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A Genomic Analysis of Subclinical Hypothyroidism in Hippocampus and Neocortex of the Developing Brain -- JN
Citation:
ROYLAND, J. E., J. Parker, AND M. E. GILBERT. A Genomic Analysis of Subclinical Hypothyroidism in Hippocampus and Neocortex of the Developing Brain -- JN. NEUROENDOCRINOLOGY. Karger Libri AG, Basel, Switzerland, 20(12):1319-1338, (2008).
Impact/Purpose:
. The findings reported in this manuscript detail dose-dependent up- and down-regulation of a number of gene transcripts known to control critical developmental processes, including neuronal migration, plasticity and myelination. In addition, expression levels of a subset of ~25 genes were altered at a very low dose of PTU (1 ppm) that induced only mild hypothyroxinemia in dams and pups. These data reveal that genes necessary for normal brain development are sensitive to relatively modest perturbations of the thyroid axis, and that the level of gene expression change is related to the degree of hormone reduction. Dose-dependent alterations in gene expression indicate that thyroid disease must be viewed as a continuum and that conditions considered “subclinical” may induce structural and functional abnormalities in the developing central nervous system.
Description:
Hypothyroidism during pregnancy and the early postnatal period has severe neurological consequences for the developing offspring. The impact of milder degrees of perturbation of the thyroid axis, typically considered subclinical, however, has not been established. Thyroid hormone action is mediated through nuclear receptors (TRs) that regulate gene expression. The present investigation examined the impact of graded levels of hypothyroidism, from subclinical to severe, on gene expression in the developing rodent brain. Thyroid hormone insufficiency were induced by administration of propylthiouracil (PTU, 0, 1, 2, 3 ppm) to pregnant rats via the drinking water beginning in early gestation. Gene expression was assessed using Affymetrix Rat-230A chips in the neocortex and hippocampus of PN14 pups. The expression pattern of 223 and 66 of >15,000 transcripts was significantly altered in neocortex and hippocampus, respectively. Dose-dependent up- and down-regulation were observed for many gene transcripts known to control critical developmental processes, including neuronal migration, plasticity and myelination. In addition, expression levels of a subset of ~25 genes were altered at a dose of PTU (1 ppm) that induced mild hypothyroxinemia in dams and pups. These data reveal that genes necessary for normal brain development are sensitive to relatively modest perturbations of the thyroid axis, and that the level of gene expression change is related to the degree of hormone reduction. Dose-dependent alterations in gene expression indicate that thyroid disease must be viewed as a continuum and that conditions considered “subclinical” may induce structural and functional abnormalities in the developing central nervous system.
