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THYROID HORMONE INSUFFICIENCY AND BRAIN DEVELOPMENT -- DETERMINATION OF NEUROTOXICITY AT LOW LEVELS OF HORMONE DISRUPTION.
Citation:
GILBERT, M. E., M. TAYLOR, D. SHARLIN, W. L. ANDERSON, D. FERGUSON, AND R. T. ZOELLER. THYROID HORMONE INSUFFICIENCY AND BRAIN DEVELOPMENT -- DETERMINATION OF NEUROTOXICITY AT LOW LEVELS OF HORMONE DISRUPTION. Presented at Society of Toxicology, Charlotte, NC, March 25 - 29, 2007.
Description:
Thyroid hormone (TH) deficiencies during development produce deleterious effects on brain structure and function. The degree to which TH must be perturbed to induce neurotoxicity remains unclear. The present study was conducted as part of a Cooperative Agreement between US EPA, U Georgia, and U Massachusetts to define dose-response relationships between low level TH reductions induced by the goitrogen propylthiouracil (PTU) and brain dysfunction. Pregnant rats were administered PTU via the drinking water (0, 1, 2, 3ppm) from gestational day (GD) 6 until weaning of pups on postnatal (PN) day 23. Maternal weight gain was similar across dose groups. Pup weights were similar from birth to PN15, with a slight decrease in the 3ppm dose group on PN21. Eye opening was delayed by 3ppm PTU. Modest reductions in dam T4 levels were observed, with no change in T3 detected at any dose. Pups displayed dose-dependent reductions in T4 between PN4-22, with modest reductions in T3 limited to the high dose group. TH returned to control values by PN127. Cognitive function was assessed in adults using 2 fear conditioning (FC) paradigms. Trace FC was induced in male offspring by presenting a neutral stimulus (light/tone) paired 30s later (trace interval) with mild footshock. To increase task difficulty, a 2nd FC paradigm incorporated a flashing light randomly presented throughout training (Distract FC). Conditioning to context in trace FC was enhanced at 1 and 2ppm dose levels, with no effect at the high dose. Cue learning was impaired in the 3ppm dose group. Deficits were observed in Distract FC in context and cue learning at the high dose. Context learning in female offspring in Distract FC was impaired at all dose levels. These findings reveal learning deficits at low levels of TH insufficiency, potential gender differences in susceptibility, and the power of postnatal serum T4 levels to predict alterations in some but not all toxicological and functional endpoints. (Does not reflect US EPA policy)