Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology.
M. A. Taylor,Jarod Swant,John J. Wagner,Jeffrey W. Fisher,Duncan C. Ferguson,Duncan C. Ferguson +5 more
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During depletion of serum T(4), D2 activity served as a sensitive marker of tissue thyroid status, an indicator of the brain's compensatory response to maintain cT(3), and correlated with a neurophysiological outcome.Abstract:
The developing central nervous system of the fetus and neonate is recognized as very sensitive to maternal or gestational hypothyroidism. Despite this recognition, there is still a lack of data concerning the relationship between thyroid-related biomarkers and neurological outcomes. We used propylthiouracil administered at 0, 3, or 10 ppm in drinking water from gestational d 2 until weaning to create hypothyroid conditions to study the relationship between hypothalamic-pituitary-thyroid axis compensation and impaired neurodevelopment. In addition to serum T(3), T(4), free T(4), and TSH concentrations, cerebrocortical T(3) concentration (cT(3)), hepatic type I and cerebrocortical type II (D2) 5'-deiodinase activity, and thyroidal mRNA for thyroglobulin and sodium iodide symporter were measured. Extracellular recordings from the CA1 region in hippocampal slices were obtained from both postnatal d 21-32 (pups) and postnatal d 90-110 (adults) rats to assess neurophysiological effects. Thyroidal mRNA for thyroglobulin and sodium iodide symporter were increased in pups but not in dams. Both propylthiouracil doses increased cerebrocortical D2 activity approximately 5-fold in pups but only 10 ppm increased D2 activity in dams. In dams, cT(3) concentrations were maintained at 3 ppm but fell 75% at 10 ppm. cT(3) concentration in pups fell 50% at 3 ppm and more than 90% at 10 ppm. In both 3 and 10 ppm pups, hippocampal baseline synaptic activity correlated negatively with cerebrocortical D2 activity. In 3 ppm adults, impaired long-term potentiation was evident. In summary, during depletion of serum T(4), D2 activity served as a sensitive marker of tissue thyroid status, an indicator of the brain's compensatory response to maintain cT(3), and correlated with a neurophysiological outcome.read more
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Approaches to dose finding in neonates, illustrating the variability between neonatal drug development programs
John N. van den Anker,Susan McCune,Pieter Annaert,Gerri Baer,Yeruk Mulugeta,Ramy Abdelrahman,Kunyi Wu,Kevin Krudys,Jeffrey W. Fisher,William Slikker,Connie L. Chen,Gilbert J. Burckart,Karel Allegaert,Karel Allegaert +13 more
TL;DR: The variability between neonatal drug development programs for Neonatal diseases that are similar to those seen in other populations, neonatal diseases related but not similar to pediatric or adult populations, and diseases unique to neonates are illustrated.
Journal ArticleDOI
Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function.
TL;DR: In this paper, low doses of propylthiouracil (PTU 0, 1, 2, and 3 ppm) were administered to pregnant rats to induce varying degrees of developmental hypothyroidism.
Journal ArticleDOI
The Nature of the Compensatory Response to Low Thyroid Hormone in the Developing Brain
TL;DR: A model of graded T4 reductions using doses of propylthiouracil that were 200‐ to 67‐fold lower than the dose traditionally used to produce hypothyroidism in rats did not support the currently envisioned concept of the developing brain being capable of compensating for low T4.
Journal ArticleDOI
An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome.
Mary E. Gilbert,Joan M. Hedge,Liza Valentin-Blasini,Benjamin C. Blount,Kurunthachalam Kannan,Joseph E. Tietge,R. Thomas Zoeller,Kevin M. Crofton,Jeffrey M. Jarrett,Jeffrey W. Fisher +9 more
TL;DR: A 15% reduction in cortical T4 in the fetal brain was sufficient to induce permanent reductions in synaptic function in adults and suggest that standard behavioral assays do not readily detect neurotoxicity induced by modest developmental TH disruption.
Journal ArticleDOI
Maternal Subclinical Hypothyroidism Impairs Neurodevelopment in Rat Offspring by Inhibiting the CREB Signaling Pathway
Yuanyuan Zhang,Yuxin Fan,Xiaohui Yu,Xinyi Wang,Suqing Bao,Jiashu Li,Chenling Fan,Zhongyan Shan,Weiping Teng +8 more
TL;DR: The findings suggested that decreased activation of the CREB signaling pathway in pups was related to impairments of cognitive function caused by maternal subclinical hypothyroidism.
References
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Journal ArticleDOI
Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia
TL;DR: It is proposed that the screening of pregnant women for thyroid disorders should include the determination of free T4 as soon as possible during the first trimester as a major test, because hypothyroxinemia has been related to poor developmental outcome, irrespective of the presence of high titers of thyroid autoantibodies or elevated serum TSH.
Journal ArticleDOI
Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings.
R. T. Zoeller,J. Rovet +1 more
TL;DR: Recent studies confirm that the specific action of TH on brain development depends upon developmental timing, and studies informing us about molecular mechanisms of TH action are generating hypotheses concerning possible mechanisms to account for these pleiotropic actions.
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