Folic acid and methionine in the prevention of teratogen-induced congenital defects in mice

Daria Cipollone, Rita Carsetti, Angela Tagliani, Maria Manuela Rosado, Paola Borgiani, Giuseppe Novelli, Giulia D'Amati, Lorenzo Fumagalli, Bruno Marino, Rita Businaro

Research output: Contribution to journalArticle

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Abstract

Introduction: 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. Materials and methods: A total of 132 outbred CD1 litters were studied. Pregnant mice were divided into four experimental groups, and an oral supplementation of H2O 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.

Original languageEnglish
Pages (from-to)100-109
Number of pages10
JournalCardiovascular Pathology
Volume18
Issue number2
DOIs
Publication statusPublished - Mar 2009

Fingerprint

Teratogens
Folic Acid
Methionine
Thymus Gland
Neural Tube Defects
Heart Diseases
Fetus
Pregnancy
Incidence
Tretinoin
Histology
Embryonic Structures
Central Nervous System
Cell Proliferation
Pathology

Keywords

  • BMS-189453
  • Congenital anomalies
  • Folic acid
  • Methionine
  • Retinoic acid

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pathology and Forensic Medicine

Cite this

Cipollone, D., Carsetti, R., Tagliani, A., Rosado, M. M., Borgiani, P., Novelli, G., ... Businaro, R. (2009). Folic acid and methionine in the prevention of teratogen-induced congenital defects in mice. Cardiovascular Pathology, 18(2), 100-109. https://doi.org/10.1016/j.carpath.2008.02.007

Folic acid and methionine in the prevention of teratogen-induced congenital defects in mice. / Cipollone, Daria; Carsetti, Rita; Tagliani, Angela; Rosado, Maria Manuela; Borgiani, Paola; Novelli, Giuseppe; D'Amati, Giulia; Fumagalli, Lorenzo; Marino, Bruno; Businaro, Rita.

In: Cardiovascular Pathology, Vol. 18, No. 2, 03.2009, p. 100-109.

Research output: Contribution to journalArticle

Cipollone, D, Carsetti, R, Tagliani, A, Rosado, MM, Borgiani, P, Novelli, G, D'Amati, G, Fumagalli, L, Marino, B & Businaro, R 2009, 'Folic acid and methionine in the prevention of teratogen-induced congenital defects in mice', Cardiovascular Pathology, vol. 18, no. 2, pp. 100-109. https://doi.org/10.1016/j.carpath.2008.02.007
Cipollone, Daria ; Carsetti, Rita ; Tagliani, Angela ; Rosado, Maria Manuela ; Borgiani, Paola ; Novelli, Giuseppe ; D'Amati, Giulia ; Fumagalli, Lorenzo ; Marino, Bruno ; Businaro, Rita. / Folic acid and methionine in the prevention of teratogen-induced congenital defects in mice. In: Cardiovascular Pathology. 2009 ; Vol. 18, No. 2. pp. 100-109.
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abstract = "Introduction: 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. Materials and methods: A total of 132 outbred CD1 litters were studied. Pregnant mice were divided into four experimental groups, and an oral supplementation of H2O 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.",
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