Journal
MOLECULAR NUTRITION & FOOD RESEARCH
Volume 61, Issue 8, Pages -Publisher
WILEY
DOI: 10.1002/mnfr.201600646
Keywords
fetal growth; folate deficiency; gene expression; microRNA; placental dysfunction
Categories
Funding
- Wellcome Trust Value in People Scheme
- Manchester Biomedical Research Centre
- Tommy's, an Action Medical Research Endowment
- Greater Manchester Comprehensive Research Network
- Wellcome Trust
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Scope: 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. Methods and results: 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-mycmyelocytomatosis viral oncogene homolog (avian), and cyclin-dependent kinase 6) were reduced (p < 0.05) in placentas with lowmaternal folate status. Conclusion: 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.
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