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AOP: 176
Title
Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis
Short name
Graphical Representation
Point of Contact
Contributors
- Jonathan Haselman
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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1.29 |
This AOP was last modified on April 29, 2023 16:02
Revision dates for related pages
Page | Revision Date/Time |
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Inhibition, Na+/I- symporter (NIS) | April 04, 2019 08:52 |
Decrease of Thyroidal iodide | April 04, 2019 09:00 |
Thyroid hormone synthesis, Decreased | November 04, 2022 09:25 |
Thyroxine (T4) in serum, Decreased | October 10, 2022 08:52 |
Altered, Amphibian metamorphosis | September 02, 2020 11:19 |
Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, Decreased | May 29, 2018 07:24 |
Inhibition, Na+/I- symporter (NIS) leads to T4 in serum, Decreased | December 09, 2020 12:16 |
Thyroidal Iodide, Decreased leads to TH synthesis, Decreased | June 04, 2018 06:11 |
T4 in serum, Decreased leads to Altered, Amphibian metamorphosis | August 25, 2020 16:43 |
TH synthesis, Decreased leads to T4 in serum, Decreased | October 10, 2022 08:56 |
Perchlorate | November 29, 2016 18:42 |
Abstract
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.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 424 | Inhibition, Na+/I- symporter (NIS) | Inhibition, Na+/I- symporter (NIS) |
KE | 425 | Decrease of Thyroidal iodide | Thyroidal Iodide, Decreased |
KE | 277 | Thyroid hormone synthesis, Decreased | TH synthesis, Decreased |
KE | 281 | Thyroxine (T4) in serum, Decreased | T4 in serum, Decreased |
AO | 1101 | Altered, Amphibian metamorphosis | Altered, Amphibian metamorphosis |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, Decreased | adjacent | High | Moderate |
Thyroidal Iodide, Decreased leads to TH synthesis, Decreased | adjacent | High | Moderate |
TH synthesis, Decreased leads to T4 in serum, Decreased | adjacent | High | High |
Inhibition, Na+/I- symporter (NIS) leads to T4 in serum, Decreased | non-adjacent | Moderate | Moderate |
T4 in serum, Decreased leads to Altered, Amphibian metamorphosis | non-adjacent | High | High |
Network View
Prototypical Stressors
Name |
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Perchlorate |
Life Stage Applicability
Life stage | Evidence |
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Development | High |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
African clawed frog | Xenopus laevis | High | NCBI |
Sex Applicability
Sex | Evidence |
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Unspecific | High |
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Evidence Assessment
Known Modulating Factors
Quantitative Understanding
Considerations for Potential Applications of the AOP (optional)
References
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.