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ToxSci Advance Access published online on July 7, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi246
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Published by Oxford University Press 2005.
Received March 29, 2005
Accepted June 15, 2005

Endocrine Toxicology

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

Sigmund J. Degitz 1*, Gary W. Holcombe 1, Kevin M.. Flynn 1, Patricia A. Kosian 1, Joseph J. Korte 1, and Joseph E. Tietge 1

1 U.S. Environmental Protection Agency, Office of Research and Development, National Heath and Environment Effect Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Boulevard, Duluth, MN, 55804 USA

* To whom correspondence should be addressed.
Sigmund J. Degitz, E-mail: degitz.sigmund{at}epa.gov


  Abstract

In response to the initial Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) recommendations, research was conducted on the development of a Xenopus laevis based tail resorption assay for evaluating thyroid axis disruption. This research highlighted key limitations associated with relying on tail resorption as a measure of anti/thyroid activity. The most critical limitation being that tail tissues of tadpoles at metamorphic climax are insensitive to perturbation by thyroid axis agonists/antagonists. To improve upon the initial proposal, we have conducted experiments comparing the sensitivity of pre-metamorphic (stage 51) and pro-metamorphic (stage 54) larvae to the model thyroid axis disruptors methimazole (control, 6.25, 12.5, 25, 50, 100 mg/L), 6-propylthiouracil (PTU) (control, 1.25, 2.5, 5, 10, and 20 mg/L) and thyroxine (T4) (0.25, 0.5, 1, 2, 4 ug/l). Exposures were conducted using two different experimental designs. For experimental design 1, tadpoles were exposed to methimazole or PTU starting at either NF stage 51 or NF 54 for 14 days. For experimental design 2, tadpoles were exposed to PTU or T4 starting at NF stage 51 or NF 54 for 14 and 21 days respectively. Methimazole and PTU, which are thyroid hormone synthesis inhibitors, both caused a concentration dependent delay in larval development. As determined from this endpoint, there were only minor differences in sensitivity observed among the two stages examined. Further, both compounds caused concentration dependent changes in thyroid gland morphology. These changes were characterized as reduced colloid, glandular hypertrophy, and cellular hyperplasia and hypertrophy. Treatment failed to negatively affect growth, even in tadpoles which experienced significant metamorphic inhibition. T4 treatment resulted in a concentration dependent increase in developmental rate, as would be expected. Similar to studies with methimazole, there were no differences in sensitivity among the two developmental stages examined. These results indicate that tadpoles in the early stages of metamorphosis are sensitive to thyroid axis disruption and that development of a short term, diagnostic amphibian-based thyroid screening assay shows considerable promise.

Keywords: Thyroid; Metamorphosis; Amphibian.

Disclaimer: This paper has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Mention of trade names of commercial products does not constitute endorsement/recommendation for use.


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