This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Type II iodothyronine deiodinase (DIO2) inhibition leading to altered amphibian metamorphosis
- 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 December 09, 2020 14:27
|Inhibition, Deiodinase 2||December 02, 2020 03:04|
|Decreased, Triiodothyronine (T3) in tissues||September 01, 2020 16:29|
|Altered, Amphibian metamorphosis||September 02, 2020 11:19|
|Increased, Thyroid-stimulating hormone (TSH)||September 16, 2017 10:17|
|Increased, Thyroxine (T4) in serum||December 09, 2020 14:21|
|Altered, Thyroid hormone-dependent gene expression||December 09, 2020 14:22|
|Inhibition, Deiodinase 2 leads to Decreased, Triiodothyronine (T3) in tissues||December 03, 2016 16:38|
|Increased, Thyroxine (T4) in serum leads to Altered, Amphibian metamorphosis||December 09, 2020 14:26|
|Decreased, Triiodothyronine (T3) in tissues leads to Increased, Thyroid-stimulating hormone (TSH)||December 09, 2020 14:24|
|Increased, Thyroxine (T4) in serum leads to Altered, TH-dependent gene expression||December 09, 2020 14:27|
|Decreased, Triiodothyronine (T3) in tissues leads to Altered, TH-dependent gene expression||December 09, 2020 14:25|
|Increased, Thyroid-stimulating hormone (TSH) leads to Increased, Thyroxine (T4) in serum||December 09, 2020 14:25|
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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1002||Inhibition, Deiodinase 2||Inhibition, Deiodinase 2|
|2||KE||1116||Decreased, Triiodothyronine (T3) in tissues||Decreased, Triiodothyronine (T3) in tissues|
|KE||1023||Increased, Thyroid-stimulating hormone (TSH)||Increased, Thyroid-stimulating hormone (TSH)|
|KE||1828||Increased, Thyroxine (T4) in serum||Increased, Thyroxine (T4) in serum|
|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 2 leads to Decreased, Triiodothyronine (T3) in tissues||adjacent||Moderate||Low|
|Decreased, Triiodothyronine (T3) in tissues leads to Increased, Thyroid-stimulating hormone (TSH)||adjacent||Moderate||Low|
|Decreased, Triiodothyronine (T3) in tissues leads to Altered, TH-dependent gene expression||adjacent||Moderate||Low|
|Increased, Thyroid-stimulating hormone (TSH) leads to Increased, Thyroxine (T4) in serum||adjacent||Moderate||Low|
|Increased, Thyroxine (T4) in serum leads to Altered, Amphibian metamorphosis||non-adjacent||Moderate||Low|
|Increased, Thyroxine (T4) in serum leads to Altered, TH-dependent gene expression||non-adjacent||Moderate||Low|
Life Stage Applicability
|African clawed frog||Xenopus laevis||Moderate||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.
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.