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Jennifer H. Olker, 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: Contributions and Comments Welcome||1.29||Under Development|
This AOP was last modified on February 07, 2020 14:54
|Inhibition, Iodotyrosine deiodinase (IYD)||September 16, 2017 10:17|
|Decrease of Thyroidal iodide||April 04, 2019 09:00|
|Thyroid hormone synthesis, Decreased||August 11, 2018 13:21|
|Decreased, Thyroxine (T4) in serum||September 16, 2017 10:16|
|Decreased, Thyroxine (T4) in tissues||November 29, 2016 19:42|
|Decreased, Triiodothyronine (T3) in tissues||November 29, 2016 19:43|
|Altered, Amphibian metamorphosis||December 03, 2016 16:37|
|Inhibition, Iodotyrosine deiodinase (IYD) leads to Thyroidal Iodide, Decreased||December 03, 2016 16:38|
This putative adverse outcome pathway describes the linkage between inhibition of iodotyrosine deiodinase (dehalogenase, IYD) and altered amphibian metamorphosis. Initial development of this AOP is based largely on IYD literature of clinical evidence in humans, rat model experiments, and biochemical and genetic analyses. The enzyme IYD catalyzes the recycling of iodide from the byproducts of thyroid hormone (TH) synthesis [monoiodotyrosine (MIT) and diiodotyrosine (DIT)] within the thyroid gland as well as other organs, including liver and kidney. IYD protects against excretion of critical iodide and promotes accumulation of iodide in thyroid follicular cells for TH synthesis, which is especially critical for low iodine diets and low iodine environments (including most freshwater ecosystems). Therefore, failure or chemical inhibition of IYD could reduce TH synthesis, resulting in TH insufficiency in tissues and subsequent altered development. Failure of this enzyme in humans, due to mutations in the IYD gene (DEHAL1), has been shown to have negative developmental consequences, including hypothyroidism, goiter, and mental retardation. In rat exposures with suspected IYD inhibitors, serum T4 and T3 were reduced, thyroid gland size and TSH increased, and weight gain was reduced. Additionally, IYD has been shown to be a potential chemical target for thyroid axis disruption through in vitro inhibition assays with polychlorinated biphenyls, polybrominated diphenyl ethers, agrichemicals, antiparasitics, pharmaceuticals, and food colorants. This molecular initiating event, inhibition of IYD, may have broad taxonomic applicability; IYD genes are highly conserved across a wide range of multicellular organisms with evidence that iodide salvage is important for many species.
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1152||Inhibition, Iodotyrosine deiodinase (IYD)||Inhibition, Iodotyrosine deiodinase (IYD)|
|2||KE||425||Decrease of Thyroidal iodide||Thyroidal Iodide, Decreased|
|3||KE||277||Thyroid hormone synthesis, Decreased||TH synthesis, Decreased|
|4||KE||426||Decreased, Thyroxine (T4) in serum||Decreased, Thyroxine (T4) in serum|
|5||KE||1093||Decreased, Thyroxine (T4) in tissues||Decreased, Thyroxine (T4) in tissues|
|6||KE||1116||Decreased, Triiodothyronine (T3) in tissues||Decreased, Triiodothyronine (T3) in tissues|
|7||AO||1101||Altered, Amphibian metamorphosis||Altered, Amphibian metamorphosis|
Relationships Between Two Key Events
(Including MIEs and AOs)
|Inhibition, Iodotyrosine deiodinase (IYD) leads to Thyroidal Iodide, Decreased||adjacent||Low||Low|
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)
Afink, G.; Kulik, W.; Overmars, H.; de Randamie, J.; Veenboer, T.; van Cruchten, A.; Craen, M.; Ris-Stalpers, C. (2008). Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism. Journal of Clinical Endocrinology and Metabolism, 93, 4894-4901.
Fujimoto, K.; Matsuura, K.; Das, B.; Fu, L.; Shi, Y-B. (2012). Direct activation of Xenopus iodotyrosine deiodinase by thyroid hormone receptor in the remodeling intestine during amphibian metamorphosis. Endocrinology, 153, 5082-5089.
Gaupale, T.; Mathi, A.; Ravikuma, A.; Bhargave, S. (2009). Localization and enzyme activity Iodotyrosine dehalogenase 1 during metamorphosis of frog Microhyla ornata. Trends in Comparative Endocrinology and Neurobiology, 1163, 402-406.
Green, W.L. (1971). Effects of 3-nitro-L-tyrosine on thyroid function in the rat: an experimental model for the dehalogenase defect. The Journal of Clinical Investigation, 50, 2474-2484.
Moreno, J.; Klootwijk, W.; van Toor, H.; Pinto, G.; D’Alessandro, M.; Leger, A.; Goudie, D.; Polak, M.; Gruters, A.; Visser, T. (2008). Mutations in the iodotyrosine deiodinase gene and hypothyroidism. The New England Journal of Medicine, 358, 1811-1818
Meinhold, H.; Buchholz, R. (1983). Effects of iodotyrosine deiodinase inhibition on serum concentrations and turnover of diiodotyrosine (DIT) and thyrosine (T4) in the rat. Acta endocrinologica, 103, 521-527.
Phatarphekar, A.; Buss, J.; Rokita, S. (2014). Iodotyrosine deiosinase: a unique flavoprotein present in organisms of diverse phyla. Molecular Biosystems, 10, 86-92.
Shimizu, R.; Yamaguchi, M.; Uramaru, N.; Kuroki, H.; Ohta, S.; Kitamura, S.; Sugihara, K. (2013). Structure-activity relationships of 44 halogenated compounds for iodotyrosine deiodinase-inhibitory activity. Toxicology, 314, 22-29.