title: Effect of folic acid on human trophoblast health and function in vitro.
abstract: BACKGROUND
  The combined intake of folic acid (FA) from prenatal multivitamin supplements and fortified foods can result in FA intake values that exceed the tolerable upper intake level (UL). It is unclear what impact FA intake above the UL may have on the feto-placental unit. Our objective was to determine the effects of increasing concentrations of FA on trophoblast health and function in vitro.
  
  
  METHODS
  Two human placental cell lines [HTR-8/SVneo (n = 5 experiments) and BeWo (n = 5 experiments)] and human placenta tissue explants (n = 6 experiments) were exposed to increasing concentrations of FA (2-2000 ng/mL) for 48-h. Intracellular total folate concentration, trophoblast proliferation, viability, apoptosis, placenta cell invasion and β-hCG hormone release were assessed.
  
  
  RESULTS
  Exposure to increasing FA concentrations resulted in higher intracellular total folate in placental cell lines and tissue explants (p < 0.05); yet, only minimal effects of excess folic acid were observed on the primary indicators of placental health and function studied. Specifically, treatment with excess folic acid (2000 ng/mL) resulted in reduced cellular viability in the villous trophoblast BeWo cell line and increased rates of proliferation in the HT8-8/SVneo extravillous trophoblast cell line (p < 0.05). Further, deficient concentrations of folic acid (2 ng/mL) resulted in decreased cell viability and invasive capabilities of the HTR-8/SVneo extravillous trophoblast cell line (p < 0.05).
  
  
  CONCLUSIONS
  Our results demonstrate that placental health and function may be compromised in conditions of folate deficiency, and not necessarily in conditions of excess FA. This finding supports the recommendation of prenatal folic acid supplementation in the North American population. Further work aimed at clarifying the therapeutic window of FA intake in the obstetrical population is warranted.
authors.affiliation: Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada. Electronic address: tasfia@live.com.
authors.forename: Tasfia
authors.initials: T
authors.lastname: Ahmed
authors.affiliation: Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada. Electronic address: ifell101@uottawa.ca.
authors.forename: Ilan
authors.initials: I
authors.lastname: Fellus
authors.affiliation: Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada. Electronic address: jeremiah.gaudet@uottawa.ca.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Gaudet
authors.affiliation: Nutrition Research Division, Health Canada, 251 Sir Frederick Banting Driveway, AL2203E, Ottawa, K1A 0K9, Canada. Electronic address: amanda.macfarlane@hc-sc.gc.ca.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: MacFarlane
authors.affiliation: School of Nutrition Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada. Electronic address: bfontain@uottawa.ca.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Fontaine-Bisson
authors.affiliation: Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, K1N 6N5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, Canada; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, K1Y 4E9, Canada. Electronic address: Shannon.bainbridge@uottawa.ca.
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Bainbridge
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D006801:Humans; D010929:Placentation / Q000187:drug effects; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
chemical_list: D018997:Chorionic Gonadotropin, beta Subunit, Human; D005492:Folic Acid
keywords: Apoptosis; Folic acid; Invasion; Placenta; Proliferation; Trophoblast