Academic journal article Environmental Health Perspectives

Molecular Characterization of Thyroid Toxicity: Anchoring Gene Expression Profiles to Biochemical and Pathologic End Points

Academic journal article Environmental Health Perspectives

Molecular Characterization of Thyroid Toxicity: Anchoring Gene Expression Profiles to Biochemical and Pathologic End Points

Article excerpt

Organic iodides have been shown to induce thyroid hypertrophy and increase alterations in colloid in rats, although the mechanism involved in this toxicity is unclear. To evaluate the effect that free iodide has on thyroid toxicity, we exposed rats for 2 weeks by daily gavage to sodium iodide (NaI). To compare the effects of compounds with alternative mechanisms (increased thyroid hormone metabolism and decreased thyroid hormone synthesis, respectively), we also examined phenobarbital (PB) and propylthiouracil (PTU) as model thyroid toxicants. Follicular cell hypertrophy and pale-staining colloid were present in thyroid glands from PB-treated rats, and more severe hypertrophy/colloid changes along with diffuse hyperplasia were present in thyroid glands from PTU-treated rats. In PB-and PTU-treated rats, thyroid-stimulating hormone (TSH) levels were significantly elevated, and both thyroxine and triiodothyronine hormone levels were significantly decreased. PB induced hepatic uridine diphosphate-glucuronyltransferase (UDPGT) activity almost 2-fold, whereas PTU reduced hepatic 5'-deiodinase I (5'-DI) activity to < 10% of control in support of previous reports regarding the mechanism of action of each chemical. NaI also significantly altered liver weights and UDPGT activity but did not affect thyroid hormone levels or thyroid pathology. Thyroid gene expression analyses using Affymetrix U34A GeneChips, a regularized t-test, and Gene Map Annotator and Pathway Profiler demonstrated significant changes in rhodopsin-like G-protein-coupled receptor transcripts from all chemicals tested. NaI demonstrated dose-dependent changes in multiple oxidative stress-related genes, as also determined by principal component and linear regression analyses. Differential transcript profiles, possibly relevant to rodent follicular cell tumor outcomes, were observed in rats exposed to PB and PTU, including genes involved in Wnt signaling and ribosomal protein expression. Key words: excess iodide, gene expression, micro arrays, oxidative stress, phenobarbital, propylthiouracil, thyroid, Wnt signaling. Environ Health Perspect 113:1354-1361 (2005). doi: 10.1289/ehp.7690 available via http://dx.doi.org/[Online 12 May 2005]

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Thyroid cancer, a fairly uncommon form of cancer in the human population, has causal links to environmental radiation exposures (Meirmanov et al. 2003). Although there are multiple epidemiology studies that associate radiation exposure with thyroid cancer, there have been no studies to associate human thyroid cancer with environmental chemical exposures (Hard 1998). The human thyroid responds toxicologically to multiple anti-thyroid drugs, including excess iodide, propylthiouracil (PTU), and thionamides, but the progression to cancer after repetitive administration has not been observed (Hard 1998; Hill et al. 1998; Markou et al. 2001). In contrast, multiple antithyroid drugs administered to the rat have demonstrated an increase in thyroid tumors, including PTU, thionamides, and the hepatic enzyme inducer phenobarbital (PB) (Capen 1997; Hurley et al. 1998; McClain et al. 1988). Other xenobiotics, including several organic iodides such as amiodarone and erythrosine, have also been associated with thyroid tumor development in the rat. Many organic iodides alter rat thyroid homeostasis, causing thyroid hypertrophy and alterations in colloid that may potentially lead to thyroid tumors after chronic administration (Capen 1997; Hurley et al. 1998).

The mechanisms by which organic iodides induce thyroid toxicity are varied and may include excess iodide being released into the blood during xenobiotic metabolism, toxicity to the liver that alters thyroid hormone metabolism, and/or direct thyroid toxicity that inhibits the release of thyroid hormones into the circulation (Capen 1997; Hurley et al. 1998). In subchronic toxicology studies it has been difficult to predict whether early changes in thyroid pathology could lead to thyroid cancer in the rat after chronic administration of organic iodides. …

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