa.gov>

Sally A. Mayasich, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <mayasich.sally@epa.gov>

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
Jonathan Haselman   (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
  • Jonathan Haselman

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under Development: Contributions and Comments Welcome 1.29 Under Development
This AOP was last modified on June 04, 2021 13:58

Revision dates for related pages

Page Revision Date/Time
Inhibition, Deiodinase 2 September 08, 2021 08:03
Decreased, Triiodothyronine (T3) in tissues September 01, 2020 16:29
Altered, Amphibian metamorphosis September 02, 2020 11:19
Increased, Thyroid-stimulating hormone (TSH) September 16, 2017 10:17
Increased, Thyroxine (T4) in serum December 09, 2020 14:21
Altered, Thyroid hormone-dependent gene expression December 09, 2020 14:22
Inhibition, Deiodinase 2 leads to Decreased, Triiodothyronine (T3) in tissues December 03, 2016 16:38
Increased, Thyroxine (T4) in serum leads to Altered, Amphibian metamorphosis December 09, 2020 14:26
Decreased, Triiodothyronine (T3) in tissues leads to Increased, Thyroid-stimulating hormone (TSH) December 09, 2020 14:24
Increased, Thyroxine (T4) in serum leads to Altered, TH-dependent gene expression December 09, 2020 14:27
Decreased, Triiodothyronine (T3) in tissues leads to Altered, TH-dependent gene expression December 09, 2020 14:25
Increased, Thyroid-stimulating hormone (TSH) leads to Increased, Thyroxine (T4) in serum December 09, 2020 14:25

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 putative AOP describes the potential for an adverse outcome resulting from the inhibition of Type 2 iodothyronine deiodinase (DIO2) during amphibian metamorphosis. Initial development of this AOP is based largely on literature in which amphibian deiodinases are genetically disrupted or blocked by the deiodinase inhibitor iopanoic acid, and prediction from tissue expression patterns. Thyroid hormones (THs) are essential for normal sequential development of amphibian tissues and organs, and activities of the three deiodinases found in amphibians, as in mammals, function in a highly regulated balance. Chemical inhibition of DIO2, the molecular-initiating event (MIE), results in decreased transformation of thyroxine (T4) to the active form, 3,5,3’-triiodothyronine (T3) in peripheral tissues. Chemicals that interfere with the DIO2 catalyzing reaction of T4 to T3 have the potential to cause insufficiency of the active form that may result in altered metamorphosis. Adverse consequences of T3 insufficiency may vary based on timing of exposure and produce different effects at different developmental stages. For example, T3 insufficiency due to DIO2 inhibition in the African clawed frog, Xenopus laevis, within several days post-fertilization (pre-metamorphosis) could affect brain development, and could alter T4/T3 feedback. It has been found that DIO2 does not regulate T3 levels in serum. However, D2 inhibition in peripheral tissues through the larval phase and post-metamorphic climax may cause alterations in limb development, intestinal remodeling, gill resorption and/or tail resorption.

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
MIE 1002 Inhibition, Deiodinase 2 Inhibition, Deiodinase 2
KE 1116 Decreased, Triiodothyronine (T3) in tissues Decreased, Triiodothyronine (T3) in tissues
KE 1023 Increased, Thyroid-stimulating hormone (TSH) Increased, Thyroid-stimulating hormone (TSH)
KE 1828 Increased, Thyroxine (T4) in serum Increased, Thyroxine (T4) in serum
KE 1829 Altered, Thyroid hormone-dependent gene expression Altered, TH-dependent gene expression
AO 1101 Altered, Amphibian metamorphosis Altered, Amphibian metamorphosis

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

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

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Development High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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. More help
Term Scientific Term Evidence Link
African clawed frog Xenopus laevis Moderate NCBI

Sex Applicability

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

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

Quantitative Understanding

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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

References

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

Becker, K.B., Stephens, K.C., Davey, J.C., Schneider, M.J., Galton, V.A. (1997). “The Type 2 and Type 3 iodothyronine deiodinases play important roles in coordinating development in Rana catesbeiana tadpoles.” Endocrinology 138(7): 2989-2997.

Cai, L. Q., Brown, D.D. (2004). "Expression of type II iodothyronine deiodinase marks the time that a tissue responds to thyroid hormone-induced metamorphosis in Xenopus laevis." Developmental Biology 266(1): 87-95.

Galton, V.A., Schneider, M.J., Clark, A.S., St. Germain, D.L. (2009). “Life without thyroxine to 3,5,3’-triiodothyronine conversion: studies in mice devoid of the 5’-deiodinases.” Endocrinology 150(6): 2957–2963.

Huang, H., Cai, L., Remo, B. F., Brown, D. D.. (2001). "Timing of metamorphosis and the onset of the negative feedback loop between the thyroid gland and the pituitary is controlled by type II iodothyronine deiodinase in Xenopus laevis." Proc Natl Acad Sci U S A 98(13): 7348-7353.

Morvan-Dubois, G., Demeneix, B.A., Sachs, L.M. (2008). “Xenopus laevis as a model for studying thyroid hormone signaling: From development to metamorphosis.” Mol Cell Endocrinol. 293: 71-79.

Morvan-Dubois, G., Sebillot, A., Kuiper, G.G.J.M., Verhoelst, C.H.J., Darras, V.M., Visser, T.J., Demeneix, B.A. (2006). “Deiodinase activity is present in Xenopus laevis during early embryogenesis.” Endocrinolgy 147(10): 4941-4949.

Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St Germain DL, GaltonVA (2001) Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol 15:2137–2148.