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Dose-Response Analysis of Developmental Iodide Deficiency: Reductions in Thyroid Hormones and Impaired Hippocampal Synaptic Transmission
Citation:
GILBERT, M. E., J. M. HEDGE, K. M. CROFTON, R. T. ZOELLER, K. KRISHNAN, J. Fisher, B. Blount, AND L. Valentin-Blasini. Dose-Response Analysis of Developmental Iodide Deficiency: Reductions in Thyroid Hormones and Impaired Hippocampal Synaptic Transmission. Presented at Ssociety of Toxicology (SOT) Annual Meeting, Washingotn, DC, March 06 - 10, 2011.
Impact/Purpose:
The present study examined the impact of graded levels of ID in pregnant rats on a number of aspects of the thyroid axis and their relationship to behavioral and electrophysiological indices of brain function in exposed offspring.
Description:
Iodide is an essential nutrient for thyroid hormone synthesis and severe iodide deficiency (ID) during early development is associated with neurological impairments. Several environmental contaminants can perturb the thyroid axis and this perturbation may be more acute under conditions of marginal iodine deficiency (ID). The present study examined the impact of graded levels of ID in pregnant rats on a number of aspects of the thyroid axis and their relationship to behavioral and electrophysiological indices of brain function in exposed offspring. Female Long Evans rats (60-80 days of age) were placed on diets with varying degrees of ID for 6 weeks prior to breeding. Iodine was added to a casein-based diet to produce 5 levels of iodine, ranging from adequate (>200 ng/gm) to deficient <25 ng/gm). Nominally these diets contained 1000, 225, 150,50 and 25 ng of iodine/gm of chow. Based on direct chow iodine measurements and daily food consumption, these diets resulted in daily iodine intake levels of 26, 4, 2.5,0.65 and 0.21 ug/day, respectively. Pups were sacrificed on postnatal day (PN) 4, 14 and 21 and blood, thyroid glands, and brain were harvested. Dams were sacrificed on PN21 at the time pups were weaned and tissue collected for serum and thyroid gland hormone analyses. Behavioral assessments of spatial learning (Morris water maze), and associative learning (trace fear conditioning) were performed in adult offspring. Hippocampal synaptic transmission was assessed.in adult male offspring under urethane anesthesia in three of the ID groups (225, 50 and 25 ng/gm). Thyroxine (T4) was reduced in pups on PN21 (~20 and 45% in the two most deficient diets) and TSH modestly increased (2-3-fold) in dams and pups in the most deficient iodine group. No changes in T3 were evident at any time and T4 had returned to euthyroid levels at the time of adult testing. Thyroid weights were increased in pups in the most deficient diet, with a similar but nonsignificant trend in dams. Iodine content in the thyroid gland ofdams and pups was reduced in all treatment groups relative to the 1000 ng/gm and a standard Purina chow diet. Thyroid gland T4 content of PN14 pups was significantly reduced in the 3 most deficient diets, but only in the 2 most deficient diets in dams. No differences in T4 content in the cortex ofPN14 pups were detected. Neither were deficits detected in the two hippocampally-mediated cognitive tasks examined. However, impairments in baseline synaptic function were seen in field potentials recorded from the dentate gyrus of the two lowest iodine groups. EPSP slope, peak, and population spike amplitudes were significantly reduced and to comparable degrees in the two lowest iodine groups. No change in inhibitory function was seen in tests of paired pulse depression. Neither were alterations detected in long-term potentiation, a synaptic model of learning. These data indicate that ill inducing modest reductions in serum hormones is associated with persistent impairments in hippocampal synaptic transmission. (Does not necessarily reflect EPA policy)