title: Molecular characterization of thyroid toxicity: anchoring gene expression profiles to biochemical and pathologic end points.
abstract: 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.
authors.affiliation: DuPont Haskell Laboratory, Newark, Delaware, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Glatt
authors.forename: Ming
authors.initials: M
authors.lastname: Ouyang
authors.forename: William
authors.initials: W
authors.lastname: Welsh
authors.forename: John W
authors.initials: JW
authors.lastname: Green
authors.forename: John O
authors.initials: JO
authors.lastname: Connor
authors.forename: Steven R
authors.initials: SR
authors.lastname: Frame
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Everds
authors.forename: Greg
authors.initials: G
authors.lastname: Poindexter
authors.forename: Suzanne
authors.initials: S
authors.lastname: Snajdr
authors.forename: Don A
authors.initials: DA
authors.lastname: Delker
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D020869:Gene Expression Profiling; D014453:Glucuronosyltransferase / Q000378:metabolism; D007453:Iodide Peroxidase / Q000378:metabolism; D007454:Iodides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D009929:Organ Size; D010634:Phenobarbital / Q000494:pharmacology; D011441:Propylthiouracil / Q000494:pharmacology; D051381:Rats; D013961:Thyroid Gland / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism
chemical_list: D013956:Antithyroid Agents; D007454:Iodides; D013963:Thyroid Hormones; D011441:Propylthiouracil; D007453:Iodide Peroxidase; D014453:Glucuronosyltransferase; D010634:Phenobarbital