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ESCOBAR
Mechanisms of adaptation to iodine deficiency in rats: thyroid status is tissue specific. Its relevance for man.Pedraza PE, Obregon MJ, Escobar-Morreale HF, del Rey FE, de Escobar GM. Endocrinology. 2006 May;147(5):2098-108. Epub 2006 Feb 2.
"Many animals, man included, live in areas providing insufficient iodine (I) for optimal health. Degrees of I deficiency (ID) vary from mild-moderate to very severe, with quali- and quantitatively different negative consequences. To understand the mechanisms involved in adaptation to different grades of ID, we fed rats a low-iodine diet, plus additions resulting in a 250-fold range of I daily available to the thyroid, ranging from 5 mug (adequate) down to 0.02 microg I. We measured thyroid weight, total I, T(4), T(3), and type I 5' iodothyronine deiodinase (D1) activity, TSH, T(4), free T(4), and T(3) in plasma, T(4) and T(3) in 11 tissues, and two 5' deiodinase isoenzymes in four. TSH-independent thyroid autoregulation plays an important role in addition to TSH-dependent mechanisms in the adaptation to ID, avoiding a decrease of T(3) in plasma and most tissues, despite a marked decrease of plasma T(4), whereas extrathyroidal responses of D2 mitigate T(3) deficiency in tissues in which T(3) is mostly generated from T(4). We focused on mild and moderate ID, the least investigated experimentally, despite its current frequency in industrialized countries. The novel and important finding of our study is that thyroid status cannot be defined for the animal as a whole: at all grades of ID, T(3) is simultaneously elevated, normal, and low in different tissues. Present findings in mild-moderate ID draw attention to the importance, for man, of the resulting hypothyroxinemia that may affect mental functions and neurodevelopment of the inhabitants, even when they do not have the increased TSH or clinical hypothyroidism, often wrongly attributed to them."
Role of thyroid hormone during early brain development.Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Eur J Endocrinol. 2004 Nov;151 Suppl 3:U25-37. Review.
"The present comments are restricted to the role of maternal thyroid hormone on early brain development, and are based mostly on information presently available for the human fetal brain. It emphasizes that maternal hypothyroxinemia - defined as thyroxine (T4) concentrations that are low for the stage of pregnancy - is potentially damaging for neurodevelopment of the fetus throughout pregnancy, but especially so before midgestation, as the mother is then the only source of T4 for the developing brain. Despite a highly efficient uterine-placental 'barrier' to their transfer, very small amounts of T4 and triiodothyronine (T3) of maternal origin are present in the fetal compartment by 4 weeks after conception, with T4 increasing steadily thereafter. A major proportion of T4 in fetal fluids is not protein-bound: the 'free' T4 (FT4) available to fetal tissues is determined by the maternal serum T4, and reaches concentrations known to be of biological significance in adults. Despite very low T3 and 'free' T3 (FT3) in fetal fluids, the T3 generated locally from T4 in the cerebral cortex reaches adult concentrations by midgestation, and is partly bound to its nuclear receptor. Experimental results in the rat strongly support the conclusion that thyroid hormone is already required for normal corticogenesis very early in pregnancy. The first trimester surge of maternal FT4 is proposed as a biologically relevant event controlled by the conceptus to ensure its developing cerebral cortex is provided with the necessary amounts of substrate for the local generation of adequate amounts of T3 for binding to its nuclear receptor. Women unable to increase their production of T4 early in pregnancy would constitute a population at risk for neurological disabilities in their children. As mild-moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia in Western societies, the birth of many children with learning disabilities may already be preventable by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible."
Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism.Martinez-Galan JR, Pedraza P, Santacana M, Escobar del Ray F, Morreale de Escobar G, Ruiz-Marcos A. J Clin Invest. 1997 Jun 1;99(11):2701-9.
"The most severe brain damage associated with thyroid dysfunction during development is observed in neurological cretins from areas with marked iodine deficiency. The damage is irreversible by birth and related to maternal hypothyroxinemia before mid gestation. However, direct evidence of this etiopathogenic mechanism is lacking. Rats were fed diets with a very low iodine content (LID), or LID supplemented with KI. Other rats were fed the breeding diet with a normal iodine content plus a goitrogen, methimazole (MMI). The concentrations of -thyroxine (T4) and 3,5,3'triiodo--thyronine (T3) were determined in the brain of 21-d-old fetuses. The proportion of radial glial cell fibers expressing nestin and glial fibrillary acidic protein was determined in the CA1 region of the hippocampus. T4 and T3 were decreased in the brain of the LID and MMI fetuses, as compared to their respective controls. The number of immature glial cell fibers, expressing nestin, was not affected, but the proportion of mature glial cell fibers, expressing glial fibrillary acidic protein, was significantly decreased by both LID and MMI treatment of the dams. These results show impaired maturation of cells involved in neuronal migration in the hippocampus, a region known to be affected in cretinism, at a stage of development equivalent to mid gestation in humans. The impairment is related to fetal cerebral thyroid hormone deficiency during a period of development when maternal thyroxinemia is believed to play an important role."
Cerebral hypothyroidism in rats with adult-onset iodine deficiency.Obregon MJ, Santisteban P, Rodriguez-Pena A, Pascual A, Cartagena P, Ruiz-Marcos A, Lamas L, Escobar del Rey F, Morreale de Escobar G. Endocrinology. 1984 Aug;115(2):614-24. [abstract only]
"Rats fed chronically a low iodine diet may have low serum T4 and high circulating TSH, despite normal serum T3. As the brain depends to a great extent on intracellular generation of T3 from T4 for its total and nuclear T3, we have carried out two experiments to determine whether the brain of iodine-deficient rats may become hypothyroid, despite normal serum T3 levels. In both experiments we confirmed previous data, showing that the pituitary and liver of iodine-deficient rats with very low plasma T4 levels are hypothyroid as compared to those of animals receiving the same diet supplemented with KI, though not as markedly as animals which had undetectable circulating levels of both T4 and T3 as a consequence of chronic ingestion of KC1O-4, or of surgical thyroidectomy. We have further found that the nuclear T3 content was decreased in the brain of iodine-deficient rats, as compared with the animals on the iodine-supplemented diet. The nuclear to plasma ratios of labeled T3 showed that the uptake of this hormone into liver and brain nuclei is not decreased in the iodine-deficient rats as compared with those on the iodine-supplemented diet. This finding indicates that the decreased liver and brain nuclear T3 contents of iodine-deficient rats are likely to be a consequence of the marked reduction of their T4 pool, leading to decreased amounts of intracellularly generated T3. The number of spines on shafts of pyramidal neurons from the visual cortex of iodine-deficient rats was lower than that of rats fed the same diet supplemented with KI. Their distributions along the shaft were also not the same. Such changes might well be an index of cerebral hypothyroidism, as they are similar to those found after thyroidectomy of adult rats. It is concluded from the present findings that normal circulating T3 levels may not be sufficient to maintain brain euthyroidism in rats fed a diet iodine deficient enough to result in very low circulating T4 levels."
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