API

Aop: 189

AOP Title

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

Short name:

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DIO1 inhib alters metamorphosis

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

Contributors

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  • Jonathan Haselman

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.29 Included in OECD Work Plan


This AOP was last modified on December 03, 2016 16:37

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Revision dates for related pages

Page Revision Date/Time
Inhibition, Deiodinase 1 November 29, 2016 19:36
Decreased, Triiodothyronine (T3) in tissues November 29, 2016 19:43
Decreased, Triiodothyronine (T3) in serum September 26, 2017 11:03
Altered, Amphibian metamorphosis December 03, 2016 16:37
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.



Background (optional)

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Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
Inhibition, Deiodinase 1 Inhibition, Deiodinase 1

Key Events

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Title Short name
Decreased, Triiodothyronine (T3) in tissues Decreased, Triiodothyronine (T3) in tissues
Decreased, Triiodothyronine (T3) in serum Decreased, Triiodothyronine (T3) in serum

Adverse Outcome

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Title Short name
Altered, Amphibian metamorphosis Altered, Amphibian metamorphosis

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
Inhibition, Deiodinase 1 leads to Decreased, Triiodothyronine (T3) in tissues Directly leads to Moderate Weak
Decreased, Triiodothyronine (T3) in tissues leads to Altered, Amphibian metamorphosis Directly leads to Strong Moderate

Network View

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Life Stage Applicability

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Life stage Evidence
Development Strong

Taxonomic Applicability

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Term Scientific Term Evidence Link
African clawed frog Xenopus laevis Weak NCBI

Sex Applicability

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Sex Evidence
Unspecific Strong

Graphical Representation

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Click to download graphical representation template

W1siziisijiwmtyvmtevmjkvnzc0relpmv9bt1bfz3jhcghpy2fslmpwzyjdlfsiccisinrodw1iiiwintaweduwmcjdxq?sha=a04a7f004b4aa0b2

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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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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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.