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GENOMIC ANALYSIS OF PTU-INDUCED HYPOTHYROIDISM IN RAT HIPPOCAMPUS.
Citation:
ROYLAND, J. E. AND M. E. GILBERT. GENOMIC ANALYSIS OF PTU-INDUCED HYPOTHYROIDISM IN RAT HIPPOCAMPUS. Presented at Society of Toxicology, San Diego, CA, March 05 - 09, 2006.
Description:
Propylthiouracil (PTU) exposure results in depletion of thyroid hormone by blocking its synthesis. It often is used to study the effects of hypothyroidism in the brain, where deficits during critical periods lead to neuroanatomical, molecular and neurochemical alterations. Decreases in proliferation, migration, dendritic arborization, synapse formation and mylination have been reported. Functionally, exposure to PTU during development has been shown to result in hippocampal dependent learning tasks, synaptic transmission and plasticity. As thyroid hormone receptors are ligand-regulated transcription factors, hypothyroidism could lead to alterations in gene expression. Normal thyroid hormone action in the brain has a role in fine tuning of gene expression, with changes in expression for individual genes exhibiting different time windows during brain development. In this study we use the Affymetrix rat neuroarray U34 chip (1322 genes) to examine gene expression changes in the hippocampi of PND16 Long-Evans rat brains from dams dosed with 0 or 10 ppm PTU in their drinking water from GD6 through sampling. Gestational dosing with PTU has been shown to permanently alter hippocampal ultrastructure and function. At PND16 cell migration, dendritic aborization and the formation of neuronal connections are still in progress. Differentially expressed genes were verified by two methods 1) t-Test (P < .05) followed by filtering on fold change and 2) SAM (Significance Analysis of Microarrays) at a false discovery rate of ~10%. At the time point examined, 53 genes were found to be changed ? 1.25 fold by PTU exposure, the majority of which were down regulated (81%). Analysis of gene function by pathway analysis software showed genes involved in cellular assembly and organization (17 genes) and cell function and maintenance (14 genes) to predominate, followed by cell-to-cell signaling and interactions (12 genes). Whether these changes reflect permanent alterations or merely changes in the normal 'windows of expression' is unknown. (This abstract does not necessarily reflect USEPA policy).