Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study.
BACKGROUND
Vitamin A and its metabolites have been shown to be teratogenic in animals and humans producing defects of neural crest derived structures that include abnormalities of the craniofacial skeleton, heart, and thymus. Our prior studies with retinoic acid have established that gestational day (gd) 9 is a sensitive embryonic age in the mouse for inducing craniofacial and thymic defects.


METHODS
We exposed pregnant mice to variable doses of vitamin A (retinyl acetate) on gd 9 and embryos were evaluated for changes in developing pharyngeal arch and pouch morphology, neural crest cell migration and marker gene expression. Additionally, we investigated whether a single organ system was more sensitive to low doses of vitamin A and could potentially be used as an indicator of vitamin A exposure during early gestation.


RESULTS
High (100 mg/kg) and moderate (50 and 25 mg/kg) doses of vitamin A resulted in significant craniofacial, cardiac outflow tract and thymic abnormalities. Low doses of vitamin A (10 mg/kg) produced craniofacial and thymic abnormalities that were mild and of low penetrance. Exposed embryos showed morphologic changes in the 2nd and 3rd pharyngeal arches and pouches, changes in neural crest migration, abnormalities in cranial ganglia, and altered expression of Hoxa3.


CONCLUSIONS
These animal studies, along with recent epidemiologic reports on human teratogenicity with vitamin A, raise concerns about the potential for induction of defects (perhaps subtle) in offspring of women ingesting even moderate to low amounts of supplemental vitamin A during the early gestational period.
Mulder
G B
GB
University Laboratory Animal Resources, University of California, Irvine, California 92697, USA.
Manley
N
N
Grant
J
J
Schmidt
K
K
Zeng
W
W
Eckhoff
C
C
Maggio-Price
L
L
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000015:Abnormalities, Multiple / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001934:Branchial Region / Q000002:abnormalities; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003391:Cranial Nerves / Q000002:abnormalities*; D019465:Craniofacial Abnormalities; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006330:Heart Defects, Congenital / Q000139:chemically induced; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000002:abnormalities* / Q000187:drug effects; D011247:Pregnancy; D013950:Thymus Gland / Q000002:abnormalities; D014801:Vitamin A / Q000633:toxicity*
D004268:DNA-Binding Proteins; C489832:HOXA3 protein, human; D018398:Homeodomain Proteins; C080331:Hoxa3 protein, mouse; D014801:Vitamin A