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Methylenetetrahydrofolate reductase deficiency and low dietary folate increase embryonic delay and placental abnormalities in mice

Authors

  • Laura Pickell,

    1. Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
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  • Deqiang Li,

    1. Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    2. Department of Pediatrics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    Current affiliation:
    1. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202
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  • Katharine Brown,

    1. Department of Biology, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    Current affiliation:
    1. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720
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  • Leonie G. Mikael,

    1. Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    2. Department of Pediatrics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
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  • Xiao-Ling Wang,

    1. Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    2. Department of Pediatrics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
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  • Qing Wu,

    1. Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    2. Department of Pediatrics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
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  • Li Luo,

    1. Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    2. Department of Pediatrics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
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  • Loydie Jerome-Majewska,

    1. Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    2. Department of Pediatrics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
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  • Rima Rozen

    Corresponding author
    1. Department of Human Genetics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    2. Department of Pediatrics, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    3. Department of Biology, McGill University and Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
    • McGill-Montreal Children's Hospital Research Institute, 4060 Ste Catherine Street West, Room 242, Montreal, PQ, Canada H3Z 2Z3
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  • Paper presented at the 3rd Canadian Developmental Biology Conference, 6–9 April 2006, Mont-Tremblant, Quebec, Canada; and at the FASEB Folic Acid, Vitamin B12 and One-Carbon Metabolism Conference, 5–10 August 2006, Indian Wells, CA.

Abstract

BACKGROUND: Despite extensive research on mild methylenetetrahydrofolate reductase (MTHFR) deficiency and low dietary folate in different disorders, the association of these metabolic disturbances with a variety of congenital defects and pregnancy complications remains controversial. In this study we investigated the effects of MTHFR and dietary folate deficiency at 10.5 days post coitum (dpc) in our mouse model of mild MTHFR deficiency. METHODS:Mthfr +/+ and +/− female mice were fed a control or folic acid–deficient diet for 6 weeks, then mated with Mthfr +/− males. At 10.5 dpc, embryos were examined and placentae were collected for histologic evaluation. RESULTS: Maternal MTHFR and folate deficiencies resulted in increased developmental delays and smaller embryos. We also observed a low frequency of a variety of embryonic defects in the experimental groups, such as neural tube, heart looping, and turning defects; these results mimic the low incidence and multifactorial nature of these anomalies in humans. Folate-deficient mice also had increased embryonic losses and severe placental defects, including placental abruption and disturbed patterning of placental layers. Folate-deficient placentae had decreased ApoA-I expression, and there was a trend toward a negative correlation between ApoA-I expression with maternal homocysteine concentrations. CONCLUSIONS: Our study provides biological evidence linking maternal MTHFR and dietary folate deficiencies to adverse pregnancy outcomes in mice. It underscores the importance of folate not only in reducing the incidence of early embryonic defects, but also in the prevention of developmental delays and placental abnormalities that may increase susceptibility to other defects and to reproductive complications. Birth Defects Research (Part A), 2009. © 2009 Wiley-Liss, Inc.

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