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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 Do not cite||1.29||Under Development|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 1||November 29, 2016 19:36|
|Decreased, Triiodothyronine (T3) in tissues||November 29, 2016 19:43|
|Decreased, Triiodothyronine (T3) in serum||September 26, 2017 11:03|
|Altered, Amphibian metamorphosis||December 03, 2016 16:37|
|Inhibition, Deiodinase 1 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 an adverse outcome that results from the inhibition of Type I iodothyronine deiodinase (DIO1) 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 DIO1, the molecular-initiating event (MIE), results in decreased transformation of thyroxine (T4) to the active form, 3,5,3’-triiodothyronine (T3), but also decreased inactivation of T3 to 3,3’,5’-triiodothyronine (rT3). 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. Therefore, chemicals that interfere with the DIO1 catalyzing reaction of T4 to T3 have the potential to cause insufficiency of the active form, but also disrupt the balance between active T3 and inactive rT3. Consequences of T4/T3/rT3 imbalance may vary based on timing of exposure and produce different effects in different tissues at different developmental stages. For example, T3 insufficiency due to DIO1 inhibition in the African clawed frog, Xenopus laevis, within several days post-fertilization (pre-metamorphosis) could affect brain development, and like the DIO2 enzyme, DIO1 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||1009||Inhibition, Deiodinase 1||Inhibition, Deiodinase 1|
|2||KE||1116||Decreased, Triiodothyronine (T3) in tissues||Decreased, Triiodothyronine (T3) in tissues|
|3||KE||1003||Decreased, Triiodothyronine (T3) in serum||Decreased, Triiodothyronine (T3) in serum|
|4||AO||1101||Altered, Amphibian metamorphosis||Altered, Amphibian metamorphosis|
Relationships Between Two Key Events
(Including MIEs and AOs)
|Inhibition, Deiodinase 1 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||Low||NCBI|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
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.
Kuiper, G.G.J.M., Klootwijk, W., Morvan-Dubois, G., Destree, O., Darras, V.M., Van der Geyten, S., Demeneix, B.A., Visser, T.J. (2006). “Characterization of recombinant Xenopus laevis Type I Iodothyronine deiodinase: Substitution of a proline residue in the catalytic center by serine (Pro132Ser) restores sensitivity to 6-propyl-2-thiouricil.” Endocrinology 147(7): 3519-3529.
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.