Aop:191

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Status

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

https://aopwiki.org/aops/191


AOP Title

Type III iodotyrosine deiodinase (DIO3) inhibition leading to altered amphibian metamorphosis
Short name: DIO3 inhib alters metamorphosis

Authors

Sally A. Mayasich, National Health and Environmental Effects Research Laboratory, US EPA, Duluth, MN, USA <mayasich.sally@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 AOP describes the potential for an adverse outcome resulting from the inhibition of Type III iodothyronine deiodinase (DIO3) during amphibian metamorphosis. Initial development of this AOP is based on literature in which amphibian deiodinases are genetically disrupted and prediction from tissue expression patterns. Chemical inhibition of DIO3, the molecular-initiating event (MIE), results in decreased transformation of thyroxine (T4) to the inactive form, 3,3’,5’-triiodothyronine (reverse T3, or rT3) and also decreased transformation of T3 to inactive form T2 in peripheral tissues. Thyroid hormones (THs), including appropriate levels of the inactive rT3 form, are essential for normal sequential development of amphibian tissues and organs, and activities of the three deiodinases found in amphibians, as in mammals, function in a highly regulated balance. Therefore, chemicals that interfere with the DIO3 catalyzing reaction of T4 inner-ring deiodination (IRD) to rT3 have the potential to cause overabundance of T4 as well as the active T3 form, potentially resulting in altered metamorphic development. Adverse consequences of rT3 insufficiency may vary based on timing of exposure and produce different effects at different developmental stages. In the African clawed frog, Xenopus laevis, DIO3 seems to be predominant during the early pre-metamorphosis development phase, protecting tissues from the actions of TH. Inhibition of DIO3 could alter T4/T3/rT3 feedback balance causing events that normally occur during pro-metamorphosis and post-metamorphic climax to occur too early and result in alterations in limb development, intestinal remodeling, gill resorption and/or tail resorption.

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Deiodinase 3, Inhibition Weak

Key Events

Event Support for Essentiality
Triiodothyronine (T3) in tissues, Increased Moderate

Adverse Outcome

Adverse Outcome
Amphibian metamorphosis, Altered

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Deiodinase 3, Inhibition Directly Leads to Triiodothyronine (T3) in tissues, Increased Weak Weak
Triiodothyronine (T3) in tissues, Increased Directly Leads to Amphibian metamorphosis, Altered Moderate 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 Strong 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

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Considerations for Potential Applications of the AOP (optional)

References


Becker, K.B., Stephens, K.C., Davey, J.C., Schneider, M.J., Galton, V.A. (1997). “The Type 2 and Type 3 iodothyronine deiodinases play important roles in coordinating development in Rana catesbeiana tadpoles.” Endocrinology 138(7): 2989-2997.

Galton VA, de Waard E, Parlow AF, St Germain DL, Hernndez, A. (2014) “Life without deiodinases.” Endocrinology. 155(10): 4081–4087.

Galton, V.A., Schneider, M.J., Clark, A.S., St. Germain, D.L. (2009). “Life without thyroxine to 3,5,3’-triiodothyronine conversion: studies in mice devoid of the 5’-deiodinases.” Endocrinology 150(6): 2957–2963.

Hernandez, A., Martinez ME, Fiering S, Galton VA, St Germain D (2006). Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest 116:476–484.

Morvan-Dubois, G., Demeneix, B.A., Sachs, L.M. (2008). “Xenopus laevis as a model for studying thyroid hormone signaling: From development to metamorphosis.” Mol Cell Endocrinol. 293: 71-79.

Morvan-Dubois, G., Sebillot, A., Kuiper, G.G.J.M., Verhoelst, C.H.J., Darras, V.M., Visser, T.J., Demeneix, B.A. (2006). “Deiodinase activity is present in Xenopus laevis during early embryogenesis.” Endocrinolgy 147(10): 4941-4949.

Huang, H., Marsh-Armstrong, N., Brown, D.D. (1999). Metamorphosis is inhibited in transgenic Xenopus laevis tadpoles that overexpress type III deiodinase. Proc. Nat. Acad. Sci. USA 96: 962-967.