API

Aop: 190

AOP Title

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

Short name:

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DIO2 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 Do not cite Under Development 1.29 Included in OECD Work Plan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 2 November 29, 2016 19:36
Decreased, Triiodothyronine (T3) in tissues November 29, 2016 19:43
Altered, Amphibian metamorphosis December 03, 2016 16:37
Inhibition, Deiodinase 2 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 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.


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 2 Inhibition, Deiodinase 2

Key Events

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Title Short name
Decreased, Triiodothyronine (T3) in tissues Decreased, 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 2 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 Moderate NCBI

Sex Applicability

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Sex Evidence
Unspecific Strong

Graphical Representation

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Click to download graphical representation template

W1siziisijiwmtyvmtevmjkvmte0relpml9bt1bfz3jhcghpy2fslmpwzyjdlfsiccisinrodw1iiiwintaweduwmcjdxq?sha=907407810e64e4ec

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.

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.