Maternal Hypothyroidism Delayed Retinal Opsin-Development in the Neonatal Period: Analysis of TRH-Deficient Mice

Abstract

Abstract Introduction: Retinal cone photoreceptor cells contain short (S) and medium (M) wavelength opsins, which are light-sensitive substances involved in color vision and visual acuity by sensing lights of different wavelengths. Thyroid hormones promote M-opsin expression and suppress S-opsin expression during the differentiation of cone photoreceptors. It was previously reported that M-opsin expression was delayed and S-opsin expression increased in TSH receptor-deficient mice and methimazole-induced hypothyroid mice. In addition, no M-opsin expression and increased S-opsin expression were observed in thyroid hormone receptor (TR) β2-deficient mice (Ng L et al, Nature Genetics. 2001; 27(1): 94-98.). This suggested that impaired thyroid function affects opsin development. We therefore examined retinal development in TRH-deficient mice, which are a model of central hypothyroidism established in our laboratory. Methods: We performed HE staining of the retina at postnatal 30 days and electroretinography at postnatal 10 weeks using TRH-/- and wild-type (WT) mice. We also examined expression levels of S/M opsin mRNA in WT, TRH-/- and TRH-/- pups born from TRH-/- dams at postnatal 12,17 and 30 days, and TRβΔ337T knock-in mice (TRβmut/mut) at postnatal 30 days. Furthermore, we performed immunohistochemistry to examine S/M opsin protein expression in these mice. Results: The retinal structures by HE staining and retinal functions by electroretinography in TRH-/- mice were unchanged compared with those in WT mice. Although M-opsin expression was not detected and S-opsin expression was higher in TRβmut/mut mice than in WT mice, the mRNA and protein expression levels of S/M-opsin did not significantly differ between TRH-/- pups born from TRH+/- dams and WT pups at all postnatal days. TRH-/- pups born from TRH-/- dams exposed to maternal hypothyroidism had similar serum total T4 levels to TRH-/- pups born from TRH+/- with normal maternal thyroid function. In contrast, the mRNA expression level of M-opsin was significantly lower (1.00±0.06 vs 0.64±0.05: mean ± SE, p<0.01) and the protein expression level was lower in TRH-/- pups born from TRH-/- dams than in WT pups at postnatal 12 days. However, these differences disappeared after postnatal 17 days, and there was no difference in M-opsin expression in TRH-/- pups born from TRH-/- dams compared with WT pups. Conclusions: Although no delay in opsin development was observed in TRH-/- pups born from TRH+/- dams, TRH-/- pups born from central hypothyroid dams exhibited delayed opsin development, suggesting that maternal hypothyroidism affects the development of retinal opsin in the neonatal period.