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Sally A. Mayasich, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <firstname.lastname@example.org>
Jonathan T. Haselman, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <email@example.com>
Sigmund J. Degitz, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <firstname.lastname@example.org>
Michael W. Hornung, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <email@example.com>
Point of Contact
Jonathan Haselman (email point of contact)
- Jonathan Haselman
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite||1.29||Under Development|
This AOP was last modified on January 27, 2018 15:34
|Inhibition, Deiodinase 2||August 20, 2019 09:52|
|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|
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
Events: Molecular Initiating Events (MIE)
|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|
|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 Altered, Amphibian metamorphosis||adjacent||High||Moderate|
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.