A Genomic Analysis of Subclinical Hypothyroidism in Hippocampus and Neocortex of the Developing Rat Brain

Abstract

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 as encompassed in conditions of subclinical hypothyroidism and hypothyroxinemia, however, has not been established. The present investigation examined the effects of graded levels of hypothyroidism, from subclinical to severe, on global gene expression in the developing rodent brain. Thyroid hormone insufficiency was induced by administration of propylthiouracil (PTU) to pregnant rats via drinking water from gestational day 6 until sacrifice of pups prior to weaning. In the first study a specialised microarray, the Affymetrix Rat Neurobiology array RN_U34, was used to contrast gene expression in the hippocampus of animals exposed to 0 or 10 ppm (10 mg/l) PTU, a treatment producing severe hypothyroidism. In the second study, a more complete genome array (Affymetrix Rat 230A) was used to compare gene expression in the neocortex and hippocampus of postnatal day (PN) 14 animals experiencing graded degrees of thyroid hormone insufficiency induced by delivery of 0, 1, 2 or 3 ppm PTU to the dam. Dose-dependent up- and down-regulation were observed for gene transcripts known to play critical roles in brain development and brain function. Expression levels of a subset of approximately 25 genes in each brain region were altered at a dose of PTU (1 ppm) that induced mild hypothyroxinemia in dams and pups. These data indicate that genes driving important developmental processes are sensitive to relatively modest perturbations of the thyroid axis, and that the level of gene expression is related to the degree of hormone reduction. Altered patterns of gene expression during critical windows of brain development indicate that thyroid disease must be viewed as a continuum and that conditions typically considered 'subclinical' may induce structural and functional abnormalities in the developing central nervous system.

Developmental Iodine Deficiency and Hypothyroidism Impair Spatial Memory in Adolescent Rat Hippocampus: Involvement of CaMKII, Calmodulin and Calcineurin

“…We tested the hypothesis that developmental ID and hypothyroidism may cause spatial learning impairments through a CaM-dependent pathway, which is supported by the literature. Indeed, hypothyroidism has well been identified to cause synaptic function deficits Dong et al 2005;Gerges et al 2005Gerges et al , 2001Gilbert et al 2007;Sui and Gilbert 2003;Sui et al 2005) and some gene expressions (Royland et al 2008) and impairs spatial learning and memory in the hippocampus by using adult animal models (Alzoubi et al 2009;Gilbert and Sui 2006;van Wijk et al 2008). Furthermore, PTU exposure leads to an irreversible dose-dependent learning deficits on spatial learning tasks (Gilbert and Sui 2006).…”

Thyroid diseases in pregnancy

“…Early abortion could not be determined as only intact pregnancies were examined, but women taking levothyroxine had a more frequent history of previous miscarriages (OR 1.12, CI 1.07-1. 18). The limitation of this study is that no information was available on the thyroid hormone status of the mothers, but it is assumed that the majority of women were suffering from AITD, as Sweden is an area with sufficient iodine intake.…”

“…This could be confirmed in a recent study using genome array analysis (Affymetrix Rat 230A) to compare the gene expression in the neocortex and hippocampus in neonate pups of rats treated with different amounts of propylthiouracil. These data clearly show that there is a continuum in the disturbance of genes important for neuronal development [18 ]. Low thyroxine, but normal TSH in dams and pups already significantly affected gene expression (46% in hippocampus and 12% in cortex).…”

Developmental Iodine Deficiency and Hypothyroidism Impair Neural Development, Upregulate Caveolin-1, and Downregulate Synaptotagmin-1 in the Rat Cerebellum

“…Neurons need to increase the expression levels of caveolin-1 when iodine deficiency and hypothyroidism interrupt neural development and impair cells. The increase of caveolin-1 may represent a compensatory response to adapt for cerebellar impairments induced by low levels of thyroid hormone [47]. Loss of caveolin-1 is found to accelerate neurodegeneration and aging in caveolin-1 knockout mice.…”