Sheep foetuses were surgically thyroidectomized at 50-60 days gestation, when thyroid function begins, and the pregnancy was then allowed to continue until 90, 120 or 150 days (term). At these times the foetuses were removed by caesarean delivery, exsanguinated, weighed and dissected. The central nervous system was divided--cerebral hemispheres, brain stem, cerebellum and spinal cord for subsequent analysis. Comparison was made with sham operations on seven foetuses. Thyroidectomy led to a fall in body weight (24.7%) and brain weight (11.7%) at 120 days and 150 days, 31.1% and 24.5% respectively. The hemispheres showed the greatest change and the cerebellum the least. DNA and protein contents were reduced in the hemispheres and cerebellum at 150 days, while in the brain stem and spinal cord the DNA content was not significantly affected. Protein content was, however, reduced indicating a reduced cell size, but not a reduced cell number as in the other two regions. Somatic changes included reduced wool growth, delayed osseous development in the limbs (X-ray assessment) a reduced heart weight (39.1%) and an increased pituitary weight (48.1%). The thyroidectomized lambs failed to survive for more than a few hours after birth or caesarean delivery at 150 days. The findings indicate significant effects of foetal thyroidectomy on brain development in the sheep late in pregnancy along with other evidence of foetal hypothyroidism.

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PubMedDate not supplied

Foetal brain development in the sheep.

The pattern of normal foetal brain development has been described for the Merino sheep. Controlled flock matings were used and foetuses removed by hysterotomy at 40, 54, 67, 81, 90, 95, 109, 121 and 150 days of gestation. Lambs at 7 days after birth and adults were also studied. The CNS was dissected, separated and weighed as four segments--cerebral hemispheres, brain stem, cerebellum and spinal cord. Determinations of DNA, RNA, protein, cholesterol and water content were subsequently carried out on each segment. Brain weight increased from 0.264 g (40 days) to 52.74 g at 150 days. The ratio to body weight decreased from 6.7% (40 days) to 1.5% (150 days). DNA increased more rapidly from 40 to 90 days in the cerebral hemispheres and brain stem than in the cerebellum and spinal cord and this increase preceded the main increase in weight. Increases in cholesterol and decreases in water content were also more marked in the cerebral hemispheres and brain stem. Increase in brain weight occurred in two phases, one up to 90 days followed by a more rapid and larger increase after 90 days which continued to birth. These two phases appear to reflect an increase in neuroblast multiplication followed by neuroglial multiplication and myelination respectively. At birth, brain weight had reached 50% of adult size, the cerebral hemispheres 52% of adult size, the cerebellum 40% and spinal cord 40%. The relative maturity of the brain at birth justifies the classification of the sheep as a prenatal brain developer.

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PubMedDate not supplied

Retarded fetal brain development resulting from severe dietary iodine deficiency in sheep.

Sheep have been used to study the effect of dietary iodine deficiency on the development of the fetal brain. Severe iodine deficiency caused reduction in fetal brain and body weights and in brain DNA and protein from 70 days gestation to parturition. The lowered brain weight and brain DNA at 70 days gestation indicates a reduced number of cells, probably due to slower neuroblast multiplication which normally occurs from 40-80 days in the sheep, and the reduction in DNA and protein after 80 days implies that the development of neuroglia could be slowed also in iodine deficiency. Morphological changes were observed in both the cerebral hemispheres and the cerebellum. In the cerebral hemispheres of the iodine-deficient fetuses an increased density of neurons was apparent histologically in the motor cortex and visual cortex and in the CA1 and CA4 areas of the hippocampus in comparison with controls. In the cerebellum there was delayed migration of cells from the external granular layer to the internal granular layer and increased density of Purkinje cells in the iodine-deficient fetal brains. In addition, the molecular area was increased and the medullary area reduced in comparison with controls. These change are indicative of delayed brain maturation. Evidence of fetal hypothyroidism was provided by low fetal thyroid iodine and plasma T4 values, thyroid hyperplasia from 70 days gestation, significant reduction in body weight at the same time as the brain retardation, and absence of wool growth and delayed skeletal maturation near parturition. It is apparent from the biochemical and histological changes observed during iodine deficiency that iodine is an essential element for normal fetal brain and physical development in the sheep.

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PubMedDate not supplied

The effect of maternal and fetal thyroidectomy on fetal brain development in the sheep.

The combination of maternal and fetal thyroidectomy was found to have a significant influence on brain development in the fetal sheep at 140 days. There was reduced body weight (36%), brain weight (23%), DNA (26%) and protein (34%) content in five fetuses of ewes, subjected to thyroidectomy six weeks before mating and fetal thyroidectomy at 98 days gestation, compared with six sham operated controls. Cholesterol content was also reduced (36%) and water content increased (2.4%). The cerebellum was most severely affected and showed histologically an increased cell density associated with a significant reduction in the ratio of the molecular to granular cell layer area. The cell density was also significantly increased in the CA1 region of the hippocampus, but not in the CA4 region. It was also increased in the parietal layer of the cerebral cortex but not in the motor region. There was a significant reduction in the weight of heart (28.6%) and lungs (33.4%), while the kidneys and pituitary were enlarged (20.5% and 48.5% respectively) as a result of double thyroidectomy. The combined thyroidectomy was similar to iodine deficiency in its effect on fetal brain development, indicating that it is probable that iodine deficiency has its effects in the sheep by a combination of maternal and fetal hypothyroidism.

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PubMedDate not supplied

The brain in iodine deficiency.

Global descriptive, epidemiological studies have established the relation of iodine deficiency to endemic cretinism which, in its fully developed form, is characterized by mental deficiency, deaf mutism and spastic diplegia. However, a second less common variant--myxedematous or hypothyroid cretinism--is characterized by severe hypothyroidism with dwarfism. Mixed forms occur. It has been shown that both conditions can be prevented by correction of the iodine deficiency before pregnancy. Cretinism and development--now termed iodine deficiency disorders (IDD). A number of recently developed animal models establish the effect of severe iodine deficiency on brain development. These include the rat, the marmoset monkey and the sheep. These models are all characterized by the production of severe maternal and fetal hypothyroidism which is associated with effects on the maturation of the cerebral cortex and cerebellum. There was a reduced brain weight with a reduced number of cells as indicated by reduced DNA, a greater density of cells in the cerebral cortex and reduced cell acquisition in the cerebellum. Studies of the mechanisms involved have been carried out in the sheep. The findings reveal significant, though less severe, effects of fetal thyroidectomy (late gestation) and a significant effect of maternal thyroidectomy on brain development in mid-gestation. A combination of maternal and fetal thyroidectomy has similar but more severe effects than iodine deficiency. In the light of current knowledge of the embryology of the brain it is suggested that the critical time for the effect of iodine deficiency is the mid-trimester (14-18 weeks) when the neurons of the cerebral cortex and basal ganglia are formed and could be damaged by the effect of iodine deficiency on maternal thyroid function. There is now recent evidence indicating transfer of maternal thyroxine across the placental barrier early in pregnancy. In this way, neurological cretinism might be produced. Impaired fetal thyroid function would follow in the third trimester and augment the effect of reduced maternal thyroid function. Impaired fetal thyroid function alone could produce the hypothyroid form of cretinism. Further experimental studies, particularly into the postnatal period, are required to substantiate these suggestions. Apart from this, further study of the effects of iodine deficiency on brain development at the subcellular and cellular levels are likely to be most productive.

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