This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Type III iodotyrosine deiodinase (DIO3) inhibition leading to altered amphibian metamorphosis
Point of Contact
- Jonathan Haselman
|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 13:59
|Inhibition, Deiodinase 3||December 03, 2016 16:37|
|Increased, Triiodothyronine (T3) in tissues||December 03, 2016 16:37|
|Altered, Amphibian metamorphosis||September 02, 2020 11:19|
|Altered, Thyroid hormone-dependent gene expression||December 09, 2020 14:22|
|Inhibition, Deiodinase 3 leads to Increased, Triiodothyronine (T3) in tissues||December 03, 2016 16:38|
|Increased, Triiodothyronine (T3) in tissues leads to Altered, TH-dependent gene expression||December 09, 2020 14:36|
|Altered, TH-dependent gene expression leads to Altered, Amphibian metamorphosis||December 09, 2020 14:38|
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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1153||Inhibition, Deiodinase 3||Inhibition, Deiodinase 3|
|2||KE||1154||Increased, Triiodothyronine (T3) in tissues||Increased, Triiodothyronine (T3) in tissues|
|KE||1829||Altered, Thyroid hormone-dependent gene expression||Altered, TH-dependent gene expression|
|3||AO||1101||Altered, Amphibian metamorphosis||Altered, Amphibian metamorphosis|
Relationships Between Two Key Events (Including MIEs and AOs)
|Inhibition, Deiodinase 3 leads to Increased, Triiodothyronine (T3) in tissues||adjacent||Low||Low|
|Increased, Triiodothyronine (T3) in tissues leads to Altered, TH-dependent gene expression||adjacent||Moderate||Low|
|Altered, TH-dependent gene expression leads to Altered, Amphibian metamorphosis||adjacent||Moderate||Low|
Life Stage Applicability
|African clawed frog||Xenopus laevis||High||NCBI|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
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.