Delayed Ultrastructural Lung Maturation in the Fetal and Newborn Hypothyroid (Hyt/Hyt) Mouse

Abstract

Thyroid hormones influence fetal and neonatal lung showed a large amount of intracellular glycogen and fewer growth and maturation. However, the effect of naturally lamellar bodies in epithelial type I1 cells compared with occurring, genetically determined hypo-or hyperthy-Balb-c fetal mouse lungs. The neonatal hytlhyt mouse also roidism on fetal or neonatal lung maturation has not been showed signs of lung immaturity such as persistent epitheexamined. In the hythyt mouse, primary hypothyroidism, lial cell glycogen, few lamellar bodies, reduced disaturated which is characterized by a high serum TSH concentration, phosphatidylcholine content, and absent tubular myelin. is transmitted as an autosomal recessive trait. It occurs due We conclude that fetal and neonatal lung maturation is to a mutational defect in the P-subunit of the TSH receptor. delayed in the hytlhyt mouse with primary hypothyWe studied the lung ultrastructure of the fetal (18- Abbreviations and total phospholipid contents of newborn hythyt mouse TH, thyroid hormone lungs were determined. Male and female hythyt mice with T,, 3,5,3'-triiodothyronine a high serum TSH concentration were made euthyroid by EM, electron microscopy adding 3,5,3'-triiodothyronine to drinking water and then LB, lamellar body mated. Balb-c mice served as euthyroid controls. Fetal and TM, tubular myelin neonatal hythyt mice had a higher serum TSH concentra-TPL, total phospholipid tion than the Balb-c controls. Fetal hytlhyt mouse lungs DSPC, disaturated phosphatidylcholineTH are potent regulators of fetal and neonatal lung growth a n d maturation, whereas hypothyroidism is associated with a maturational delay (1, 2). Naturally occurring, genetically determined hypothyroidism in the mouse is a useful model for studying the effect of TH deficiency (3-8). In the hythyt mouse, primary hypothyroidism is transmitted a s an autosomal recessive trait and is due to a mutational abnormality in the TSH receptor (7). Adult and adolescent homozygous hytlhyt mice have small thyroid glands with a decreased number of follicles, very low serum TH concentration, and markedly elevated serum TSH activity (4-8). In this study, we have characterized the hypothyroid state and analyzed lung ultrastructure in the hythyt mouse fetus and 1-d-old pup and quantitated newborn lung DSPC and T P L content.-- METHODSAnimal care and euthanasia. The study protocol for the use of Balb hytlhyt and normal Balblc ( + I + ) mice was approved by the Animal Care Committee of St. Louis University. Care of these mice was in accord with the guidelines set by the National Institutes of Health. Our colony of genetically hypothyroid mice was established from two homozygous (hytlhyt) males and two heterozygous (hyt/+) females (Jackson Laboratories, Bar Harbor, ME). Mice were housed individually and allowed to eat food and drink water ad libitum. T o restore fertility, T, was added to the drinking water (0.2 kg/mL) of male mice. Homozygous mice could be separated easily from the heterozygous litter mates by -4 wk of age bec...

Pregnant rat uterus expresses high levels of the type 3 iodothyronine deiodinase

“…Considerable evidence suggests that a principal function of thyroid hormones during development is as an activator of differentiation programs in multiple tissues (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). For example, in the central nervous system, thyroid hormone deficiency results in a generalized delay in brain growth, while thyroid hormone excess accelerates neurogenic development (2,3,43).…”

Effect of Prenatal Glucocorticoid on Fetal Lung Ultrastructural Maturation in hyt/hyt Mice with Primary Hypothyroidism

“…We have developed a colony of hyt/hyt males and hyt/hyt females in which primary hypothyroidism was confirmed by a very low serum free T 4 and a high serum TSH concentration [14,15]. Hypothyroid (hyt/hyt) mice were made euthyroid by T 3 supplementation of drinking water (0.2 Ìg/ml) and bred to carry hyt/hyt fetuses [14,15]. The female was separated from the male after mating (positive vaginal plug = day 1 of pregnancy, term F20 days).…”

“…The female was separated from the male after mating (positive vaginal plug = day 1 of pregnancy, term F20 days). To ensure fetal hypothyroidism, T 3 -supplemented water was stopped on day 12 of pregnancy [14,15].…”

“…Recently, we have developed an animal model for naturally occurring genetically determined primary hypothyroidism in the hyt/hyt mouse fetus [14,15]. In these mice, there is a point mutation in the amino acid at position 556 of the transmembrane domain 4 of the beta subunit of the thyroid-stimulating hormone (TSH) receptor [16,17].…”

“…The failure of TSH binding to the receptor prevents induction of postreceptor events, leading ultimately to the development of primary hypothyroidism which is transmitted in an autosomal recessive manner [18,19]. Fetal and 1-day-old newborn hypothyroid mice manifest delayed lung ultrastructural maturation [13,14]. In this study, we examined the effect of maternal GC on the fetal lung ultrastructure in the hyt/hyt mouse.…”