{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T07:02:25Z","timestamp":1779951745481,"version":"3.53.1"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>High folic acid (FA; synthetic folate) intake is associated with increased risk of gestational diabetes mellitus (GDM), but the underlying mechanisms remain unknown. As the placenta is a key regulator of maternal glucose homeostasis, it represents a plausible target for FA-mediated effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To determine how increased FA exposure modulates trophoblast function, placental folate receptor\/transporter expression, and secretion of hormones that maintain maternal euglycaemia, providing a potential mechanism linking excess FA to GDM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Trophoblast cells (HTR-8\/SVneo, JEG-3 and BeWo) and early- to mid-gestation human placental explants (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f66) were cultured across a FA dose range representing acute physiological deficiency to excess (0\u202fnM, 10\u202fnM, 40\u202fnM; 200\u202fnM; 2000\u202fnM). Trophoblast proliferation, migration and invasion were assessed in real time; placental explant proliferation and apoptosis by immunohistochemistry; folate receptor\/transporter abundance by immunoblotting; and hormone secretions by enzyme-linked immunosorbent assays (ELISA). Statistical analyses were performed relative to 40\u202fnM FA (physiological norm).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      FA exposure produced a U-shaped response in trophoblast proliferation, migration, invasion, placental folate receptor (FOLR1) expression and human placental lactogen (hPL) secretion, where both acute deficiency and excess induced similar results relative to physiological norm. Notably, only excess FA significantly increased placental growth hormone (GH2) secretion (\u219126%,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.03), a hormone that promotes maternal insulin resistance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Human placental function and folate transport pathways are sensitive to FA exposure under conditions of deficiency and excess. Because folate deficiency is known to compromise pregnancy health, these findings suggest that excessive FA exposure may also disrupt placental function and perturb maternal and infant outcomes. The selective increase in GH2 under FA excess offers a plausible mechanism linking high FA exposure to increased GDM risk. Given widespread FA food fortification and increased use of high-dose prenatal supplements, the potential impact of FA excess on overall pregnancy metabolic health warrants urgent consideration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1813142","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:16:04Z","timestamp":1779948964000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Excess folic acid disrupts placental endocrine function in vitro: a potential mechanism linking elevated folic acid exposure with gestational diabetes mellitus"],"prefix":"10.3389","volume":"13","author":[{"given":"Jessica M.","family":"Williamson","sequence":"first","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya L.","family":"Arthurs","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie D.","family":"Smith","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalem","family":"Leemaqz","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Phillips-Hughes","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan","family":"McCullough","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire T.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Jankovic-Karasoulos","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University","place":["Adelaide, SA, Australia"]},{"name":"Robinson Research Institute, School of Biomedicine, The University of Adelaide, North Terrace","place":["Adelaide, SA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"ref1","volume-title":"System taMNI","year":"2015"},{"key":"ref2","first-page":"420","article-title":"Pregnancy myths and practical tips","volume":"102","author":"Caro","year":"2020","journal-title":"Am Fam Physician"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1002\/bdra.20691","article-title":"A case-control study of the effects of pregnancy planning on neural tube defects and 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