Folic acid and methionine in the prevention of teratogen-induced congenital defects in mice.
BACKGROUND
Periconceptional supplementation with multivitamins containing folic acid reduces the risk of congenital malformations. We have previously investigated the effect on the murine development of a multiple retinoic acid competitive antagonist, Bristol-Myers-Squibb 189453, showing that treated fetuses were affected with heart defects, thymus aplasia or hypoplasia, and severe anomalies of the central nervous system. Hereby, we analyzed the effects of nutritive therapy involving folic acid and methionine on teratogen-induced congenital defects in mice.


METHODS
A total of 132 outbred CD1 litters were studied. Pregnant mice were divided into four experimental groups, and an oral supplementation of H(2)O or folic acid, or methionine, or folic acid+methionine was administered from 0.5 days postcoitum until the end of pregnancy. At 7.5 days postcoitum, mice from all these groups were administered Bristol-Myers-Squibb 189453 to induce the teratogenic effect. At the end of pregnancy, fetuses were dissected and tissues were analyzed by histology and flow cytometric assays.


RESULTS
Folic acid reduces congenital heart diseases from 81.3% to 64.8%, neural tube defects from 20.3% to 3.7%, and thymus abnormalities from 98.4% to 27.8%, restoring a normal number of differentiated thymus cells. Methionine is less effective in contrasting congenital heart diseases and neural tube defects, and induces thymus cell proliferation but not differentiation. Folic acid+methionine weakly reduce congenital heart diseases and neural tube defects, but consistently reduce the incidence of fetuses affected with thymus pathologies from 98.4% to 67.7%.


CONCLUSIONS
Our results suggest that folic acid and methionine periconceptional supplementations may influence the incidence of congenital defects and may probably induce negative selection of embryos presenting developmental anomalies.
Cipollone
Daria
D
Department of Biopathology and Diagnostic Imaging, University "Tor Vergata," Rome, Italy.
Carsetti
Rita
R
Tagliani
Angela
A
Rosado
Maria Manuela
MM
Borgiani
Paola
P
Novelli
Giuseppe
G
D'Amati
Giulia
G
Fumagalli
Lorenzo
L
Marino
Bruno
B
Businaro
Rita
R
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D000015:Abnormalities, Multiple / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D021461:Animals, Outbred Strains; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000517:prevention & control; D008715:Methionine / Q000494:pharmacology*; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced / Q000517:prevention & control; D011247:Pregnancy; D012176:Retinoids / Q000633:toxicity; D013723:Teratogens / Q000633:toxicity; D013950:Thymus Gland / Q000002:abnormalities / Q000187:drug effects
C423184:BMS 189453; D012176:Retinoids; D013723:Teratogens; D005492:Folic Acid; D008715:Methionine