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Aop: 176

AOP Title

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Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis

Short name:

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NIS inhib alters metamorphosis

Graphical Representation

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Click to download graphical representation template

Authors

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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 Do not cite 1.29 Under Development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, Na+/I- symporter (NIS) May 25, 2018 11:37
Decrease of Thyroidal iodide September 16, 2017 10:17
Thyroid hormone synthesis, Decreased September 17, 2017 18:27
Thyroxine (T4) in serum, Decreased May 25, 2018 11:41
Decreased, Thyroxine (T4) in tissues November 29, 2016 19:42
Altered, Amphibian metamorphosis December 03, 2016 16:37
Decreased, Triiodothyronine (T3) in tissues November 29, 2016 19:43
Perchlorate November 29, 2016 18:42

Abstract

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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.


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 424 Inhibition, Na+/I- symporter (NIS) Inhibition, Na+/I- symporter (NIS)
2 KE 425 Decrease of Thyroidal iodide Thyroidal Iodide, Decreased
3 KE 277 Thyroid hormone synthesis, Decreased TH synthesis, Decreased
4 KE 281 Thyroxine (T4) in serum, Decreased T4 in serum, Decreased
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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Network View

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Stressors

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Name Evidence Term
Perchlorate

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 High 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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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.