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An animal model of marginal iodine deficiency during development: The thyroid axis and neurodevelopmental outcome. ##
Gilbert, M., J. Hedge, L. Valentin-Blasini, B. Blount, K. Kannan, J. Tietge, R. Zoeller, K. Crofton, J. Jarrett, AND J. Fisher. An animal model of marginal iodine deficiency during development: The thyroid axis and neurodevelopmental outcome. ##. TOXICOLOGICAL SCIENCES. Society of Toxicology, 132(1):177-95, (2013).
Thyroid hormones (TH) are essential for brain development and iodine is required for TH synthesis. Environmental chemicals that perturb the thyroid axis result in modest reductions in TH, yet there is a paucity of data on the extent of neurological impairments associated with low level TH disruption. This study examined the dose-response characteristics of marginal iodine deficiency (ID) on parameters of thyroid function and neurodevelopment. ID diets were prepared by adding 975, 200, 125, 25, or 0 ug/kg potassium iodate to the base casein diet to produce 5 nominal iodine levels ranging from ample (Diet 1: 1000 ug iodine/kg chow, Dl) to deficient (Diet 5: 25 ug iodine/kg chow, D5). Female Long Evans rats were maintained on these diets beginning 7 wk prior to breeding until the end of lactation. Dams were on gestational days 16 and 20, or when pups were weaned on postnatal day (PN)2 1. Fetal tissue was harvested with the dams, pups were sacrificed on PN 14 and PN2 1. Blood, thyroid gland, and brain were collected for analysis of iodine, TH, and TH precursors and metabolites. Serum and thyroid gland iodine and TH were reduced in the two most deficient diets. T4 was reduced in the fetal brain but was not altered in the neonate. Neurobehavior, assessed by acoustic startle, water maze learning and fear conditioning, was unchanged in adult offspring, but excitatory synaptic transmission was impaired in the dentate gyms by the two most deficient diets. A 15% reduction in cortical T4 in the fetal brain was sufficient to induce permanent reductions in synaptic function in the adult. These findings have implications for regulation of TH-disrupting chemicals, and suggest that standard behavioral assays do not readily detect neurotoxicity induced by modest developmental TH disruption.
The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone (TH). The critical role of TH in brain development is well established, severe deficiencies leading to significant neurological dysfunction, but there is a paucity of data in the literature on neurological impairments that may accompany modest degrees of TH disruption. We have for several years been working on developing animal models low level TH disruption to determine the impact of environmental thyroid hormone disruptors on nervous system development. The present manuscript describes the effects of marginal levels dietary iodine deficiency in pregnant rats on neurotoxicological endpoints including synaptic transmission in the hippocampus, in vivo and a suite of neurobehavioural assays. In addition, we have fully characterized the serum and thyroid gland hormone profiles in dams, neonates and fetuses in order to produce a range of TH insufficiencies that emulate those seen with xenobiotics. Data were collected in a way to be maximally applicable to the development of biologically-based dose-response (BBDR) models of the thyroid axis in the pregnant and lactating dam, the fetus and the neonate. The results of these efforts in quantitative modeling of the hypothalamic-pituitary-thyroid axis for the lactating dam and nursing neonate are described the companion paper (Fisher et al., Evaluation of Iodide Deficiency in the Lactating Rat and Pup using a Biologically-Based-Dose-Response Model). The present work, in the intact animal, with its extensive dose-response analysis, lays the foundation for the development of the kinds of models that are needed in toxicology, especially the arena of endocrine disruptors. We report reductions in serum and thyroid gland iodine and hormones in the two most deficient diets. Serum T3 did not change at any time in dams or neonates and TSR was only marginally increased under the most deficient conditions. The maximal degree of T4 reduction was <50% in the most deficient diet at any life stage. Neurobehavioral assessments (acoustic startle, Morris water maze, and fear conditioning) were intact in adult offspring, but excitatory synaptic transmission was impaired in the hippocampus. The fetus appears more at risk than the neonate - brain T4 was not altered by ID in the neonate despite reductions in serum T4, but serum and brain T4 were both dose-dependently reduced in the fetus. Reductions in fetal brain T4, although modest, were consistent with declines in fetal serum T4, and importantly, were associated with persistent deficits in brain function. Our data suggest that a reduction in cortical T4 as little as 15% during fetal brain development is sufficient induce permanent alterations in excitatory synaptic function in the adult offspring, and that this degree of fetal cortical T4 decline was present with serum T4 reductions of< 20% in the dam or fetus. These findings have implications for regulation of chemicals that perturb the thyroid axis and the identification of sensitive life stages (pregnant woman and her fetus) and populations (ID). They further suggest that standard behavioral tests of neurotoxicity appear relatively insensitive in their ability to detect brain impairment that accompanies a modest degree developmental TH disruption.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
TOXICOLOGY ASSESSMENT DIVISION