Citation:

Spring, S., T. Bastian, W. Y, Pat Kosian, G. Anderson, AND M. Gilbert. Thyroid Hormone-Dependent Formation of a Subcortical Band Heterotopia (SBH) in the Neonatal Brain is not Exacerbated Under Conditions of Low Dietary Iron (FeD). NEUROTOXICOLOGY AND TERATOLOGY. Elsevier Science Ltd, New York, NY, , 41-46, (2016).

Impact/Purpose:

Although the critical role of thyroid hormone (TH) in brain development is well established - severe deficiency producing significant neurological dysfunction - there is a paucity of data on neurological impairments that accompany modest degrees of TH disruption. Quantitative modeling of serum TH to predict adverse neurological outcomes is limited not only by lack of dose-response information on serum TH declines, but also the lack of sensitive indices of the neurodevelopmental phenotype that accompanies these disruptions. We have recently demonstrated dose and serum TH-dependent increases in the incidence and size of a brain malformation (a subcortical band heterotopia, SBH) in offspring of rat dams experiencing TH insufficiencies from a chemical that blocks synthesis of hormone in the thyroid gland (i.e., propylthiouracil, PTU). Dietary deficiencies of iron (Fe) affects ~ 1 billion individuals worldwide, and also reduce circulating levels of TH by acting on the same hormone synthesis pathways as PTU. Individually, dietary goitrogens, environmental chemicals, and micronutrient deficiencies may exert relatively minor effects on the thyroid axis, but in combination, these effects may exacerbate each other to potentiate the severity of insult to the thyroid axis and lead to more severe developmental impairments. The current paper addresses whether the combined effect of dietary Fe deficiencies that reduce serum TH produce a brain malformation, and if the presence of this malformation is exacerbated when chemical and dietary manipulations are combined. We used FeD diets in the presence of various concentrations of PTU in the drinking water of pregnant rat dams. Consistent with previous results, SBH volume increased with degree of TH insufficiency induced by PTU, but contrary to our predictions, no SBH was detected in the offspring of FeD dams. Neither was the presence or size of the SBH further exacerbated with combined treatments of FeD+PTU. We conclude that although FeD reduced serum and brain TH in the neonate, and reduced expression of TH-responsive genes in the postnatal brain, this may not reflect the TH status in the serum or brain of the fetus of a FeD dam. Rather the absence of effects of FeD on serum TH in the dam at weaning suggests that the thyroid status of the fetus was not sufficiently compromised by FeD to induce a SBH. These data indicate that different neurodevelopmental phenotypes follow when TH insufficiencies occur during different critical windows of brain development. Serum TH in neonates may be more predictive than dams for some adverse neurodevelopmental outcome, whereas in the absence of information of fetal TH levels, dam TH may be more accurate for others, including the formation of SBH. The data clearly identify the need for development of sensitive assays to detect and quantify TH concentrations in the serum and the brain of the developing fetus.

Description:

Although the critical role of thyroid hormone (TH) in brain development is well established - severe deficiency producing significant neurological dysfunction - there is a paucity of data on neurological impairments that accompany modest degrees of TH disruption. Quantitative modeling of serum TH to predict adverse neurological outcomes is limited not only by lack of dose-response information on serum TH declines, but also the lack of sensitive indices of the neurodevelopmental phenotype that accompanies these disruptions. We have recently demonstrated dose and serum TH-dependent increases in the incidence and size of a brain malformation (a subcortical band heterotopia, SBH) in offspring of rat dams experiencing TH insufficiencies from a chemical that blocks synthesis of hormone in the thyroid gland (i.e., propylthiouracil, PTU). Dietary deficiencies of iron (Fe) affects ~ 1 billion individuals worldwide, and also reduce circulating levels of TH by acting on the same hormone synthesis pathways as PTU. Individually, dietary goitrogens, environmental chemicals, and micronutrient deficiencies may exert relatively minor effects on the thyroid axis, but in combination, these effects may exacerbate each other to potentiate the severity of insult to the thyroid axis and lead to more severe developmental impairments. The current paper addresses whether the combined effect of dietary Fe deficiencies that reduce serum TH produce a brain malformation, and if the presence of this malformation is exacerbated when chemical and dietary manipulations are combined. We used FeD diets in the presence of various concentrations of PTU in the drinking water of pregnant rat dams. Consistent with previous results, SBH volume increased with degree of TH insufficiency induced by PTU, but contrary to our predictions, no SBH was detected in the offspring of FeD dams. Neither was the presence or size of the SBH further exacerbated with combined treatments of FeD+PTU. We conclude that although FeD reduced serum and brain TH in the neonate, and reduced expression of TH-responsive genes in the postnatal brain, this may not reflect the TH status in the serum or brain of the fetus of a FeD dam. Rather the absence of effects of FeD on serum TH in the dam at weaning suggests that the thyroid status of the fetus was not sufficiently compromised by FeD to induce a SBH. These data indicate that different neurodevelopmental phenotypes follow when TH insufficiencies occur during different critical windows of brain development. Serum TH in neonates may be more predictive than dams for some adverse neurodevelopmental outcome, whereas in the absence of information of fetal TH levels, dam TH may be more accurate for others, including the formation of SBH. The data clearly identify the need for development of sensitive assays to detect and quantify TH concentrations in the serum and the brain of the developing fetus.

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