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AOP Title

Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis
Short name: NIS inhib alters metamorphosis


Jonathan T. Haselman, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <>

Sigmund J. Degitz, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <>

Michael W. Hornung, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <>


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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

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

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This AOP describes how intracellular iodine deficits in thyroid follicular cells via chemical inhibition of sodium-iodide symporter (NIS) decrease thyroid hormone (TH) synthesis and cause delayed amphibian metamorphosis, or in extreme cases, arrests development. Amphibian metamorphosis is mediated by TH and successful completion of metamorphosis is generally required for organism survival. NIS is a critical transport protein that mediates iodine uptake into thyroid follicular cells making it available for thyroperoxidase (see TPO AOP) to catalyze its covalent bonding to tyrosine residues of thyroglobulin. TPO subsequently couples the iodinated tyrosines to form thyroxine (T4). Conversion of T4 to the active hormone, triiodothyronine (T3), is catalyzed by type I or II deiodinase enzymes (see DIO1 and DIO2 pAOPs) located within the peripheral organs and tissues, which then binds to thyroid receptor (TR). Activated TR then stimulates gene expression that drives the anatomical and physiological changes encompassed by the metamorphic process including limb emergence and development, lung development, gill and tail resorption, gut remodeling, metabolic profile changes in the liver, skin keratinization, etc. The model NIS inhibitor, perchlorate, has been tested in amphibian model species Xenopus laevis using in vivo study designs aiming to characterize temporal profiles of glandular hormone levels in addition to serum hormone levels and associated thyroid gland histopathology. Although there are only a few studies in amphibians that directly address NIS inhibition, these studies provide a strong weight of evidence supporting the specificity and essentiality of NIS inhibition leading to well-supported essential key events downstream.

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Na+/I- symporter (NIS), Inhibition Strong

Key Events

Event Support for Essentiality
Thyroidal iodide uptake, Decreased Strong
Thyroid hormone synthesis, Decreased Strong
Thyroxin (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

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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 Strong NCBI

Sex Applicability

Sex Evidence Links
Unspecific Strong

Graphical Representation

Amphib NIS AOP.jpg

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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

Summary Table
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Quantitative Considerations

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


Hornung, M.W., Degitz, S.J., Korte, L.M., Olson, J.M., Kosian, P.A., Linnum, A.L. and Tietge, J.E., 2010. Inhibition of thyroid hormone release from cultured amphibian thyroid glands by methimazole, 6-propylthiouracil, and perchlorate. Toxicological Sciences, 118(1), pp.42-51.

Tietge, J.E., Holcombe, G.W., Flynn, K.M., Kosian, P.A., Korte, J.J., Anderson, L.E., Wolf, D.C. and Degitz, S.J., 2005. Metamorphic inhibition of Xenopus laevis by sodium perchlorate: effects on development and thyroid histology. Environmental Toxicology and Chemistry, 24(4), pp.926-933.

Tietge, J.E., Butterworth, B.C., Haselman, J.T., Holcombe, G.W., Hornung, M.W., Korte, J.J., Kosian, P.A., Wolfe, M. and Degitz, S.J., 2010. Early temporal effects of three thyroid hormone synthesis inhibitors in Xenopus laevis. Aquatic Toxicology, 98(1), pp.44-50.