Having previously observed that T4 and T3 levels in fetal rat brain and brown adipose tissue are clearly higher than expected from their low circulating levels, we have now studied thyroid hormone concentrations and 5'-deiodinase activities (5′D) in several other rat fetal tissues during the last 6 days of gestation (dg), namely 17–22 dg. This period comprises the onset of fetal thyroid activity. Total thyroidal T4 and T3 contents increased 100- and 400-fold, respectively; T4 concentrations increased 8- to 10-fold in plasma, carcass, lung, and liver, and T3 increased 4.5- to 9-fold, except in plasma and liver, where T3 levels increased less than 2-fold in plasma and 3-fold in liver. During this developmental period 5′D activity increased 5- and 10-fold in fetal liver and lung, respectively. In fetuses from hypothyroid [thyroidectomized (T)] dams, body weight was lower than in fetuses from normal dams. Total thyroidal T4 and T3 contents were initially the same, but decreased markedly in fetuses from T dams...

Thyroid hormones and 5'-deiodinase in the rat fetus late in gestation: effects of maternal hypothyroidism.

Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: a physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat.

Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can be prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related changes in maternal thyroid status when treating a pregnant woman is crucial to preventing fetal goitrous hypothyroidism. Maternal levels of free T(4) are the most consistent indication of maternal and fetal thyroid status. In patients with fetal goitrous hypothyroidism, intra-amniotic levothyroxine injections improve fetal outcome. The best way to avoid maternal overtreatment with antithyroid drugs is to monitor closely the maternal thyroid status, especially estimates of free T(4) levels.

Antithyroid drug-induced fetal goitrous hypothyroidism

Thyroid glands of fetal hypothyroid (hyt/hyt) mice were studied to determine the effects of the mutant gene during embryogenesis. Comparisons of mutant and normal thyroids were made with respect to morphology, iodine-concentrating ability, and glandular thyroxine (T4) content at day 18 of gestation. Fetal hyt/hyt thyroid tissue was properly located, but incompletely differentiated. The mutant thyroid was characterized microscopically by small, poorly developed follicles with colloid diminished in PAS-staining properties. The mutant glands' ability to concentrate iodine was found to be only 5--16% of that exhibited by normal glands. When litters contained both mutant and normal off-spring, the differential iodine-concentrating ability allowed fetuses to be separated into two distinct, nonoverlapping populations. The distribution of fetal mice into high or low iodine-concentrating groups agreed closely with predicted frequencies for normal and mutant phenotypes. Thyroid content of T4 in mutant mice was found to be approximately equal to that found in age-matched normal controls. The poorly developed morphology and deficient iodine-concentrating ability of fetal thyroids from day 18 hyt/hyt mice indicated that the mutant gene acts during the ontogeny of this gland. Although such data are not available on human fetuses affected by thyroid dysgenesis, postnatal hyt/hyt mice display characteristics similar to those of infants born with this form of congenital primary hypothyroidism. Thus, elucidation of the site of mutant gene action in the mouse should contribute to our knowledge of disturbed fetal thyroid development and its implications in the adult mammal.

Defective thyroid ontogenesis in fetal hypothyroid (hyt/hyt) mice

The effects of treatment with L-thyroxine (T4;20 ng/g body weight, given subcutaneously on days 1, 3, 5, 7 and 9), 2.5 S nerve growth factor (NGF; 2 ng/mg brain weight, given intracerebroventricularly on days 1, 3, 5, 7 and 9), monoclonal anti-NGF (2 ng/mg wet weight, given intracerebroventricularly on days 1, 3, 5, 7 and 9), and monoclonal anti-NGF receptor (192 IgG; 2 ng/mg wet weight, injected daily from day 1 to day 9) antibodies, separately or together, were studied on the biochemical development of hippocampal formation, olfactory bulbs and cerebellum in 10-day-old and 15-day-old normal and hypothyroid rats. The results provide the following information: (1) CNS structures other than the basal forebrain are sensitive to NGF during early development. (2) Both normal and hypothyroid rats are more sensitive to NGF deprivation than NGF supplementation. (3) The effects of anti-NGF antibodies in normal rats are similar to those induced by anti-NGFr antibodies. (4) NGF alone had little or no effect, but interacts with T4 in promoting cell maturation, especially in hypothyroid rats. (5) Hypothyroid rats are more sensitive to T4 and to T4 plus NGF than are normal ones. (6) The synergistic action of both trophic factors, but not that of T4, tend to disappear at long term in hypothyroid rats. (7) The differential sensitivity of the brain areas to T4, NGF, or both trophic factors correlates with their cell acquisition rate, especially in hypothyroid rats. (8) T4 and NGF together act more markedly (but not exclusively) on the cholinergic structures in both normal and hypothyroid rats. (9) RNA appears to be very sensitive to NGF, especially in hypothyroid rats. In close correlation with preliminary morphological observations, the results clearly demonstrate that an interaction between T4 and NGF regulates the ontogeny of a number of neuronal structures in CNS independently of their neurotransmitter phenotype, but with a regional specificity. The possibilities of accounting for this interaction, in particular the major role of thyroxine, are discussed.

An interaction between thyroid hormone and nerve growth factor promotes the development of hippocampus, olfactory bulbs and cerebellum: a comparative biochemical study of normal and hypothyroid rats.

The critical time of onset of the reciprocal relationship between the pituitary and the thyroid in fetal rats was assessed by the appearance of goiters in fetuses after maternal treatment with goitrogen, propylthiouracil (PTU), on various days of gestation. The assessment was based on changes in the weight and histology of the fetal thyroids. The day following overnight mating was regarded as day 1 of gestation. Pregnant rats were treated with 40 mg PTU each day for two days and autopsied on the third day. The various experimental periods were days 16--18, 17--19, 18--20, 19--21, and 20--22. PTU given to pregnant rats on days 16 and 17 did not cause any change in the fetal thyroids. PTU given on days 17 and 18 caused only a slight increase of fetal "thyroid weight/body weight" ratio. In all other experimental periods (days 18--20, 19--21, and 20--22), PTU induced conspicuous goiters in fetuses, which was reflected by an increased weight of thyroids, an increased height of follicular cells, and a decreased amount of colloid stored in follicles. The results suggest that in fetal rats, the reciprocal relationship between the pituitary and the thyroid is established on approximately days 19--20 of gestation.

Yonetaka Fukiishi

Papers

Ontogeny of the pituitary‐thyroid system in fetal rats: Observations on the fetal thyroid after maternal treatment with goitrogen