{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:50:59Z","timestamp":1765878659650,"version":"3.48.0"},"reference-count":61,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neural tube defects (NTDs) are developmental malformations affecting 1300 newborns in the United States each year. Valproic acid (VA), a drug to treat seizures and mood disorders, can cause NTDs. Apoptosis is increased in the developing neural tubes (NTs) of embryos exposed to VA thereby identifying a possible mechanism for NTD formation. Numerous studies show that maternal immune stimulation (MIS) in the periconceptual period reduces birth defects including VA\u2010induced NTDs. It is hypothesized that immunoregulatory cytokines may normalize the dysregulated apoptosis. This study examined maternal cytokine production and embryonic apoptotic gene expression following prebreeding stimulation with interferon\u2010\u03b3 (IFN\u2010\u03b3) and gestational VA exposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Concentrations of granulocyte monocyte colony stimulating factor (GM\u2010CSF), IFN\u2010\u03b3, interleukin\u20106 (IL\u20106), interleukin\u201010 (IL\u201010), and tumor necrosis factor\u2010\u03b1 (TNF\u03b1) were determined in VA\u2009+\u2009IFN\u2010\u03b3\u2010treated pregnant mice. Expression of pro\u2010apoptotic and antiapoptotic pathway genes was determined in VA and VA\u2009+\u2009IFN\u2010\u03b3 exposed embryos.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NTDs decreased from 45.3% to 21.2% per litter with MIS. MIS altered the profiles of GM\u2010CSF and IFN\u2010\u03b3 throughout pregnancy and altered the profiles of GM\u2010CSF, IL\u20106, and IL\u201010 over the time of NT closure. Pro\u2010apoptotic genes were upregulated, and anti\u2010apoptotic genes were downregulated in VA\u2010exposed embryonic heads with open or closed NTs. Gene expression was normalized with VA\u2009+\u2009IFN\u2010\u03b3 in embryonic heads with closed NTs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identified GM\u2010CSF and IFN\u2010\u03b3 as possible effectors of MIS and specifically GM\u2010CSF, IL\u20106, and IL\u201010 in preventing NTDs. MIS normalized apoptotic gene expression in embryos with closed NTs identifying a possible molecular mechanism for the prevention of VA\u2010induced NTDs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bdr2.2541","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T07:01:09Z","timestamp":1762412469000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Maternal Immune Stimulation With Interferon\u2010Gamma Limits Embryonic Valproic Acid Induced Apoptotic Gene Expression"],"prefix":"10.1002","volume":"117","author":[{"given":"Daniel","family":"Frascella","sequence":"first","affiliation":[{"name":"Edward Via College of Osteopathic Medicine, Virginia Campus  Blacksburg Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murali K.","family":"Mallela","sequence":"additional","affiliation":[{"name":"Virginia\u2010Maryland College of Veterinary Medicine Virginia Tech  Blacksburg Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Cullen","sequence":"additional","affiliation":[{"name":"Virginia\u2010Maryland College of Veterinary Medicine Virginia Tech  Blacksburg Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry C.","family":"Hrubec","sequence":"additional","affiliation":[{"name":"Edward Via College of Osteopathic Medicine, Virginia Campus  Blacksburg Virginia USA"},{"name":"Virginia\u2010Maryland College of Veterinary Medicine Virginia Tech  Blacksburg Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000178750.84837.ed"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20610"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJICMR.S22848"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1161067"},{"key":"e_1_2_11_6_1","unstructured":"Centers for Disease Control and Prevention.2025.Neural Tube Defects.https:\/\/www.cdc.gov\/birth\u2010defects\/about\/neural\u2010tube\u2010defects.html."},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.10026"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476\u20104598\u20105\u201071"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495\u2010010\u20100552\u20102"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.32.9.724"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2005.07.008"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20102008\u20101071396"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1741\u20104520.2008.00213.x"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096\u20109926(200012)62:6<413::AID\u2010TERA8>3.0.CO;2\u2010B"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1567\u20105769(01)00183\u20107"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1017\/S204017441100078X"},{"key":"e_1_2_11_17_1","first-page":"33","article-title":"Reduction of Teratogen\u2010Induced Birth Defects in Mice: The Role of Maternal Immune Stimulation","volume":"2","author":"Hrubec T. 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