Type II iodothyronine deiodinase (DIO2) inhibition leading to altered amphibian metamorphosis

Jonathan T. Haselman, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <haselman.jon@epa.gov>

Sigmund J. Degitz, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <degitz.sigmund@epa.gov>

Michael W. Hornung, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <hornung.michael@epa.gov>

Sally A. Mayasich, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <mayasich.sally@epa.gov>

This putative AOP describes the potential for an adverse outcome resulting from the inhibition of Type 2 iodothyronine deiodinase (DIO2) during amphibian metamorphosis. Initial development of this AOP is based largely on literature in which amphibian deiodinases are genetically disrupted or blocked by the deiodinase inhibitor iopanoic acid, and prediction from tissue expression patterns. Thyroid hormones (THs) 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. Chemical inhibition of DIO2, the molecular-initiating event (MIE), results in decreased transformation of thyroxine (T4) to the active form, 3,5,3’-triiodothyronine (T3) in peripheral tissues. Chemicals that interfere with the DIO2 catalyzing reaction of T4 to T3 have the potential to cause insufficiency of the active form that may result in altered metamorphosis. Adverse consequences of T3 insufficiency may vary based on timing of exposure and produce different effects at different developmental stages. For example, T3 insufficiency due to DIO2 inhibition in the African clawed frog, Xenopus laevis, within several days post-fertilization (pre-metamorphosis) could affect brain development, and could alter T4/T3 feedback. It has been found that DIO2 does not regulate T3 levels in serum. However, D2 inhibition in peripheral tissues through the larval phase and post-metamorphic climax may cause alterations in limb development, intestinal remodeling, gill resorption and/or tail resorption.

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