Aop:188

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/188


AOP Title

Iodotyrosine deiodinase (IYD) inhibition leading to altered amphibian metamorphosis
Short name: IYD inhib alters metamorphosis

Authors

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>

Status

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OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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Abstract

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.

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Iodotyrosine deiodinase (IYD), Inhibition Weak

Key Events

Event Support for Essentiality
Thyroidal iodide uptake, Decreased Weak
Thyroid hormone synthesis, Decreased Strong
Thyroxine (T4) in serum, Decreased Strong
Thyroxine (T4) in tissues, Decreased Moderate
Triiodothyronine (T3) in tissues, Decreased Moderate

Adverse Outcome

Adverse Outcome
Amphibian metamorphosis, Altered

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Iodotyrosine deiodinase (IYD), Inhibition Directly Leads to Thyroidal iodide uptake, Decreased Weak Weak

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Life Stage Applicability

Life Stage Evidence Links
development Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
African clawed frog Xenopus laevis Weak NCBI

Sex Applicability

Sex Evidence Links
Unspecific Strong

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References


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.