{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:09:41Z","timestamp":1760238581467,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Croatian Ministry of Science, Education and Sport","award":["108-1080399-0335","1.2.1.17","1101310 BM1.22","KK.01.1.1.01.0008"],"award-info":[{"award-number":["108-1080399-0335","1.2.1.17","1101310 BM1.22","KK.01.1.1.01.0008"]}]},{"name":"Scientific Center of Excellence for Reproductive and Regenerative Medicine, Republic of Croatia","award":["108-1080399-0335","1.2.1.17","1101310 BM1.22","KK.01.1.1.01.0008"],"award-info":[{"award-number":["108-1080399-0335","1.2.1.17","1101310 BM1.22","KK.01.1.1.01.0008"]}]},{"name":"European Union through the European Regional Development Fund","award":["108-1080399-0335","1.2.1.17","1101310 BM1.22","KK.01.1.1.01.0008"],"award-info":[{"award-number":["108-1080399-0335","1.2.1.17","1101310 BM1.22","KK.01.1.1.01.0008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The teratogenic activity of valproate (VPA), an antiepileptic and an inhibitor of histone deacetylase (HDACi), is dose-dependent in humans. Previous results showed that VPA impairs in vitro development and neural differentiation of the gastrulating embryo proper. We aimed to investigate the impact of a lower VPA dose in vitro and whether this effect is retained in transplants in vivo. Rat embryos proper (E9.5) and ectoplacental cones were separately cultivated at the air-liquid interface with or without 1 mM VPA. Embryos were additionally cultivated with HDACi Trichostatin A (TSA), while some cultures were syngeneically transplanted under the kidney capsule for 14 days. Embryos were subjected to routine histology, immunohistochemistry, Western blotting and pyrosequencing. The overall growth of VPA-treated embryos in vitro was significantly impaired. However, no differences in the apoptosis or proliferation index were found. Incidence of the neural tissue was lower in VPA-treated embryos than in controls. TSA also impaired growth and neural differentiation in vitro. VPA-treated embryos and their subsequent transplants expressed a marker of undifferentiated neural cells compared to controls where neural differentiation markers were expressed. VPA increased the acetylation of histones. Our results point to gastrulation as a sensitive period for neurodevelopmental impairment caused by VPA.<\/jats:p>","DOI":"10.3390\/ijms23168861","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T02:42:53Z","timestamp":1660099373000},"page":"8861","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Valproate Targets Mammalian Gastrulation Impairing Neural Tissue Differentiation and Development of the Placental Source In Vitro"],"prefix":"10.3390","volume":"23","author":[{"given":"Ana","family":"Katu\u0161i\u0107-Bojanac","sequence":"first","affiliation":[{"name":"Scientific Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milvija","family":"Plazibat","sequence":"additional","affiliation":[{"name":"Pediatrics Department, General Hospital Zabok, 49210 Zabok, Croatia"},{"name":"Dental Medicine and Health, School of Medicine, University of Osijek, 31000 Osijek, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2143-6968","authenticated-orcid":false,"given":"Marta","family":"Himelreich-Peri\u0107","sequence":"additional","affiliation":[{"name":"Scientific Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarina","family":"Eck-Rakovi\u0107","sequence":"additional","affiliation":[{"name":"Anesthesiology and Intensive Care Department, Karolinska University Hospital, 14152 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8991-3927","authenticated-orcid":false,"given":"Jure","family":"Krasi\u0107","sequence":"additional","affiliation":[{"name":"Scientific Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2584-6654","authenticated-orcid":false,"given":"Nino","family":"Sin\u010di\u0107","sequence":"additional","affiliation":[{"name":"Scientific Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordana","family":"Juri\u0107-Leki\u0107","sequence":"additional","affiliation":[{"name":"Scientific Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Histology and Embryology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1528-5462","authenticated-orcid":false,"given":"Davor","family":"Je\u017eek","sequence":"additional","affiliation":[{"name":"Scientific Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Histology and Embryology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5538-4692","authenticated-orcid":false,"given":"Floriana","family":"Buli\u0107-Jaku\u0161","sequence":"additional","affiliation":[{"name":"Scientific Centre of Excellence for Reproductive and Regenerative Medicine, Unit for Biomedical Investigation of Reproduction and Development, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13023-019-1064-y","article-title":"Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability","volume":"14","author":"Bromley","year":"2019","journal-title":"Orphanet J. 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