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J Toxicol Pathol
2012 Mar 01;251:1-9. doi: 10.1293/tox.25.1.
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Thyroid Hormone-disrupting Effects and the Amphibian Metamorphosis Assay.
Miyata K
,
Ose K
.
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There are continued concerns about endocrine-disrupting chemical effects, and appropriate vertebrate models for assessment of risk are a high priority. Frog tadpoles are very sensitive to environmental substances because of their habitat and the complex processes of metamorphosis regulated by the endocrine system, mainly thyroid hormones. During metamorphosis, marked alteration in hormonal factors occurs, as well as dramatic structural and functional changes in larval tissues. There are a variety of mechanisms determining thyroid hormone balance or disruption directly or indirectly. Direct-acting agents can cause changes in thyroxine synthesis and/or secretion in thyroid through effects on peroxidases, thyroidal iodide uptake, deiodinase, and proteolysis. At the same time, indirect action may result from biochemical processes such as sulfation, deiodination and glucuronidation. Because their potential to disrupt thyroid hormones has been identified as an important consideration for the regulation of chemicals, the OECD and the EPA have each established guidelines that make use of larval African clawed frogs (Xenopus laevis) and frog metamorphosis for screening and testing of potential endocrine disrupters. The guidelines are based on evaluation of alteration in the hypothalamic-pituitary-thyroid axis. One of the primary endpoints is thyroid gland histopathology. Others are mortality, developmental stage, hind limb length, snout-vent length and wet body weight. Regarding histopathological features, the guidelines include core criteria and additional qualitative parameters along with grading. Taking into account the difficulties in evaluating amphibian thyroid glands, which change continuously throughout metamorphosis, histopathological examination has been shown to be a very sensitive approach.
Fig. 1. Arrows indicate thyroid glands in Stage 51.
Fig. 2. Overview of the thyroid hormone pathway.
Fig. 3. The stage of metamorphosis is divided into 3 stages. The premetamorphic stage is the period until the appearance of the hind limbs, and the prometamorphic period is from their appearance to that of the forelimbs. During the period of metamorphic climax, resorption of the tail and gills and development of lungs occur.
Fig. 4. Thyroid glands after exposure for 21 days beginning at Stage 51. Left: Control. Middle: PTU 25 ppm. Right: T4 5.0 ppb.
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