Antagonism of hypervitaminosis A-induced anterior neural tube closure defects with a methyl-donor deficiency in murine whole-embryo culture.
The interaction of a dietary excess of vitamin A (retinoid) and deficiency of methyl-donor compounds was examined in murine early-organogenesis embryonic development. Female mice were fed one of six diets from the time of vaginal plug detection until gestational d 8.0, when embryos were removed and grown in whole embryo culture for 46 h, using serum from rats fed the same diet for 36 d as the culture medium. The six diets were either methyl-donor deficient (designated -FCM: devoid of folic acid, choline and supplemental L-methionine, but having methionine as a component of the protein portion of the diet) or methyl-donor sufficient (designated +FCM: containing folic acid, choline and L-methionine supplementation), in combination with one of three concentrations of retinyl palmitate (0.016, 0.416 or 4.016 g/kg diet). The high dose of retinyl palmitate induced a failure of anterior neuropore closure and hypoplasia of the visceral arches, both of which were significantly ameliorated by simultaneous administration of the methyl-donor-deficient diet. The primary acidic retinoid detected in the rat serum was 9,13-di-cis-retinoic acid, although we hypothesize that teratogenic retinoids were formed by embryonic biotransformation of the retinyl esters to toxic metabolites. Biochemical measurements of metabolites in relevant pathways were performed. We propose that the amelioration of these malformations may be used to determine biochemical pathways critical for retinoid teratogenesis.
Santos-Guzmán
Jesús
J
UCLA School of Public Health, Los Angeles, CA 90095, USA.
Arnhold
Thomas
T
Nau
Heinz
H
Wagner
Conrad
C
Fahr
Sharon H
SH
Mao
Gloria E
GE
Caudill
Marie A
MA
Wang
Jennie C
JC
Henning
Susanne M
SM
Swendseid
Marian E
ME
Collins
Michael D
MD
D000818:Animals; D004032:Diet; D004195:Disease Models, Animal; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D006986:Hypervitaminosis A / Q000150:complications*; D008297:Male; D008745:Methylation; D051379:Mice; D008813:Mice, Inbred ICR; D009436:Neural Tube Defects / Q000139:chemically induced*; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats