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Aop: 188

AOP Title

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Iodotyrosine deiodinase (IYD) inhibition leading to altered amphibian metamorphosis

Short name:

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IYD inhib alters metamorphosis

Graphical Representation

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Click to download graphical representation template

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Authors

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Jennifer H. Olker, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <olker.jennifer@epa.gov>

Jonathan T. Haselman, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <haselman.jon@epa.gov>

Sigmund J. Degitz, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <degitz.sigmund@epa.gov>

Michael W. Hornung, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <hornung.michael@epa.gov>

Point of Contact

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Jonathan Haselman   (email point of contact)

Contributors

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  • Jonathan Haselman

Status

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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 Do not cite 1.29 Under Development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

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Revision dates for related pages

Page Revision Date/Time
Inhibition, Iodotyrosine deiodinase (IYD) September 16, 2017 10:17
Decrease of Thyroidal iodide September 16, 2017 10:17
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

Abstract

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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.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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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)

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Title Adjacency Evidence Quantitative Understanding
Inhibition, Iodotyrosine deiodinase (IYD) leads to Thyroidal Iodide, Decreased adjacent Low Low

Network View

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Stressors

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Life Stage Applicability

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Life stage Evidence
Development High

Taxonomic Applicability

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Term Scientific Term Evidence Link
African clawed frog Xenopus laevis Low NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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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.