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THE EFFECTS OF LOW DOSE PTU ON ENDPOINTS OF THYROID HORMONE ACTION IN THE DEVELOPING BRAIN.
Citation:
SHARLIN, D. S., D. TIGHE, M. E. GILBERT, AND R. T. ZOELLER. THE EFFECTS OF LOW DOSE PTU ON ENDPOINTS OF THYROID HORMONE ACTION IN THE DEVELOPING BRAIN. Presented at Society of Toxicology, Charlotte, NC, March 25 - 27, 2007.
Description:
Thyroid hormone (TH) is essential for normal brain development. Therefore, there is concern that any factor that reduces TH levels may permanently alter brain development. As part of an EPA Cooperative Agreement, the goal of this work was to characterize the degree to which circulating TH levels must decline to alter endpoints of TH action in the developing brain. We induced graded decreases in circulating TH levels in timed pregnant rats by exposure to the goitrogen propylthiouracil (PTU; 0, 1, 2, and 3ppm). Measures of TH action included RC3 expression in the hippocampus and cingulate cortex, and the oligodendrocyte to astrocyte ratio in the corpus callosum (CC) and anterior commisure (AC). To characterize potential adaptive responses to TH insufficiency, we measured the expression of the deiodinase enzymes (D2 and D3), and the TH transporters MCT8 and OATP14 in the hippocampus. The results presented here are focused on post-natal day 15, a time when TH levels are at their peak during development. We report that PTU treatment induced a dose-dependent decrease in serum T4 levels. In addition, we observed a dose-dependent decrease in the oligodendrocyte to astrocyte ratio in the both the AC and CC. Two additional points are worth noting regarding this TH sensitive endpoint. Interestingly, we found that the dose of PTU necessary to significantly reduce T4 levels (1ppm), was less than the dose necessary to measure an altered glial ratio (2ppm) and second, the CC was more sensitive then the AC to TH insufficiency. These data will be evaluated from the perspective of finding the degree to which TH levels must decline before adverse effects result and, in addition, to identify adaptive mechanisms that may account for differences in the shape of the dose response observed between individual endpoints of TH action and different thyroid toxicants.
This work is supported by an EPA STAR predoctoral fellowship (FP916424 to DSS) and an EPA STAR Grant (RD-83213701-0 to RTZ). Does not reflect US EPA policy.