title: Placental dysfunction is associated with altered microRNA expression in pregnant women with low folate status.
abstract: Low maternal folate status during pregnancy increases the risk of delivering small for gestational age (SGA) infants, but the mechanistic link between maternal folate status, SGA, and placental dysfunction is unknown. microRNAs (miRNAs) are altered in pregnancy pathologies and by folate in other systems. We hypothesized that low maternal folate status causes placental dysfunction, mediated by altered miRNA expression.
  
  
  
  A prospective observational study recruited pregnant adolescents and assessed third trimester folate status and placental function. miRNA array, QPCR, and bioinformatics identified placental miRNAs and target genes. Low maternal folate status is associated with higher incidence of SGA infants (28% versus 13%, p < 0.05) and placental dysfunction, including elevated trophoblast proliferation and apoptosis (p < 0.001), reduced amino acid transport (p < 0.01), and altered placental hormones (pregnancy-associated plasma protein A, progesterone, and human placental lactogen). miR-222-3p, miR-141-3p, and miR-34b-5p were upregulated by low folate status (p < 0.05). Bioinformatics predicted a gene network regulating cell turnover. Quantitative PCR demonstrated that key genes in this network (zinc finger E-box binding homeobox 2, v-myc myelocytomatosis viral oncogene homolog (avian), and cyclin-dependent kinase 6) were reduced (p < 0.05) in placentas with low maternal folate status.
  
  
  
  This study supports that placental dysfunction contributes to impaired fetal growth in women with low folate status and suggests altered placental expression of folate-sensitive miRNAs and target genes as a mechanistic link.
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK.
authors.forename: Bernadette C
authors.initials: BC
authors.lastname: Baker
authors.affiliation: Centre of Women's and Newborn's Health & Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Mackie
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK.
authors.forename: Samantha C
authors.initials: SC
authors.lastname: Lean
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Greenwood
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK.
authors.forename: Alexander E P
authors.initials: AEP
authors.lastname: Heazell
authors.affiliation: Division of Reproduction and Early Development, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Forbes
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D005260:Female; D005494:Folic Acid Deficiency / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D039382:Maternal Nutritional Physiological Phenomena / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics*; D010920:Placenta / Q000502:physiology / Q000503:physiopathology*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011263:Pregnancy Trimester, Third
chemical_list: D035683:MicroRNAs; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6
keywords: fetal growth; folate deficiency; gene expression; microRNA; placental dysfunction