title: Folic acid and methionine in the prevention of teratogen-induced congenital defects in mice.
abstract: 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.
authors.affiliation: Department of Biopathology and Diagnostic Imaging, University "Tor Vergata," Rome, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Cipollone
authors.forename: Rita
authors.initials: R
authors.lastname: Carsetti
authors.forename: Angela
authors.initials: A
authors.lastname: Tagliani
authors.forename: Maria Manuela
authors.initials: MM
authors.lastname: Rosado
authors.forename: Paola
authors.initials: P
authors.lastname: Borgiani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Giulia
authors.initials: G
authors.lastname: D'Amati
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Bruno
authors.initials: B
authors.lastname: Marino
authors.forename: Rita
authors.initials: R
authors.lastname: Businaro
mesh_terms: 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
chemical_list: C423184:BMS 189453; D012176:Retinoids; D013723:Teratogens; D005492:Folic Acid; D008715:Methionine