Effect of Primary Hypothyroidism on Fetal Mouse Lung Surfactant Protein A, B and C, and Thyroid Transcription Factor-1 Protein and Gene Expression.† 1456

Abstract

Primary hypothyroidism in the Hyt/Hyt mice is due to a point mutation(Pro-556-Leu) in the β subunit of the TSH receptor of the thyroid gland and is transmitted as an autosomal recessive trait. Fetal hypothyroidism is associated with delayed fetal lung ultrastructural maturation (Ped. Res. 36:380:94). Surfactant proteins (SP-A, B & C) & Thyroid Transcription Factor-1 (TTF-1) play an important role in fetal lung surfactant function and type II cell differentiation, but the effect of primary hypothyroidism on the developmental expression of fetal lung SP-A, SP-B, SP-C or TTF-1 has not been investigated. Hyt/Hyt mice identified by high serum TSH and low free T4 levels were made euthyroid by supplemental T3. The mice were then bred to carry Hyt/Hyt pups. Balb-c euthyroid mice served as controls. All mice were killed on d 18 of gestation (term ≈20 d, vaginal plug = d 1 of pregnancy). Fetal lung immunostaining for SP-A, SP-B, SP-C and TTF-1 was performed and gene expression of these proteins was determined by Northern blot analysis. The TTF-1 immunoreactivity was nuclear in localization and confined to the type II cells, while staining for SP-A, SP-B and SP-C was cytoplasmic and present in type II cells as well as within the alveolar lumen. The intensity and distribution of the immunoreactivity scored on a scale of 0 to 3, for SP-A, SP-B and SP-C and TTF-1 (n=5) was markedly decreased in the Hyt/Hyt fetal lungs when compared to the controls (n=5). While gene expression for SP-C(≈0.8 kb) and TTF-1 (≈2.3 kb) was significantly decreased in the hyt/hyt mice, the gene expression for SP-B (≈0.9 kb) was similar in both groups. CON: Primary hypothyroidism is associated with a delay in the developmental expression of fetal lung SP-A, SP-B, SP-C and TTF-1 protein, and a differential expression for SP-B, SP-C and TTF-1 genes. These findings may explain a higher incidence of RDS in human neonates with hypothyroidism(NIH-HL 52839).