Molecular Characterization of Thyroid Toxicity: Anchoring Gene Expression Profiles to Biochemical and Pathologic End Points Christine M. Glatt,1 Ming Ouyang,2 William Welsh,2 John W. Green,1 John O Connor,1 Steven R. Frame,1 Nancy E. Everds,1 Greg Poindexter,1 Suzanne Snajdr,1 and Don A. Delker1 1DuPont Haskell Laboratory, Newark, Delaware, USA; 2Department of Pharmacology, Robert Wood Johnson Medical School and Informatics Institute of the University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, USA 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. Key words: excess iodide, gene expression, microarrays, 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] Address correspondence to D.A. Delker, Environmental Carcinogenesis Division, U.S. Environmental Protection Agency, 109 TW Alexander Dr. (B143-06) , Durham, NC 27711 USA. Telephone: (919) 541-7639. Fax: (919) 541-0694. E-mail: delker.don@epa.gov We acknowledge J. Stadler and B. Shertz for their help in study design and technical support, respectively. The authors declare they have no competing financial interests. Received 22 October 2004 ; accepted 12 May 2005. The full version of this article is available for free in HTML or PDF formats. |