{"doi":"10.1002/bdr2.2541","title":"Maternal Immune Stimulation With Interferon‐Gamma Limits Embryonic Valproic Acid Induced Apoptotic Gene Expression","abstract":"BACKGROUND: 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-induced 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-γ (IFN-γ) and gestational VA exposure. METHODS: Concentrations of granulocyte monocyte colony stimulating factor (GM-CSF), IFN-γ, interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNFα) were determined in VA + IFN-γ-treated pregnant mice. Expression of pro-apoptotic and antiapoptotic pathway genes was determined in VA and VA + IFN-γ exposed embryos. RESULTS: NTDs decreased from 45.3% to 21.2% per litter with MIS. MIS altered the profiles of GM-CSF and IFN-γ throughout pregnancy and altered the profiles of GM-CSF, IL-6, and IL-10 over the time of NT closure. Pro-apoptotic genes were upregulated, and anti-apoptotic genes were downregulated in VA-exposed embryonic heads with open or closed NTs. Gene expression was normalized with VA + IFN-γ in embryonic heads with closed NTs. CONCLUSION: This study identified GM-CSF and IFN-γ as possible effectors of MIS and specifically GM-CSF, IL-6, and IL-10 in preventing NTDs. MIS normalized apoptotic gene expression in embryos with closed NTs identifying a possible molecular mechanism for the prevention of VA-induced NTDs.","journal":"Birth Defects Research","year":2025,"id":580207,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9627,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1491466,"name":"Murali K. Mallela","orcid":null,"position":1,"is_corresponding":false},{"id":1327418,"name":"Robert Cullen","orcid":null,"position":2,"is_corresponding":false},{"id":497991,"name":"Terry C. Hrubec","orcid":"0000-0002-3961-9201","position":3,"is_corresponding":false},{"id":1491465,"name":"Daniel Frascella","orcid":null,"position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:58:38.868285Z","pmid":"41194526","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}