API

Aop: 191

AOP Title

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Type III iodotyrosine deiodinase (DIO3) inhibition leading to altered amphibian metamorphosis

Short name:

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DIO3 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 Do not cite Under Development 1.29 Included in OECD Work Plan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 3 December 03, 2016 16:37
Increased, Triiodothyronine (T3) in tissues December 03, 2016 16:37
Altered, Amphibian metamorphosis December 03, 2016 16:37
Inhibition, Deiodinase 3 leads to Increased, Triiodothyronine (T3) in tissues December 03, 2016 16:38
Increased, Triiodothyronine (T3) in tissues leads to Altered, Amphibian metamorphosis December 03, 2016 16:38

Abstract

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This putative AOP describes the potential for an adverse outcome resulting from the inhibition of Type III iodothyronine deiodinase (DIO3) 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 DIO3, the molecular-initiating event (MIE), results in decreased transformation of thyroxine (T4) to the inactive form, 3,3’,5’-triiodothyronine (reverse T3, or rT3) and also decreased transformation of T3 to inactive form T2 in peripheral tissues. Thyroid hormones (THs), including appropriate levels of the inactive rT3 form, 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 DIO3 catalyzing reaction of T4 inner-ring deiodination (IRD) to rT3 have the potential to cause overabundance of T4 as well as the active T3 form, potentially resulting in altered metamorphic development. Adverse consequences of rT3 insufficiency may vary based on timing of exposure and produce different effects at different developmental stages. In the African clawed frog, Xenopus laevis, DIO3 seems to be predominant during the early pre-metamorphosis development phase, protecting tissues from the actions of TH. Inhibition of DIO3 could alter T4/T3/rT3 feedback balance causing events that normally occur during pro-metamorphosis and post-metamorphic climax to occur too early and result in 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 3 Inhibition, Deiodinase 3

Key Events

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Title Short name
Increased, Triiodothyronine (T3) in tissues Increased, Triiodothyronine (T3) in tissues

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 3 leads to Increased, Triiodothyronine (T3) in tissues Directly leads to Weak Weak
Increased, Triiodothyronine (T3) in tissues leads to Altered, Amphibian metamorphosis Directly leads to Moderate Weak

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 Strong NCBI

Sex Applicability

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Sex Evidence
Unspecific Strong

Graphical Representation

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Click to download graphical representation template

W1siziisijiwmtyvmtevmjkvmdayrelpm19bt1bfz3jhcghpy2fslmpwzyjdlfsiccisinrodw1iiiwintaweduwmcjdxq?sha=1057617073be4bfd

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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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.

Galton VA, de Waard E, Parlow AF, St Germain DL, Hernndez, A. (2014) “Life without deiodinases.” Endocrinology. 155(10): 4081–4087.

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.

Hernandez, A., Martinez ME, Fiering S, Galton VA, St Germain D (2006). Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest 116:476–484.

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.

Huang, H., Marsh-Armstrong, N., Brown, D.D. (1999). Metamorphosis is inhibited in transgenic Xenopus laevis tadpoles that overexpress type III deiodinase. Proc. Nat. Acad. Sci. USA 96: 962-967.