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THYROID INSUFFICIENCY AND GENE EXPRESSION IN DEVELOPING RAT BRAIN: A DOSE RESPONSE STUDY.
Citation:
ROYLAND, J. E. AND M. E. GILBERT. THYROID INSUFFICIENCY AND GENE EXPRESSION IN DEVELOPING RAT BRAIN: A DOSE RESPONSE STUDY. Presented at American Society of Neurochemistry/International Society of Neurochemistry, Cancan, MEXICO, August 19 - 24, 2007.
Description:
Thyroid Insufficiency and Gene Expression in Developing Rat Brain: A Dose Response Study. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption is an area of major concern in environmental neurotoxicity. Deficits in thyroid hormone (TH) levels have been shown to adversely affect brain development and function. Severe depletion can alter gene expression through TH receptor-regulated transcription factors, however little is known about the effects of modest TH depletion. Affymetrix rat 230A chips were used to examine gene expression in the cortex (ctx) and hippocampus (hip) of neonatal pups exposed in utero and during lactation to the TH synthesis inhibitor, propylthiouracil (PTU). Dams received PTU in drinking water (0, 1, 2, and 3 ppm) from early gestation (G6) through sacrifice of pups on postnatal day 14. Serum T4 levels were suppressed in the pups at all doses. Genomic dose response effects were identified by EDGE (Extraction Analysis of Differential Expression; Storey, et al., 2005), which identifies patterns across multiple experimental conditions. A total of 224 and 66 differentially expressed transcripts were identified in the ctx and hip, respectively (5% FDR, 1.5 fold). The presence of 31 genes with functions specifically related to neurogenesis, cell proliferation and/or differentiation plus 23 genes with roles in synaptic function, ion channels or ion transport demonstrate the profound effect on cortical development. Similarly, in the hip, 10 of 66 genes have specific neurogenesis-related functions and 11 of 66 genes have roles in myelination. A number of these genes show >1.5 fold difference at the lowest dose (1 ppm) -- for example, Dpsl3, Rfc4 and Tmod1 in the ctx and 10 of the 11 myelin genes in the hip. 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).