Maternal folic acid-deficient diet causes congenital malformations in the mouse eye.
BACKGROUND
The eye is a very complex structure derived from the neural tube, surface ectoderm, and migratory mesenchyme from a neural crest origin. Because structures that evolve from the neural tube may be affected by a folate/folic acid (FA) deficiency, the aim of this work was to investigate whether a maternal folic acid-deficient diet may cause developmental alterations in the mouse eye.


METHODS
Female C57BL/6J mice (8 weeks old) were assigned into two different folic acid groups for periods ranging between 2 and 16 weeks. Animals were killed at gestation day 17. Hepatic folate was analyzed, and the eyes from 287 fetuses were macroscopically studied, sectioned and immunolabeled with anti-transforming growth factor (TGF)-β2 and anti-TGF-βRII.


RESULTS
Mice exposed to a FA-deficient diet exhibited numerous eye macroscopic anomalies, such as anophthalmia and microphthalmia. Microscopically, the eye was the most affected organ (43.7% of the fetuses). The highest incidence of malformations occurred from the 8th week onward. A statistically significant linear association between the number of maternal weeks on the FA-deficient diet and embryonic microscopic eye malformations was observed. The optic cup derivatives and structures forming the eye anterior segment showed severe abnormalities. In addition, TGF-β2 and TGF-βRII expression in the eye was also altered.


CONCLUSIONS
This study suggests that an adequate folic acid/folate status plays a key role in the formation of ocular tissues and structures, whereas a vitamin deficiency is negatively associated with a normal eye development even after a short-term exposure.
Departamento de Anatomía y Embriología Humana I. Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
Carmen
C
Maestro-de-las-Casas
Juliana
J
Pérez-Miguelsanz
Yamila
Y
López-Gordillo
Estela
E
Maldonado
Teresa
T
Partearroyo
Gregorio
G
Varela-Moreiras
Concepción
C
Martínez-Álvarez
D000818:Animals; D016022:Case-Control Studies; D005124:Eye Abnormalities / Q000209:etiology* / Q000473:pathology; D005260:Female; D005494:Folic Acid Deficiency / Q000150:complications* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D018709:Statistics, Nonparametric; D053781:Transforming Growth Factor beta2 / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
TGF-β2; TGF-βRII; development; eye; folate; folic acid deficiency; malformation; mouse