Central nervous system (CNS) dysfunction continues to be a problem in infants with congenital primary hypothyroidism in spite of the advances made to allow early diagnosis and treatment through neonatal screening programs. Many of these CNS abnormalities may be due to the effect of hypothyroidism in intrauterine life. The long term objective of this study is to determine the effect of fetal thyroidectomy on some markers of brain maturation and function using the ovine fetus as the experimental model.
The specific aims of the study are to prove that (1) thyroidectomy in the ovine fetus causes significant delay in the maturational pattern of the neurotransmitters norepinephrine (NE), dopamine (DA), and serotonin (5HT) in specific brain areas, and auditory and somatosensory evoked responses (ER). (2) Replacement therapy with thyroid hormones allows the normal maturational progress of NE, DA 5HT and ER in these areas to resume. (3) If therapy is delayed past a """"""""critical time period,"""""""" the normal maturation of NE, DA, 5HT and ER is permanently arrested. (4) The changes in NE, DA and 5HT caused by ovine fetal thyroidectomy cause plasma concentrations of growth hormone (GH) and prolactin (PRL) to be unresponsive to the NE receptor agonist clonidine the DA receptor agonist apomorphine, and the 5HT precursor 5 hydroxytryptophan (5HTP). To achieve these aims, ovine fetuses will undergo thyroidectomy at 85 days gestation. Control fetuses will undergo sham thyroidectomy. To accomplish Aim 1: NE, DA and 5HT in cerebrospinal fluid (CSF) and EF will be measured at set intervals in thyroidectomy and control fetuses. NE, DA and 5HT will also be measured in specific brain areas at the conclusion of the experiment.
Aim 2 : thyroid hormone replacement therapy will be given to thyroidectomized fetuses beginning at different intervals after thyroidectomy NE, DA and 5HT in CSF and ER will be measured at set intervals for the remainder of gestation. At the conclusion of the experiment, NE, DA and 5HT will be measured in specific brain areas.
Aim 3 : thyroidectomized fetuses will be studied at more frequent intervals for a limited segment of gestation with measurement of NE, DA and 5HT in CSF and in specific brain areas at the end of the experiment.
Aim 4 : the response of plasma GH and PRL to clonidine, apomorphine and 5HTP in thyroidectomized and control fetuses will be tested. The results of this study will more clearly define the mechanism by which hypothyroidism interferes with CNS function during fetal development.
| Richards, G E; Gluckman, P D; Ball, K et al. (1990) Changes in selected brain neurotransmitters and their metabolites in the lamb after thyroidectomy during the last two trimesters of gestation or the early neonatal period. Pediatr Res 28:469-72 |
| Richards, G E; Gluckman, P D; Ball, K et al. (1990) Expanded ontogeny of neurotransmitters and their metabolites in the brains of fetal and newborn lambs. J Dev Physiol 14:331-6 |
| Richards, G E; Lakoski, J M; Black, E W et al. (1990) The ontogeny of [3H]5-hydroxytryptamine binding in the lamb: effects of in vivo thyroidectomy. Int J Dev Neurosci 8:541-7 |
| Richards, G E; Gluckman, P D; Mannelli, S C (1987) Neurotransmitters and their metabolites in the brains of fetal and newborn lambs. Life Sci 41:1881-4 |
