Aop:189

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/189


AOP Title

Type I iodothyronine deiodinase (DIO1) inhibition leading to altered amphibian metamorphosis
Short name: DIO1 inhib alters metamorphosis

Authors

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>

Status

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OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

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This AOP page was last modified on 12/11/2016.

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Abstract

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.


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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Deiodinase 1, Inhibition Weak

Key Events

Event Support for Essentiality
Triiodothyronine (T3) in tissues, Decreased Strong
Triiodothyronine (T3) in serum, Decreased Moderate

Adverse Outcome

Adverse Outcome
Amphibian metamorphosis, Altered

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Deiodinase 1, Inhibition Directly Leads to Triiodothyronine (T3) in tissues, Decreased Moderate Weak
Triiodothyronine (T3) in tissues, Decreased Directly Leads to Amphibian metamorphosis, Altered Strong Moderate

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Life Stage Applicability

Life Stage Evidence Links
development Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
African clawed frog Xenopus laevis Weak NCBI

Sex Applicability

Sex Evidence Links
Unspecific Strong

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

References


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.