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Thyroid insufficiency in developing rat brain: A genomic analysis.
Citation:
ROYLAND, J. E. AND M. Gilbert. Thyroid insufficiency in developing rat brain: A genomic analysis. Presented at American Society for Neurochemistry, San Antonio, TX, March 01 - 05, 2008.
Impact/Purpose:
Provide support for criteria of MYP
Description:
Thyroid Insufficiency in the Developing Rat Brain: A Genomic Analysis. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption (ED) is an area of major concern in environmental neurotoxicity. Severe deficits in thyroid hormone (TH) levels have been shown to lead to decreased neuronal morphology and neurochemistry. Propylthiouracil (PTU), a prototypic compound that decreases circulating levels of T3 and T4, is used to model developmental TH deficiency. TH receptors act as ligand-regulated transcription factors, therefore changes in hormone levels can lead to alterations in gene expression. In this study Affymetrix rat 230A chips were used to examine gene expression in the cortex and hippocampi of PND14 Long-Evans rat pup brains from dams orally dosed with 0, 1, 2 or 3 ppm PTU. At PND14 cell migration, dendritic aborization and the synapse formation are still in progress. Serum levels of T4 were significantly decreased in the pups at every dose tested. Genomic dose response effects were analyzed by EDGE (Extraction Analysis of Differential Expression) (Storey, et al., 2005). This analysis protocol identifies patterns across multiple experimental conditions, thus is ideal for this type of study. Using this protocol 224 and 66 differentially expressed transcripts were identified in the cortex and hippocampus, respectively (5% FDR, 1.5 fold). Genes with roles in neurogenesis (9.4% of total), ion channels or transport (6.7%) and calcium metabolism (4.5%) were highly represented in the cortex. Myelination-related genes were the most prominent group (16.7% of total) in the hippocampus, followed by neurogenesis and calcium metabolism (7.6% each). These data highlight the profound consequences of EDC in neural development. Hierarchical cluster analysis confirms gene expression dose response and demonstrates the sensitivity of genomics in studying low level exposures. (This abstract does not necessarily reflect USEPA policy).