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Maternal hypothyroxinemia and the ontogeny of thyroid hormone nuclear receptors and cholinergic and monoaminergic neurotransmitter systems in developing rat brain

Evans, Ian Michael; (2000) Maternal hypothyroxinemia and the ontogeny of thyroid hormone nuclear receptors and cholinergic and monoaminergic neurotransmitter systems in developing rat brain. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Irreversible neurological dysfunction in children as a result of maternal thyroid hormone deficit is a worldwide problem. The effects of thyroid hormone insufficiency on neonatal brain development have been intensively studied, however, little is known regarding thyroid hormone action during fetal brain development. A hypothyroxinemic rat dam model was used to investigate the role of thyroid hormone in early brain development, with particular respect to cholinergic and monoaminergic neurotransmitter metabolic enzymes and receptors, and thyroid hormone nuclear receptors. Maternal hypothyroxinemia disturbed the ontogeny of choline acetyltransferase, monoamine oxidase and DOPA decarboxylase in fetal brain. During postnatal development, region-specific increases in tyrosine hydroxylase, monoamine oxidase and DOPA decarboxylase activities were observed, together with decreased p-adrenergic and D2 dopaminergic receptor binding sites. The fetal ontogeny of thyroid hormone receptors was disturbed in experimental progeny, but only in preparations of whole nuclei, which exhibited increased receptor binding sites at 16 and 21 days gestation. No differences in binding kinetics were apparent in salt-extracted receptor preparations from experimental progeny and controls. Analysis of thyroid hormone receptor isoform mRNA levels in fetal brain indicated that the non T3-binding variant, a2 (TRa2), was thyroid hormone regulated whereas the al and pi receptor isoforms were not. This thesis provides further evidence supporting a role for maternal TH in fetal brain development. Three candidate genes are identified, whose expression may be directly affected by T3 in fetal brain, namely choline acetyltransferase, monoamine oxidase (isoform A) and TRa2. Furthermore, these effects may be exacerbated by a general increase in the inhibition of thyroid hormone and retinoic acid-mediated gene transcription as a result of increased thyroid hormone receptor homodimer formation. The disturbed ontogeny of these proteins, amongst others, may underlie the region specific biochemical abnormalities exhibited in hypothyroxinemic dam progeny.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Maternal hypothyroxinemia and the ontogeny of thyroid hormone nuclear receptors and cholinergic and monoaminergic neurotransmitter systems in developing rat brain
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Maternal hypothyroxinemia
URI: https://discovery.ucl.ac.uk/id/eprint/10099829
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