ethylenethiourea and Goiter

Despite evidence for a conserved role of thyroid-stimulating hormone (TSH) in regulating vertebrate thyroid function, molecular data on thyroid responses to TSH are mainly limited to mammalian species. In this study, we examined histological and molecular changes in the thyroid of Xenopus laevis tadpoles during a 12-day treatment with 20mg/l perchlorate (PER) and 50mg/l ethylenethiourea (ETU). Inhibition of thyroid hormone (TH) synthesis by PER and ETU was evident from developmental retardation, reduced expression of TH-regulated genes and up-regulation of tshb-A mRNA. Thyroid histopathology revealed goiters with strikingly different follicular morphologies following PER and ETU treatment. Using real-time PCR, we analyzed thyroids sampled on day 12 for differential expression of 60 candidate genes. Further temporal analyses were performed for a subset of 14 genes. Relative to the control, PER and ETU treatment modulated the expression of 51 and 49 transcripts, respectively. Particularly genes related to TH synthesis and protein metabolism were similarly affected by PER and ETU. However, several genes were differentially expressed in PER- and ETU-treated tadpoles. Specifically, goiter formation in the PER treatment was associated with low expression of genes related to DNA replication but high expression of negative growth regulators. Results from this work provide for the first time a characterization of gene expression profiles during goitrogenesis in a non-mammalian vertebrate model. Overall, our data suggest that, in addition to TSH over-stimulation, further mechanisms related to the mode of goitrogen action contribute to the regulation of thyroid gene expression.

Topics: Animals; Antithyroid Agents; Brain; Disease Models, Animal; Endocrine Disruptors; Ethylenethiourea; Gene Expression Profiling; Gene Expression Regulation, Developmental; Goiter; Life Cycle Stages; Perchlorates; Thyroid Gland; Thyrotropin; Vertebrates; Xenopus laevis

N,N,N',N'-Tetramethylthiourea (TMTU) is a rat goitrogen inducing thyroid hyperplasia, hypertrophy, and tumor formation. Little is known about the exact underlying mechanism of action. As thyroid peroxidase (TPO) and type I iodothyronine deiodinase (ID-I) have been established as targets of goitrogenic thiourea derivatives, we investigated interactions of TMTU with target enzymes using a partially purified fraction from hog thyroids or solubilized hog thyroid microsomes and 10,000g supernatant from rat liver homogenate, respectively, as enzyme sources. For comparison, comprehensively characterized goitrogenic thiourea derivatives were studied as well. In contrast to propylthiouracil (PTU), and like ethylenethiourea (ETU), TMTU only marginally affected TPO-catalyzed oxidation of guaiacol. TMTU, like ETU, concentration-dependently suppressed TPO-catalyzed iodine formation with concomitant oxidative metabolism. Suppression ceased upon consumption of thiourea derivatives, the rate of the reappearing iodine formation was similar to that of controls. TMTU, like ETU, also suppressed non-enzymatic and TPO-catalyzed monoiodination of l-tyrosine with a stoichiometry of 2:1, i.e., one molecule of thiourea derivative suppressed two times monoiodination. TMTU and ETU were unable to irreversibly inhibit TPO. In contrast to PTU, TMTU did not inhibit ID-I. These findings provide evidence that TMTU interferes with thyroid hormone synthesis at the level of iodination and demonstrate a metabolic route for the oxidative detoxification of TMTU in the thyroid suggesting that low-level or intermittent exposure to TMTU would have only minimal effects on thyroid hormone synthesis. Finally, it can be concluded that meaningful toxicological studies on TPO inhibition can be performed without a need for highly purified TPO.

Topics: Amitrole; Animals; Antithyroid Agents; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethylenethiourea; Goiter; Guaiacol; Hydrogen Peroxide; Iodide Peroxidase; Iodine; Oxidation-Reduction; Propylthiouracil; Rats; Swine; Thiourea; Time Factors; Tyrosine

Topics: Abnormalities, Drug-Induced; Animals; Carcinogens; Environmental Exposure; Ethylenethiourea; Female; Fetal Diseases; Gestational Age; Goiter; Imidazoles; Male; Myxedema; Neoplasms; Pregnancy; Rats; Teratogens; Thyroid Neoplasms

Topics: Animals; Body Weight; Bromides; Diet; Drug Interactions; Eating; Ethylenethiourea; Goiter; Imidazoles; Male; Organ Size; Rats; Thyroid Gland; Thyroxine