{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T08:46:12Z","timestamp":1767861972671,"version":"3.49.0"},"reference-count":34,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2054\/18"],"award-info":[{"award-number":["2054\/18"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>We have previously shown that valproic acid (VPA) alters the expression of placental carriers of essential nutrients, including folates. Here, we exposed a placental cell line to VPA, its central nervous system\u2010active amide derivative <jats:italic>sec<\/jats:italic>\u2010butylpropylacetamide (SPD), and its individual stereoisomers to address the question of whether folate carrier expression can predict the teratogenicity of VPA\u2010related compounds. We additionally conducted a pilot analysis of folate transfer across placental cell monolayers to estimate the translation of altered carrier expression to carrier activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>BeWo cells were incubated for 2 or 5\u2009days with racemic SPD, its stereoisomers (2S,3S)\u2010SPD, (2R,3S)\u2010SPD, and (2R,3R)\u2010SPD (previously found to be teratogenic at high doses in mice; .5 or 1\u2009mmol\u00b7L<jats:sup>\u22121<\/jats:sup>), VPA (1\u2009mmol\u00b7L<jats:sup>\u22121<\/jats:sup>\u2009=\u2009144\u2009mg\/L), or their vehicle. Expression of <jats:italic>FOLR1<\/jats:italic> (folate receptor alpha), <jats:italic>SLC19A1<\/jats:italic> (reduced folate carrier), and <jats:italic>ABCG2<\/jats:italic> (breast cancer resistance protein) was measured by real\u2010time polymerase chain reaction. Folate transfer across monolayers of BeWo b30 cells exposed to .5\u2009mmol\u00b7L<jats:sup>\u22121<\/jats:sup> (2R,3R)\u2010SPD or 1\u2009mmol\u00b7L<jats:sup>\u22121<\/jats:sup> VPA was quantified by liquid chromatography\u2013mass spectrometry analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At 1\u2009mmol\u00b7L<jats:sup>\u22121<\/jats:sup>, racemic SPD, (2S,3S)\u2010SPD, and (2R,3S)\u2010SPD reduced by twofold <jats:italic>SLC19A1<\/jats:italic> expression, similar to VPA (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001). SPD and its enantiomers induced <jats:italic>FOLR1<\/jats:italic> expression by up to twofold (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.05) or did not significantly affect it, and racemic SPD increased <jats:italic>ABCG2<\/jats:italic> expression (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.01). After 5\u2009days, VPA, but not (2R,3R)\u2010SPD, enhanced both maternal\u2010to\u2010fetal and fetal\u2010to\u2010maternal folate transfer (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.01), resulting in a 15% increase in net transfer in the fetal direction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Altered expression of the studied carriers could not explain the folate transfer kinetics across placental cell monolayers. Future studies should assess the effects of VPA and other antiseizure medications on transplacental transfer of essential compounds <jats:italic>in\u00a0vivo<\/jats:italic> and the ability to predict it by functional <jats:italic>in\u00a0vitro<\/jats:italic> assays.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18470","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T05:03:58Z","timestamp":1749013438000},"page":"3544-3554","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Folate transfer in placental choriocarcinoma cells treated with valproic acid: Insights gained through comparisons with the amide derivative <i>sec<\/i>\u2010butylpropylacetamide and its individual stereoisomers"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5909-5235","authenticated-orcid":false,"given":"Natalia","family":"Erenburg","sequence":"first","affiliation":[{"name":"Institute for Drug Research School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4939-7171","authenticated-orcid":false,"given":"Roa\u2019a","family":"Hamed","sequence":"additional","affiliation":[{"name":"Institute for Drug Research School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2598-0119","authenticated-orcid":false,"given":"Alina","family":"Nemirovski","sequence":"additional","affiliation":[{"name":"Institute for Drug Research School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-4171","authenticated-orcid":false,"given":"Meir","family":"Bialer","sequence":"additional","affiliation":[{"name":"Institute for Drug Research School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem  Jerusalem Israel"},{"name":"David R. Bloom Center for Pharmacy Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1275-6094","authenticated-orcid":false,"given":"Sara","family":"Eyal","sequence":"additional","affiliation":[{"name":"Institute for Drug Research School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem  Jerusalem Israel"},{"name":"David R. 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