{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:10:56Z","timestamp":1787026256026,"version":"build-2736575974"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:00:00Z","timestamp":1741737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD100729-01S1 R01HD110400"],"award-info":[{"award-number":["R01HD100729-01S1 R01HD110400"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Glutamate dysregulation leading to neuronal excitotoxicity and neuroinflammation are associated with neurological disorders, specifically autism spectrum disorders (ASD) in preterm neonates. The lack of physiologically relevant\n                      <jats:italic>in vitro<\/jats:italic>\n                      models has limited mechanistic understanding of glutamate dysregulation and neuroinflammation during pregnancy. This study evaluated the effect of environmental pollutant and flame retardant, Polybrominated Diphenyl Ethers (PBDE) 99 and 47, on cell viability, glutamate dysregulation, and neuroinflammation using a microphysiologic system (MPS) of human fetal blood-brain-barrier organ on a chip (FB-OOC).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The FB-OOC is composed of 3-cell culture chambers, connected by microchannels, containing 1) human brain microvessel endothelial cells (HBMEC), 2) human vascular pericytes (HBVP), and 3) a triculture of neurons, astrocytes, and microglia in a 5:2:1 ratio, respectively. To assess the effect of toxicants on glutamate dysregulation and neuroinflammation, control (standard media) endothelial cells were exposed to PBDE 99 and 47 (150 ng\/mL). To mimic the passage of PBDE through the placenta, endothelial cells in FB-OOC were exposed to conditioned PDBE media (1:1) derived from a placenta-OOC. In parallel, triculture cells were directly treated in a 96-well plate. Dextran propagation over 72 h confirmed FB barrier function. The activation status of microglia was determined using immunocytochemistry for CD11 b and Iba1, respectively. Cell morphology (microscopy), cell cytotoxicity (Lactate Dehydrogenase and glutamate assays), and cytokines (multiplex assay) were measured.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Physiologic FB-OOCs were characterized by 1) viable cell cultures expressing standard cell morphologies and cell-specific markers, 2) barrier formation confirmed by decreased dextran propagation over 72 h, and 3) baseline glutamate and pro-inflammatory cytokine production. On-chip PBDE and placenta-derived metabolites of PBDE treatment in the endothelial chamber induced cell cytotoxicity and significant upregulation of glutamate in the triculture but did not induce neuroinflammation nor microglia activation compared to the controls. Conversely, 2D triculture experiments showed direct PBDE treatment-induced significant neuroinflammation (TNF-\u03b1, GM-CSF, IL-8) compared to PBDE placenta-derived metabolites or controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study established an FB model that recreated intercellular interactions. We report PBDE-induced glutamate dysregulation, often associated with the development of ASD, independent of neuroinflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2025.1543710","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T03:58:48Z","timestamp":1741751928000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["The effect of Polybrominated diphenyl ethers at the fetal blood-brain-barrier: evaluation using a microphysiological system"],"prefix":"10.3389","volume":"13","author":[{"given":"Sourabh","family":"Sharma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Vidal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souvik","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arum","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramkumar","family":"Menon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren S.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e113799","DOI":"10.1371\/journal.pone.0113799","article-title":"HMGB1 promotes a p38MAPK associated non-infectious inflammatory response pathway in human fetal membranes","volume":"9","author":"Bredeson","year":"2014","journal-title":"PLoS ONE"},{"key":"B2","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1515\/jpm-2014-0176","article-title":"The neuroprotective effect of magnesium sulfate in preterm fetal mice","volume":"43","author":"Cho","year":"2015","journal-title":"J. Perinat. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.4103\/1673-5374.241441","article-title":"Magnesium sulfate and fetal neuroprotection: overview of clinical evidence","volume":"13","author":"Chollat","year":"2018","journal-title":"Neural Regen. Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"247","DOI":"10.3389\/fneur.2018.00247","article-title":"Fetal neuroprotection by magnesium sulfate: from translational research to clinical application","volume":"9","author":"Chollat","year":"2018","journal-title":"Front. Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/j.neuro.2007.08.007","article-title":"Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants","volume":"28","author":"Costa","year":"2007","journal-title":"Neurotoxicology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e0028","DOI":"10.5041\/rmmj.10305","article-title":"Maternal inflammation, fetal brain implications and suggested neuroprotection: a summary of 10 Years of research in animal models","volume":"8","author":"Ginsberg","year":"2017","journal-title":"Rambam Maimonides Med. J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"6041","DOI":"10.1523\/jneurosci.2534-15.2016","article-title":"Maternal inflammation disrupts fetal neurodevelopment via increased placental output of serotonin to the fetal brain","volume":"36","author":"Goeden","year":"2016","journal-title":"J. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41398-021-01198-w","article-title":"Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review","volume":"11","author":"Han","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"B9","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1289\/ehp.0901340","article-title":"Prenatal exposure to PBDEs and neurodevelopment","volume":"118","author":"Herbstman","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"B10","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/s41576-022-00466-9","article-title":"Human organs-on-chips for disease modelling, drug development and personalized medicine","volume":"23","author":"Ingber","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.brainres.2010.11.057","article-title":"Neuroprotective effects of magnesium-sulfate on ischemic injury mediated by modulating the release of glutamate and reduced of hyperreperfusion","volume":"1371","author":"Kang","year":"2011","journal-title":"Brain Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1289\/ehp.1408504","article-title":"Developmental exposure to a commercial PBDE mixture: effects on protein networks in the cerebellum and hippocampus of rats","volume":"123","author":"Kodavanti","year":"2015","journal-title":"Environ. Health Perspect."},{"key":"B13","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.abb.2006.03.031","article-title":"Magnesium and the inflammatory response: potential physiopathological implications","volume":"458","author":"Mazur","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"B14","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1097\/AOG.0b013e3182a265ab","article-title":"Antecedents of cerebral palsy and perinatal death in term and late preterm singletons","volume":"122","author":"McIntyre","year":"2013","journal-title":"Obstet. Gynecol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"370","DOI":"10.5483\/BMBRep.2022.55.8.174","article-title":"Epithelial to mesenchymal transition (EMT) of feto-maternal reproductive tissues generates inflammation: a detrimental factor for preterm birth","volume":"8","author":"Menon","year":"2022","journal-title":"BMB Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1740","DOI":"10.1016\/j.ajpath.2014.02.011","article-title":"Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro","volume":"184","author":"Menon","year":"2014","journal-title":"Am. J. Pathology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e83416","DOI":"10.1371\/journal.pone.0083416","article-title":"Senescence of primary amniotic cells via oxidative DNA damage","volume":"8","author":"Menon","year":"2013","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.toxlet.2020.02.014","article-title":"Activities of metabolizing enzymes in human placenta","volume":"326","author":"Mohammed","year":"2020","journal-title":"Toxicol. Lett."},{"key":"B19","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s00204-022-03234-0","article-title":"Implementing organ-on-chip in a next-generation risk assessment of chemicals: a review","volume":"96","author":"Nitsche","year":"2022","journal-title":"Arch. Toxicol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/307462a0","article-title":"Magnesium gates glutamate-activated channels in mouse central neurones","volume":"307","author":"Nowak","year":"1984","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"715","DOI":"10.3389\/fphys.2020.00715","article-title":"Organ-on-chip technology: the future of feto-maternal interface research?","volume":"11","author":"Richardson","year":"2020","journal-title":"Front. Physiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e23000","DOI":"10.1096\/fj.202300531R","article-title":"Development of oxidative stress-associated disease models using feto-maternal interface organ-on-a-chip","volume":"37","author":"Richardson","year":"2023","journal-title":"Faseb J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4574","DOI":"10.1039\/d2lc00691j","article-title":"Testing of drugs using human feto-maternal interface organ-on-chips provide insights into pharmacokinetics and efficacy","volume":"22","author":"Richardson","year":"2022","journal-title":"Lab. Chip"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3049","DOI":"10.1016\/j.apsb.2022.02.002","article-title":"Why 90% of clinical drug development fails and how to improve it?","volume":"12","author":"Sun","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"B25","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/s0006-8993(02)03395-4","article-title":"Magnesium pre-treatment reduces neuronal apoptosis in newborn rats in hypoxia-ischemia","volume":"955","author":"T\u00fcrkyilmaz","year":"2002","journal-title":"Brain Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1039\/d3lc00998j","article-title":"Endocrine-disrupting compounds and their impact on human placental function: evidence from placenta organ-on-chip studies","volume":"24","author":"Vidal","year":"2024","journal-title":"Lab. Chip"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1016\/j.cell.2015.10.067","article-title":"Establishment and dysfunction of the blood-brain barrier","volume":"163","author":"Zhao","year":"2015","journal-title":"Cell"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1543710\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T03:58:50Z","timestamp":1741751930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1543710\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,12]]},"references-count":27,"alternative-id":["10.3389\/fcell.2025.1543710"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2025.1543710","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,12]]},"article-number":"1543710"}}