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Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*
Citation:
GILBERT, M. E. Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 124(2):432-45, (2011).
Impact/Purpose:
The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. The EPA must evaluate the risk ofexposure of the developing brain to chemicals with the potential to disrupt thyroid hormone homeostasis. The existing literature identifies morphological and neurochemical indices of severe neonatal hypothyroidism in the early postnatal period in classic animal models of hypothyroidism. Few data are available on the impact ofmore modest disruptions of the thyroid axis as would be expected to accompany exposure to environmental contaminants. Specifically, the degree to which the developing brain is sensitive to small reductions in serum thyroid hormone has not been established. The present study was designed to evaluate graded levels of TH disruption to identify sensitive metrics ofadverse neurological outcomes and relate these deficits to deficiencies in circulating levels of TH. Varying degrees of developmental hypothyroidism were induced by administration of low doses of the TH synthesis inhibitor, propylthiouracil (PTU 0, 1,2 and 3 ppm) to the drinking water of pregnant rats at concentrations 200-fold lower than those traditionally used in standard hypothyroid models. Synaptic function in the dentate gyrus was examined in adult euthyroid offspring using in vivo field potentials. Excitatory synaptic transmission (EPSP slope amplitude) was significantly reduced at 2 and 3 ppm. Paired pulse functions estimating the integrity of inhibitory synaptic processing were modestly reduced by 3 ppm PTU. Long-term potentiation (LTP) ofthe EPSP slope was impaired at all dose levels. Trace fear conditioning to context and to cue was impaired at the highest dose level when a distractor stimulus was present, whereas conditioning in a standard trace fear paradigm paradoxically revealed 'enhanced' performance at the intermediate dose and a return to control values in the high dose group. Biphasic dose-response profiles were evident in some measures (trace fear conditioning and LTP) but not others, and serve to exemplify the complexity of the role ofthyroid hormone in brain development and its consequences for brain function. The serum hormone profile at weaning closely mirrored the monotonic dose-response profile for serum T4 reductions seen in dams. For this low dose PTU model, T4 in PN21 pups or in dams appears more predictive of some of the neurophysiological and behavioral impairments than T4 measured on PN 15, but neither timepoint display a biphasic pattern ofresponse. These data caution against the application of a direct translation of serum hormones to adverse neurodevelopmental outcomes. Although serum hormones serve as sensitive bioindicators of peripheral thyroid status they may not accurately reflect either the sufficiency or integrity of thyroid hormone and its signaling in specific brain regions during critical windows of development.
Description:
The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. Much less information is available on more modest perturbations of TH on brain function. The present study induced varying degrees of developmental hypothyroidism by administration of low doses of the thyroidhormone synthesis inhibitor, propylthiouracil (PTU 0, 1, 2 and 3 ppm) to the drinking water of pregnant rats. This regimen produced dose-dependent reductions in circulating levels of T4 in dams and offspring on postnatal days (PN) 15 and 22, with return to control levels in adulthood upon termination of treatment at weaning. Modest reductions in T3 were observed in the high dose group on PNI5. Synaptic function in the dentate gyrus was examined in adult euthyroid off spring using in vivo field potentials. Excitatory synaptic transmission (EPSP slope amplitude) was significantly reduced at 2 and 3 ppm PTU, with no statistically reliable effect detected in the population spike. Paired pulse functions estimating the integrity of inhibitory synaptic processing were modestly reduced by 3 ppm PTU. Long-term potentiation (LTP) ofthe EPSP slope was impaired at all dose levels. Trace fear conditioning to context and to cue was impaired at the highest dose level when a distractor stimulus was present, whereas conditioning in a standard trace fear paradigm paradoxically revealed 'enhanced' performance at the intermediate dose and a return to control values in the high dose group. Biphasic dose-response profiles were evident in some measures (trace fear conditioning and LTP) but not others, and serve to exemplify the complexity ofthe role of thyroid hormone in brain development and its consequences for brain function.
