{"doi":"10.1016/j.jlr.2025.100930","title":"Intrauterine oxygen milieu governs placental sphingolipid metabolism","abstract":"Early placentation relies on temporal changes in intrauterine oxygen tension that regulate trophoblast differentiation events. Studies have highlighted the contribution of bioactive sphingolipids to the pathogenesis of placental disorders, characterized by hypoxia. However, it is unknown whether placental sphingolipid metabolism changes during the switch from a hypoxic to an oxygenated environment in the first trimester of gestation and if sustained hypoxia is causative of sphingolipid alterations seen in preeclampsia. Herein, we performed sphingolipid analysis of first-trimester human placentae as well as placentae from conditional (placenta-specific) Phd2 knockout mice ( Phd2 −/− cKO) that exhibit preeclampsia-like features, including placental hypoxia. Analysis revealed elevated long chain ceramide (Cer16:0, Cer18:0, Cer20:0 and Cer22:0) and reduced sphingosine-1-phosphate (So-1-P) content in Phd2 −/− cKO placentae. Expression of key regulatory sphingolipid enzymes, acid ceramidase (ASAH1) and sphingosine kinase 1 (SPHK1), was reduced in Phd2 −/− cKO placentae, while that of alkaline ceramidase ACER2 remained unchanged. Human placentae from 5-9 weeks of gestation, when intrauterine oxygen tension is low, exhibited heightened long chain ceramide (Cer14:0, Cer16:0, Cer18:0, Cer 18:1) and sphingosine content and reduced ASAH1 and SPHK1 expression, highlighting the relevance of low oxygen in regulating sphingolipid metabolism under physiological (placental development) and pathological ( Phd2 −/− cKO induced preeclampsia) conditions. Ultrastructural analyses of early (5–9 weeks) human and murine Phd2 −/− cKO placentae revealed that increased trophoblast mitochondrial fission events accompanied elevated ceramide. Together, the data support the concept that a chronic low-oxygen environment leads to placental ceramide buildup, which may alter mitochondrial homeostasis and potentially contribute to cell death events characteristic of preeclampsia.","journal":"Journal of Lipid Research","year":2025,"id":548057,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"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":320732,"name":"Martin Post","orcid":"0000-0003-4258-9303","position":1,"is_corresponding":false},{"id":320733,"name":"Isabella Caniggia","orcid":"0000-0001-7340-2359","position":2,"is_corresponding":false},{"id":320731,"name":"Julien Sallais","orcid":"0000-0001-7513-2153","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41167398","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":[]}