Event:1101

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Event Title

Amphibian metamorphosis, Altered

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Thyroperoxidase inhibition leading to altered amphibian metamorphosis AO [[Aop:175#Essentiality of the Key Events|]]
Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis AO [[Aop:176#Essentiality of the Key Events|]]
Iodotyrosine deiodinase (IYD) inhibition leading to altered amphibian metamorphosis AO [[Aop:188#Essentiality of the Key Events|]]
Type I iodothyronine deiodinase (DIO1) inhibition leading to altered amphibian metamorphosis AO [[Aop:189#Essentiality of the Key Events|]]
Type II iodothyronine deiodinase (DIO2) inhibition leading to altered amphibian metamorphosis AO [[Aop:190#Essentiality of the Key Events|]]
Type III iodotyrosine deiodinase (DIO3) inhibition leading to altered amphibian metamorphosis AO [[Aop:191#Essentiality of the Key Events|]]
Pendrin inhibition leading to altered amphibian metamorphosis AO [[Aop:192#Essentiality of the Key Events|]]
Dual oxidase (DUOX) inhibition leading to altered amphibian metamorphosis AO [[Aop:193#Essentiality of the Key Events|]]
Hepatic nuclear receptor activation leading to altered amphibian metamorphosis AO [[Aop:194#Essentiality of the Key Events|]]

Taxonomic Applicability

Name Scientific Name Evidence Links
African clawed frog Xenopus laevis Strong NCBI

Affected Organs

Synonym Scientific Name Evidence Links

Level of Biological Organization

Biological Organization
Organ

How this Key Event works

Vertebrate metamorphosis is a biological transformation process that transitions an organism from one life stage to another; it is defined by growth of new tissues, programmed death of other tissues and physiological transformation of yet other tissues (Laudet, 2011; Brown and Cai, 2007). In the case of most amphibians, metamorphosis mediates the transition from aquatic to terrestrial life, while in bony and jawless fish, metamorphosis mediates transitions between life stages that offer various advantages for survival and reproduction. In vertebrates, metamorphosis is orchestrated by the hypothalamus-pituitary-thyroid (HPT) axis involving complex timing of gene expression/repression within various tissues, whereas in some cases across taxonomic classes, metamorphosis has been shown to be controlled very differently by the HPT axis.

Thyroid hormone-mediated amphibian metamorphosis can be characterized by three phases during larval development: (1) pre-metamorphosis, (2) pro-metamorphosis and (3) metamorphic climax. All three of these phases coincide with activity states of the HPT axis. Pre-metamorphosis is characterized by a fully aquatic organism with low-level function of the thyroid gland and very low circulating levels of thyroid hormone. Pro-metamorphosis is characterized by the onset of full thyroid axis function and the initiation of rising levels of thyroid hormone in the plasma, with consequential changes in anatomy and physiology defining the transition from aquatic to terrestrial life. Metamorphic climax occurs when circulating thyroid hormone levels peak, which subsequently decrease to levels maintained homeostatically as adults. This climax period also represents the time at which all anatomical and physiological changes induced by thyroid hormone have either been initiated or are already completed. Detailed descriptions of these processes are reviewed by Brown and Cai (2007).

Altered metamorphosis occurs when these thyroid hormone-mediated processes are perturbed, primarily during pro-metamorphosis and metamorphic climax. These perturbations can lead to either, delayed/arrested development, accelerated development or asynchronous development depending on the xenobiotic mode of action or MIE. Genetic defects or xenobiotic exposure that reduce thyroid hormone synthesis can delay metamorphosis, and in extreme cases, can completely arrest development. The most profound impacts on TH-mediated metamorphosis have be demonstrated through inhibition of key proteins in the TH synthesis pathway including the sodium-iodide symporter (Tietge et al., 2005, 2010; Hornung et al., 2010) and thyroperoxidase (Degitz et al., 2005; Tietge et al., 2010, 2013; Hornung et al., 2010, 2015). Alternatively, agonism of the thyroid axis through inhibition of negative feedback at the level of the hypothalamus-pituitary, or premature activation of thyroid receptor-mediated transcription can accelerate metamorphosis (Degitz et al., 2005), which can lead to asynchronous development due to errors in gene expression timing across the various metamorphic tissues. Asynchronous development can also occur due to inhibition of deiodinase (DIO) enzymes in peripheral tissues. DIO enzymes are responsible for activation and catabolism of TH; when dio gene expression profiles are altered, or the enzymes themselves undergo chemical inhibition, the imbalance of prohormone (T4), active hormone (T3) and inactive hormone (rT3, T2) can cause aberrant tissue development.

How it is Measured or Detected

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Evidence Supporting Taxonomic Applicability

References


Brown, D.D. and Cai, L., 2007. Amphibian metamorphosis. Developmental biology, 306(1), pp.20-33.

Degitz, S.J., Holcombe, G.W., Flynn, K.M., Kosian, P.A., Korte, J.J. and Tietge, J.E., 2005. Progress towards development of an amphibian-based thyroid screening assay using Xenopus laevis. Organismal and thyroidal responses to the model compounds 6-propylthiouracil, methimazole, and thyroxine. Toxicological sciences, 87(2), pp.353-364.

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.

Laudet, V., 2011. The origins and evolution of vertebrate metamorphosis. Current Biology, 21(18), pp.R726-R737.

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.

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., Degitz, S.J., Haselman, J.T., Butterworth, B.C., Korte, J.J., Kosian, P.A., Lindberg-Livingston, A.J., Burgess, E.M., Blackshear, P.E. and Hornung, M.W., 2013. Inhibition of the thyroid hormone pathway in Xenopus laevis by 2-mercaptobenzothiazole. Aquatic toxicology, 126, pp.128-136.