A nutritional model of late embryonic vitamin A deficiency produces defects in organogenesis at a high penetrance and reveals new roles for the vitamin in skeletal development

Abstract

Vitamin A plays an essential role in vertebrate embryogenesis. In the present study, pregnant vitamin A-deficient (VAD) rats were maintained during early pregnancy on the short half-life vitamin A metabolite, all-trans retinoic acid (atRA), in an amount sufficient to support normal development to E10.5, with a higher level of atRA (250 microg atRA/g diet) provided from embryonic day (E) 8.5-10.5 to prevent mid-gestational resorption. When limiting amounts of atRA (1.5 or 12 microg/g diet) were provided after E10.5, a highly reproducible and penetrant state of late fetal vitamin A deficiency (late VAD) was induced in the organs of developing fetuses. In addition, late VAD fetuses displayed both anteriorization of cervical regions and novel posteriorization events at the thoracic and sacral levels of the skeleton, and showed sternal and pelvic malformations not previously observed in early VAD or genetic models. The expression of several Hox genes (Hoxd3 and Hoxb4) was altered in late VAD embryos, with a reduction in Hoxd3 noted as early as 1 day after instituting deficiency. All late VAD-induced malformations were prevented by the addition of retinol starting at E10.5, whereas provision of a high level of atRA throughout pregnancy improved but could not completely rescue the development of all organ systems. This work defines a nutritional model in which vitamin A deficiency can be induced during fetal development, and reveals new functions for the vitamin in the development of the axial and appendicular skeleton.

Vitamin A Deficiency Induces Congenital Spinal Deformities in Rats

“…Our findings support the hypothesis that maternal VAD could induce vertebral anomalies in the offspring. Our study has also observed other skeletal abnormalities include loss of the neural arch of cervical vertebrae 1, malformation of sternum, loss of the ribs, rib fusion, abnormal of forelimb and hindlimb, malformation of the pelvic regions, which have also been observed by others [24,30]. Another important finding of our study is that VAD repressed the expression RALDHs and RARs, which are important components of RA signaling, in the liver and vertebral body of VAD rats.…”

Regulation of germ cell meiosis in the fetal ovary

“…It was later discovered that dietary supplementation of VAD rats with either vitamin A or RA overcame the block in meiosis and restored male fertility (Morales and Griswold 1987;Van Pelt and De Rooij 1990). Studies of female VAD rats determined that 40 -230 mcg/rat/day of RA was required for ovulation, fertilisation, implantation and subsequent embryo development: the higher doses needed from mid-gestation onwards (Kaiser et al, 2003;See et al, 2008;White et al, 2000b;White et al, 1998). Such studies have uncovered the important roles for RA during many aspects of development, reviewed by (Clagett-Dame and Knutson 2011).…”

Healthy birth weight results in higher vitamin A storage in neonate piglets administered high-dose supplements

“…34 A rat study found that inducing VA deficiency in late pregnancy resulted in less growth of intestinal villi in the small intestine of fetuses. 35 The difference in liver retinol storage between LBW and HBW piglets may be due to length of the absorptive intestinal tract or stellate cell development. Little is known about the specific development of stellate cells, other than that their production arises from mesenchymal stem cells.…”