Embryonic development of folate binding protein-1 (Folbp1) knockout mice: Effects of the chemical form, dose, and timing of maternal folate supplementation

Authors

  • Ofer Spiegelstein,

    1. Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
    Current affiliation:
    1. Global Innovative R&D, Teva Pharmaceutical Industries, P.O. Box 8077, Netanya, Israel 42504
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  • Laura E. Mitchell,

    1. Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
    2. Center for Environment and Rural Health, Texas A&M University, College Station, Texas
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  • Michelle Y. Merriweather,

    1. Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
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  • Ned J. Wicker,

    1. Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
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  • Qiang Zhang,

    1. Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
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  • Edward J. Lammer,

    1. Division of Medical Genetics, Children's Hospital Oakland Research Institute, Oakland, California
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  • Richard H. Finnell

    Corresponding author
    1. Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
    2. Center for Environment and Rural Health, Texas A&M University, College Station, Texas
    • Institute of Biosciences and Technology, Center for Environmental and Genetic Medicine, Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd., Houston, Texas 77030
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Abstract

Inactivation of folate binding protein-1 (Folbp1) adversely impacts murine embryonic development, as nullizygous embryos (Folbp1-/-) die in utero. Administration of folinic acid (N5-formyl-tetrahydrofolate) to Folbp1-deficient dams before and throughout gestation rescues the majority of embryos from premature death; however, a portion of surviving embryos develop structural malformations, including neural tube defects. We examined whether maternal supplementation with L-N5-methyl-tetrahydrofolate (L-5M-THF) has superior protective effects on embryonic development of Folbp1-/- fetuses compared with L-N5-formyl-tetrahydrofolate (L-5F-THF). We also examined the critical period during gestation when folate supplementation is most beneficial to the developing Folbp1-/- embryos. Folbp1-/- pups presented with a range of malformations involving the neural tube, craniofacies, eyes, and abdominal wall. The frequencies of these malformations decreased with increasing folate dose, regardless of the form used. There was no additional benefit provided by L-5M-THF compared with L-5F-THF. Despite rescuing the phenotype in Folbp1-/- embryos, no significant elevation of Folbp1-/- maternal folate levels was observed with supplementation. Developmental Dynamics 231:221–231, 2004. © 2004 Wiley-Liss, Inc.

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