Role of Thyroid Hormone in Craniofacial and Eye Development Using a Rat Model

Abstract

Thyroid hormones (TH) are essential for somatic and neural development. Epidemiological studies have pointed to TH-dependent craniofacial features occurring during development. In an attempt to elucidate the precise role of TH in the developing eyes and adnexa (orbit, lids, nasolacrimal structures), we analysed the craniofacial and eyeball developmental characteristics in a rat model of congenital-neonatal hypothyroidism (HG), induced by combined chemical-surgical thyroidectomy. The heads and eyeballs from control and HG animals were obtained at key developmental stages and processed for scanning electron, light and transmission electron microscopy. On embryological day 13 (E13), significantly reduced values for head parameters (25% less), optic primordia area (0.053 ± 0.0085 vs. 0.111 ± 0.012 µm²; p < 0.05) and volume (3.96 ± 0.141 vs. 8.09 ± 0.123 µm³; p < 0.05) were found in the HG with respect to the controls. In addition, a delayed prenatal eye closure and postnatal eye opening took place in the treated rats. The photoreceptor and ganglion cell layer thickness displayed significantly lower values (p < 0.001) in HG, at each developmental time point. Postnatally, a delay in photoreceptor outer segment morphogenesis (in relation to retarded disc formation) and significantly lower values for ganglion cell nuclear volumes (p < 0.001) and nuclear pore density (p < 0.01) were observed in the TH-deficient animals. All data suggest that TH play a pivotal role in the development of the face and eye. Therefore, a series of defects due to a loss of TH actions involved in anterior-posterior development of the head and face and the loss of TH-dependent signals crucial for cell differentiation, migration, proliferation and establishment of definitive cell phenotypes in the eyes may appear. Gestational and neonatal screenings for thyroid functioning are suggested to paediatricians and ophthalmologists in order to prevent craniofacial malformations and visual abnormalities.

Low Thyroid Hormone Levels Impair the Perinatal Development of the Rat Retina

“…This led us to initiate the study of putative effects of thyroid deficiency on retinal development. Recently, we described how congenital-neonatal hypothyroidism in the rat induced alterations in gross morphometric parameters during eye development [25] and delayed and altered myelination and axonal outgrowth in the optic nerve [26]. In the present study, we show that low T 3 /T 4 levels, compatible with the hypothyroid condition, cause a reduction in both the number of neuroblasts and in the mitotic index during the critical period of perinatal development in the rat retina.…”

“…The rat eyeball, at the end of gestation and soon after birth, was rounded, but slightly flattened in its anterior-posterior axis. In agreement with earlier reports [3,25], the morphometric analysis of the eye developmental parameters was carried out according to the ellipsoid area and volume, as follows:…”

“…Ten right eyes were examined in fresh at each time point to determine their weight, size and volume (anterior-posterior, horizontal and vertical eyeball axes were measured by using a binocular Intralux 5000 Technos microscope with a calibration tool). All data were recorded and processed by a Basic program as previously described [21,[25][26][27][28]. The rat eyeball, at the end of gestation and soon after birth, was rounded, but slightly flattened in its anterior-posterior axis.…”

“…A small portion of the retroequatorial retina (conveniently oriented) was immersed and slightly shaken in fixative for additional 240 min. Then, the eye samples were osmicated, dehydrated and embedded in Epon resin as previously described [21,25,26]. Serial semithin transverse sections of the retina were obtained using an LKB ultramicrotome and subsequently were stained with toluidine blue for examination under an Olympus light microscope (BX-50 U-STP).…”

Development of Contrast Sensitivity in Infants with Prenatal and Neonatal Thyroid Hormone Insufficiencies

“…In the retina, TH is needed (15)(16)(17) for the differentiation of cones versus rods (18,19), specific cone subtypes (20), and retinal oligodendrocyte precursor cells (21) and for the production of essential proteins (22,23). Animal models demonstrate that when TH is lacking at a particular time prenatally, visual development and functioning will be impaired (20).…”