Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs

Abstract

Maternal hypothyroxinemia during early pregnancy poses an increased risk for poor neuropsychological development of the fetus. We tested the hypothesis that maternal hypothyroidism before the onset of fetal thyroid function also affects postnatal development of heart and lungs. This question was addressed in transgenic mice that express herpes simplex virus thymidine kinase in their thyroidal follicle cells. Treatment with ganciclovir rendered these mice severely hypothyroid because viral thymidine kinase converts ganciclovir into a cytotoxic nucleoside analog. Since ganciclovir crosses the placenta, it also destroyed the thyroid of transgenic embryos while leaving the thyroids of nontransgenic littermates unaffected. Hypothyroidism of both mother and fetus did not affect prenatal heart and lung development. However, the postnatal switch from beta- to alpha-myosin heavy chain (beta- and alpha-MHC, respectively) gene expression and the increase of SERCA-2a mRNA expression did not occur in the ventricular myocardium of either the transgenic (thyroid destroyed) or nontransgenic (intact thyroid) offspring of hypothyroid mothers. Similarly, postnatal animals of the latter two groups retained elevated surfactant protein (SP) A, B, and C mRNA levels in their alveolar epithelium. In hypothyroid pups from hypothyroid mothers, these changes were accompanied by decreased alveolar septation. Our study shows that these effects of maternal hypothyroidism become manifest after birth and are aggravated by the concomitant existence of neonatal hypothyroidism.

Thyroid hormones in fetal growth and prepartum maturation

“…Thyroidectomy of fetal sheep reduces the number of type II pneumocytes in the lungs at term as well as the number of surfactantcontaining lamellar bodies in these cells (Ayromlooi et al 1983). In vitro and in vivo studies have shown that thyroid hormones affect synthesis of both the phospholipid and protein components of surfactant in fetal mice, rats, sheep, monkeys, and human infants (Ballard et al 1984, Das et al 1984, Torday & Dow 1984, Warburton et al 1988, Romaguera et al 1993, Gilbert et al 2001, van Tuyl et al 2004. In particular, thyroid hormones promote synthesis of surfactant proteins B and C. They also increase the phospholipid content of lung liquid, although this effect may be mediated via upregulation of pulmonary b-adrenergic receptor expression and, hence, enhanced epinephrine-stimulated surfactant release (Das et al 1984, Warburton et al 1988.…”

“…In rodents, T 3 has been shown to have anabolic effects on the fetal heart with increases in cardiac protein synthesis and expression of the insulinsensitive glucose transporter, GLUT4 (Crie et al 1983, Castello et al 1994. These thyroid hormone-dependent changes in cardiomyocyte growth and differentiation are accompanied by alterations in expression of contractile proteins, mechano-signaling proteins, and various genes coding for cardiac pacemaker, potassium channels, and sarcoplasmic reticulum calcium pump proteins (Edwards et al 1994, Mai et al 2004, van Tuyl et al 2004, Kruger et al 2008, Chattergoon et al 2012a, Segar et al 2013. In particular, the thyroid hormones have an important role in the perinatal switch from b-to a-myosin heavy chains in the sacromeres (Edwards et al 1994, van Tuyl et al 2004.…”

“…These thyroid hormone-dependent changes in cardiomyocyte growth and differentiation are accompanied by alterations in expression of contractile proteins, mechano-signaling proteins, and various genes coding for cardiac pacemaker, potassium channels, and sarcoplasmic reticulum calcium pump proteins (Edwards et al 1994, Mai et al 2004, van Tuyl et al 2004, Kruger et al 2008, Chattergoon et al 2012a, Segar et al 2013. In particular, the thyroid hormones have an important role in the perinatal switch from b-to a-myosin heavy chains in the sacromeres (Edwards et al 1994, van Tuyl et al 2004. Many of these maturational effects of T 3 on cardiac contractility appear to be mediated via the phosphatidylinositol-3-kinase/AKT and mTOR pathways (Kruger et al 2008, Chattergoon et al 2012a.…”

Expression pattern and ontogenesis of thyroid hormone receptor isoforms in the mouse heart

“…The first hypothesis is supported by the finding that TRs can repress certain genes in the absence of T 3 and act as antagonists of retinoid acid receptors (RAR) (Brent et al 1989, Brand 2003, Clabby et al 2003. In addition, low levels of T 3 during pregnancy do not seem to affect prenatal heart development (van Tuyl et al 2004). However, maternal hypothyroidism seriously affects the postnatal cardiac maturation, even at normal T 3 levels (van Tuyl et al 2004).…”

“…In addition, low levels of T 3 during pregnancy do not seem to affect prenatal heart development (van Tuyl et al 2004). However, maternal hypothyroidism seriously affects the postnatal cardiac maturation, even at normal T 3 levels (van Tuyl et al 2004). Although the exact functions of the distinct TRs at this developmental stage still remain unclear, their presence in the heart indicates that they have an important role in the early cardiogenesis and may imply that the thyroid status of the mother during pregnancy affects cardiogenesis.…”