title: 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.
authors.affiliation: Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706-1544, USA.
authors.forename: Angela Wai-Man
authors.initials: AW
authors.lastname: See
authors.forename: Mary E
authors.initials: ME
authors.lastname: Kaiser
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: White
authors.forename: Margaret
authors.initials: M
authors.lastname: Clagett-Dame
mesh_terms: D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001846:Bone Development / Q000502:physiology*; D004195:Disease Models, Animal; D047109:Fetal Development / Q000502:physiology*; D005775:Gastrula / Q000502:physiology; D017403:In Situ Hybridization; D038081:Organogenesis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014212:Tretinoin / Q000627:therapeutic use; D014802:Vitamin A Deficiency / Q000188:drug therapy / Q000196:embryology*
chemical_list: D014212:Tretinoin