{"doi":"10.1101/2025.10.13.682090","title":"PERINATAL ORGANOPHOSPHATE FLAME RETARDANT EXPOSURE ALTERS ADULT STRESS AXIS AND AVOIDANCE BEHAVIOR IN MICE","abstract":"Abstract Organophosphate flame retardants (OPFRs) are ubiquitous flame-retardant additives with endocrine-disrupting properties. Despite increasing evidence that OPFRs impact neurodevelopment, their effects on the neuroendocrine stress response remain poorly understood. To examine their long-term impact on stress regulation, we treated pregnant C57Bl/6J dams to a mixture of tris(1,3-dichloro-2-propyl) phosphate (TDCPP), triphenyl phosphate (TPP), and tricresyl phosphate (TCP; 1 mg/kg each) from gestational day (GD) 7 through postnatal day (PND) 14. Adult offspring (8-9 weeks of age) were then challenged with acute stressors, including 1 h restraint or a 6-day acute variable stress (AVS) paradigm. Perinatal OPFR exposure produced persistent, sex-specific alterations in the hypothalamic–pituitary–adrenal (HPA) axis and stress-related neurocircuitry. Following 1 h restraint, OPFR-treated females showed heightened serum corticosterone. In addition, gene expression analysis revealed sex-dependent disruptions in key stress-regulatory pathways after OPFR treatment and 1 h restraint in the hypothalamus ( Crhr1, Crhr2, Ptpn5 ) and pituitary ( Crhr1, Pomc, Nr3c1 ). Females demonstrated more differences in adrenal gene expression related to steroidogenesis ( Mc2r, Cyp11b2 ) and catecholamine biosynthesis ( Dbh, Pnmt ), with OPFR-treated groups having blunted responses. OPFR AVS females displayed reduced corticosterone and Crh mRNA in the hypothalamus, and downregulated Pacap/Pac1r expression in the bed nucleus of the stria terminalis (BNST), accompanied by increased behavioral avoidance and immobility. In males, OPFR exposure led to increased BNST Pacap and Pac1r , expression, along with hyperactivity and avoidance behaviors. Together, these findings demonstrate that early-life OPFR exposure induces lasting, sex-specific dysregulation of the HPA axis and associated stress circuits, highlighting OPFRs as developmental neuroendocrine disruptors with implications for mood and stress-related disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559299,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"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":1461119,"name":"Julia DeLucca","orcid":null,"position":1,"is_corresponding":false},{"id":1460526,"name":"Bier Thomas A.","orcid":"0000-0002-8794-7824","position":2,"is_corresponding":false},{"id":331087,"name":"Ali Yasrebi","orcid":"0000-0003-1745-4298","position":3,"is_corresponding":false},{"id":1461120,"name":"Savannah Chiou","orcid":null,"position":4,"is_corresponding":false},{"id":416148,"name":"Nicholas T. Bello","orcid":"0000-0001-5300-5604","position":5,"is_corresponding":false},{"id":328415,"name":"Troy A. Roepke","orcid":"0000-0001-5426-2266","position":6,"is_corresponding":false},{"id":927867,"name":"Catherine Rojas","orcid":"0000-0001-9921-169X","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41279807","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":[]}