This AOP is licensed under a Creative Commons Attribution 4.0 International License.

Aop: 189

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 I iodothyronine deiodinase (DIO1) inhibition leading to altered amphibian metamorphosis

Short name

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DIO1 inhib alters metamorphosis

Graphical Representation

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

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Authors

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Sally A. Mayasich, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <mayasich.sally@epa.gov>

Jonathan T. Haselman, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <haselman.jon@epa.gov>

Sigmund J. Degitz, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <degitz.sigmund@epa.gov>

Michael W. Hornung, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <hornung.michael@epa.gov>

Point of Contact

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Jonathan Haselman (email point of contact)

Contributors

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Jonathan Haselman

Status

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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 1	September 08, 2021 08:03
Decreased, Triiodothyronine (T3) in tissues	September 01, 2020 16:29
Decreased, Triiodothyronine (T3)	July 08, 2022 07:22
Altered, Amphibian metamorphosis	September 02, 2020 11:19
Inhibition, Deiodinase 1 leads to Decreased, Triiodothyronine (T3) in tissues	December 03, 2016 16:38
Decreased, Triiodothyronine (T3) in tissues leads to Altered, Amphibian metamorphosis	December 03, 2016 16:38

Abstract

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This putative AOP describes an adverse outcome that results from the inhibition of Type I iodothyronine deiodinase (DIO1) during amphibian metamorphosis. Initial development of this AOP is based on literature in which amphibian deiodinases are genetically disrupted and prediction from tissue expression patterns. Chemical inhibition of DIO1, the molecular-initiating event (MIE), results in decreased transformation of thyroxine (T4) to the active form, 3,5,3’-triiodothyronine (T3), but also decreased inactivation of T3 to 3,3’,5’-triiodothyronine (rT3). 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. Therefore, chemicals that interfere with the DIO1 catalyzing reaction of T4 to T3 have the potential to cause insufficiency of the active form, but also disrupt the balance between active T3 and inactive rT3. Consequences of T4/T3/rT3 imbalance may vary based on timing of exposure and produce different effects in different tissues at different developmental stages. For example, T3 insufficiency due to DIO1 inhibition in the African clawed frog, Xenopus laevis, within several days post-fertilization (pre-metamorphosis) could affect brain development, and like the DIO2 enzyme, DIO1 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

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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

1009

Inhibition, Deiodinase 1

KE	1116	Decreased, Triiodothyronine (T3) in tissues	Decreased, Triiodothyronine (T3) in tissues
KE	1003	Decreased, Triiodothyronine (T3)	Decreased, Triiodothyronine (T3)

1101

Altered, Amphibian metamorphosis

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

Inhibition, Deiodinase 1 leads to Decreased, Triiodothyronine (T3) in tissues	adjacent	Moderate	Low
Decreased, Triiodothyronine (T3) in tissues leads to Altered, Amphibian metamorphosis	adjacent	High	Moderate

Network View

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Prototypical Stressors

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Life Stage Applicability

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

Life stage	Evidence
Development	High

Taxonomic Applicability

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Term	Scientific Term	Evidence	Link
African clawed frog	Xenopus laevis	Low	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

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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

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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

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.

Kuiper, G.G.J.M., Klootwijk, W., Morvan-Dubois, G., Destree, O., Darras, V.M., Van der Geyten, S., Demeneix, B.A., Visser, T.J. (2006). “Characterization of recombinant Xenopus laevis Type I Iodothyronine deiodinase: Substitution of a proline residue in the catalytic center by serine (Pro132Ser) restores sensitivity to 6-propyl-2-thiouricil.” Endocrinology 147(7): 3519-3529.

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.