Developmental Eye Abnormalities in Mouse Fetuses Induced by Retinoic Acid

doi:10.1016/S0021-5155(97)00134-2

Japanese Journal of Ophthalmology

Volume 42, Issue 3, May–June 1998, Pages 162-167

https://doi.org/10.1016/S0021-5155(97)00134-2 Get rights and content

Abstract

To clarify the relationship between neural crest cells and various developmental eye abnormalities, pregnant mice were administered an intraperitoneal injection of 12.5 mg/kg retinoic acid (RA) suspended in corn oil on day 7 of pregnancy (RA group). Control mice received an equal volume of corn oil only (control group). The fetuses were removed by laparotomy on day 18 of gestation. The fetal mortality was 46.3% in the RA group and 2.2% in the control group. The live fetuses in both groups were observed grossly, and the eyes were examined histologically in serial sections. In the RA group, gross malformations were observed, including microphthalmos (95.5%), cleft lip and palate (36.4%), and central nervous system anomalies (31.8%). In the control group, these malformations were seen in only 6.7%, 0%, and 2.2%, respectively. Histologic examinations in the RA group revealed microphthalmos (47.7%), anophthalmos (38.6%), faulty closure of the embryonic fissure (36.4%), developmental abnormalities of the vitreous (34.1%), aphakia (22.7%), goniodysgenesis (18.2%), and faulty separation of the lens vesicle (15.9%). They were detected in only 3.3%, 1.1%, 3.3%, 8.9%, 1.1%, 2.2%, and 2.2%, respectively, of the control group. These developmental eye abnormalities arose from abnormal migration of neural crest cells.

Introduction

The eye is formed under tissue interactions among surface ectoderm, neuroectoderm including the neural crest, and mesoderm.¹ The neural crest is a specialized population of mesenchymal cells that emigrates from the dorsal margin of the neural folds around the time of neural tube closure.¹ Cranial neural crest cells migrate and differentiate into various ocular tissues, such as the corneal endothelium and stroma, the iris stroma, the trabecular meshwork, the ciliary body stroma, uveal melanocytes, and the sclera.2, 3 The primary vitreous is thought to develop from neural crest cells.4, 5

Retinoic acid (RA) is the carboxylic acid and the biologically active form of vitamin A (retinol).⁶ This acid is regarded as a powerful teratogen that mainly affects the migration of cranial neural crest cells.7, 8, 9

The developmental mechanisms involved in eye abnormalities have not been well elucidated. In the present study, various eye abnormalities induced by RA were examined histologically to clarify their developmental mechanisms.

Section snippets

Materials and Methods

Animals used in this study were C57BL/6NJcl mice whose body weights ranged from 25 to 35 g and were 12 to 16 weeks of age postbirth. Five animals were kept in each cage, with wood-shaving bedding, and they were given commercial laboratory food and water. The room was kept on a 12-hour light/dark cycle at a constant temperature of 25°C. Pairs of mice, each including an estrous female and a potent male, were caged together overnight. Females that had vaginal plugs the next morning were determined

Results

The number of implantations in the two groups did not differ significantly (Student’s t-test). The fetal mortality was 46.3% in the RA group and 2.2% in the control group (Table 1). The incidence of fetuses with gross malformations was 95.5% in the RA group and 6.7% in the control group. Both the fetal mortality and the incidence of fetuses with gross malformations were significantly higher in the RA group than in the control group (chi-square test, P < 0.01). Distinguishing anophthalmos from

Discussion

Retinoic acid, first synthesized by Arens and van Dorp⁶ in 1946, is a biologically active form of vitamin A (retinol).¹¹ Retinol is known to induce various biologic effects after its conversion to RA. Kochhar⁷ administered RA to pregnant rats and mice, and they observed malformations including spina bifida, microphthalmos, and cleft palate in their fetuses, providing evidence of the teratogenic effect of this drug. Wiley et al⁹ demonstrated that treating pregnant hamsters with RA disturbed the

Acknowledgements

This study was supported by a Grant-in-Aid for Scientific Research No. 0967810 from the Japanese Ministry of Education, Science, and Culture. This study was published in Japanese in Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 1997;101:293–8.

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Developmental Eye Abnormalities in Mouse Fetuses Induced by Retinoic Acid

Abstract

Introduction

Section snippets

Materials and Methods

Results

Discussion

Acknowledgements

Exp Eye Res

Surv Ophthalmol

Abnormal organogenesis in the eye

Prenatal development of the eye and its adnexa

Developmental mechanisms of congenital eye abnormalities

Nippon Ganka Gakkai Zasshi (Acta Soc Ophthalmol Jpn)

The genes involved in the morphogenesis of the eye

Jpn J Ophthalmol

Synthesis of some compounds possessing vitamin A activity

Nature

Teratogenetic activity of retinoic acid

Acta Pathol Microbiol Scand

Effects of vitamin A on the behavior of migratory neural crest cells in vitro

J Cell Sci

Effects of retinoic acid on the development of the facial skeleton in hamstersEarly changes involving cranial neural crest cells

Acta Anat

Aspects of teratology of vitamin A acid (β-all trans retinoic acid)

Acta Derm Venereol Suppl (Stockh)