{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:17:04Z","timestamp":1787894224042,"version":"build-2784847793"},"reference-count":63,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000306","name":"Tommy\u2019s","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000306","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04rre2k21","id-type":"ROR","asserted-by":"publisher"}]},{"name":"UK Research and Innovation Medical Research Council","award":["MR\/R023166\/1"],"award-info":[{"award-number":["MR\/R023166\/1"]}]},{"name":"UK Research and Innovation Medical Research Council","award":["MR\/Y003659\/1"],"award-info":[{"award-number":["MR\/Y003659\/1"]}]},{"award":["MR\/R023166\/1"],"award-info":[{"award-number":["MR\/R023166\/1"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MR\/Y003659\/1"],"award-info":[{"award-number":["MR\/Y003659\/1"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["097820\/Z\/11\/B"],"award-info":[{"award-number":["097820\/Z\/11\/B"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"award":["097820\/Z\/11\/B"],"award-info":[{"award-number":["097820\/Z\/11\/B"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Low maternal folate status is associated with placental dysfunction and adverse pregnancy outcomes; however, the mechanisms linking reduced folate availability to altered placental function remain incompletely understood. We investigated whether folate deficiency directly alters trophoblast function and microRNA (miRNA) expression, and whether folate-responsive miRNAs mediate these functional changes. Methods and Results: Human placental villous explants, BeWo choriocarcinoma cells, and primary human cytotrophoblasts were cultured under physiological or folate-deficient conditions to assess the direct impact of reduced folate availability. Although intracellular folate depletion was achieved in all models, only primary cytotrophoblasts reproduced functional changes consistent with those observed in placentas from folate-deficient pregnancies, exhibiting increased apoptosis and reduced system A amino acid transport. Of sixteen miRNAs previously associated with low maternal folate status, miR-30e-3p and miR-34b-5p were significantly reduced in trophoblast following folate depletion. Targeted inhibition of either miRNA did not alter apoptosis or system A activity. Pathway analysis of differentially expressed genes following miRNA inhibition identified processes related to cytoskeletal organisation, cell adhesion, PI3K\/AKT and MAPK signalling. Conclusions: Folate deficiency directly impairs trophoblast survival, amino acid transport, and miRNA expression in primary trophoblasts. Our findings demonstrate that only a subset of folate-associated placental miRNAs respond directly to folate depletion and that inhibition of individual folate-responsive miRNAs is insufficient to reproduce the trophoblast phenotype. These results indicate that trophoblast adaptation to reduced folate availability is likely mediated through coordinated nutrient-sensitive regulatory networks rather than individual miRNAs acting in isolation.<\/jats:p>","DOI":"10.3390\/nu18172785","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:11:15Z","timestamp":1787731875000},"page":"2785","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Folate Deficiency Alters microRNA Expression and Transcriptomic Networks in a Human Trophoblast Model"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0048-0465","authenticated-orcid":false,"given":"Bernadette C.","family":"Baker","sequence":"first","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3492-1882","authenticated-orcid":false,"given":"Georgia","family":"Fakonti","sequence":"additional","affiliation":[{"name":"Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail R.","family":"Byford","sequence":"additional","affiliation":[{"name":"Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona L.","family":"Mackie","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"},{"name":"Department of Obstetrics and Gynaecology, The Royal Wolverhampton NHS Trust, New Cross Hospital, Wolverhampton WV10 0QP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha C.","family":"Lean","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainslie","family":"Garrod","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Poffley","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2833-7847","authenticated-orcid":false,"given":"Leo A. H.","family":"Zeef","sequence":"additional","affiliation":[{"name":"Bioinformatics Core Facility, University of Manchester, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Greenwood","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-7845","authenticated-orcid":false,"given":"Alexander E. P.","family":"Heazell","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8871-0589","authenticated-orcid":false,"given":"Rebecca L.","family":"Jones","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3745-1337","authenticated-orcid":false,"given":"Karen","family":"Forbes","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"St Mary\u2019s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PL, UK"},{"name":"Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1636S","DOI":"10.3945\/jn.114.206599","article-title":"Biomarkers of Nutrition for Development-Folate Review","volume":"145","author":"Bailey","year":"2015","journal-title":"J. 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