title: Maternal folic acid supplementation modulates DNA methylation and gene expression in the rat offspring in a gestation period-dependent and organ-specific manner.
abstract: Maternal folic acid supplementation can alter DNA methylation and gene expression in the developing fetus, which may confer disease susceptibility later in life. We determined which gestation period and organ were most sensitive to the modifying effect of folic acid supplementation during pregnancy on DNA methylation and gene expression in the offspring. Pregnant rats were randomized to a control diet throughout pregnancy; folic acid supplementation at 2.5× the control during the 1st, 2nd or 3rd week of gestation only; or folic acid supplementation throughout pregnancy. The brain, liver, kidney and colon from newborn pups were analyzed for folate concentrations, global DNA methylation and gene expression of the Igf2, Er-α, Gr, Ppar-α and Ppar-γ genes. Folic acid supplementation during the 2nd or 3rd week gestation or throughout pregnancy significantly increased brain folate concentrations (P<.001), while only folic acid supplementation throughout pregnancy significantly increased liver folate concentrations (P=.005), in newborn pups. Brain global DNA methylation incrementally decreased from early to late gestational folic acid supplementation and was the lowest with folic acid supplementation throughout pregnancy (P=.026). Folic acid supplementation in late gestation or throughout pregnancy significantly decreased Er-α, Gr and Ppar-α gene expression in the liver (P<.05). The kidney and colon were resistant to the effect of folic acid supplementation. Maternal folic acid supplementation affects tissue folate concentrations, DNA methylation and gene expression in the offspring in a gestation-period-dependent and organ-specific manner.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5G 2C4; Keenan Research Center for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1C6.
authors.forename: Anna
authors.initials: A
authors.lastname: Ly
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 3E2; Keenan Research Center for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1C6.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ishiguro
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 3E2; Keenan Research Center for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1C6.
authors.forename: Denise
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5G 2C4; Keenan Research Center for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1C6.
authors.forename: David
authors.initials: D
authors.lastname: Im
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 3E2; Keenan Research Center for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1C6.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5G 2C4; Keenan Research Center for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1C6.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Sohn
authors.affiliation: Freelance Statistics Consultant, Toronto, Ontario, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Croxford
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5G 2C4; Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 3E2; Division of Gastroenterology, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1W8; Keenan Research Center for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1C6. Electronic address: youngin.kim@utoronto.ca.
authors.forename: Young-In
authors.initials: YI
authors.lastname: Kim
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D019175:DNA Methylation; D019587:Dietary Supplements; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D047109:Fetal Development; D005492:Folic Acid / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D018507:Gene Expression Regulation, Developmental; D007335:Insulin-Like Growth Factor II / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D039382:Maternal Nutritional Physiological Phenomena; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009436:Neural Tube Defects / Q000097:blood / Q000378:metabolism / Q000517:prevention & control; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; C000599313:Igf2 protein, rat; D009419:Nerve Tissue Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D011965:Receptors, Glucocorticoid; D007335:Insulin-Like Growth Factor II; D005492:Folic Acid
keywords: DNA methylation; Folate; Folic acid; Gene expression; Maternal nutrition