{"doi":"10.1093/pnasnexus/pgaf381","title":"Paternal immune activation-induced alteration of 28S rRNA-derived small RNAs in sperm reprograms offspring phenotypes","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>Parental environmental exposures can induce transgenerational effects through epigenetic modifications in germ cells. Although paternal immune activation is implicated in transgenerational metabolic and neuropsychiatric disorders, the germline-encoded molecular vectors mediating this inheritance remain poorly understood. Here, we demonstrated that lipopolysaccharide-induced immune activation dynamically upregulated the abundance of 28S ribosomal RNA-derived small RNAs (28S-rsRNAs) in mouse sperm in a time-dependent manner. Furthermore, epididymal sperm maturation exhibited heightened susceptibility to acute immune perturbations compared with spermatogenic processes, and 28S-rsRNAs were selectively incorporated during their transit through the caput epididymis. Strikingly, zygotic microinjection of synthetic 28S-rsRNAs recapitulated paternal immune activation phenotypes, resulting in offspring exhibiting metabolic syndrome-like phenotypes, including obesity and impaired insulin sensitivity. Concurrently, these manipulated offspring displayed neurobehavioral abnormalities characterized by heightened anxiety-like and aggressive behaviors, accompanied by hippocampal transcriptomic alterations. Taken together, our findings demonstrate that sperm 28S-rsRNAs contribute to paternal immune activation-mediated programming of offspring behavioral and metabolic phenotypes and provide mechanistic insights into environment-germline interactions.</jats:p>","journal":"PNAS Nexus","year":2026,"id":669805,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":241384,"name":"Chenxi Liu","orcid":"0000-0003-0142-553X","position":1,"is_corresponding":false},{"id":1749377,"name":"Meiling Tan","orcid":null,"position":2,"is_corresponding":false},{"id":1749378,"name":"Jiangxue Cai","orcid":null,"position":3,"is_corresponding":false},{"id":109625,"name":"Lu Lu","orcid":"0000-0002-7343-7161","position":4,"is_corresponding":false},{"id":1749379,"name":"Yiran Sun","orcid":null,"position":5,"is_corresponding":false},{"id":770484,"name":"Bin He","orcid":"0000-0001-6884-6166","position":6,"is_corresponding":false},{"id":1314004,"name":"Chenxuan Li","orcid":"0000-0001-5421-9225","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Paternal immune activation-induced alteration of 28S rRNA-derived small RNAs in sperm reprograms offspring phenotypes","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>Parental environmental exposures can induce transgenerational effects through epigenetic modifications in germ cells. Although paternal immune activation is implicated in transgenerational metabolic and neuropsychiatric disorders, the germline-encoded molecular vectors mediating this inheritance remain poorly understood. Here, we demonstrated that lipopolysaccharide-induced immune activation dynamically upregulated the abundance of 28S ribosomal RNA-derived small RNAs (28S-rsRNAs) in mouse sperm in a time-dependent manner. Furthermore, epididymal sperm maturation exhibited heightened susceptibility to acute immune perturbations compared with spermatogenic processes, and 28S-rsRNAs were selectively incorporated during their transit through the caput epididymis. Strikingly, zygotic microinjection of synthetic 28S-rsRNAs recapitulated paternal immune activation phenotypes, resulting in offspring exhibiting metabolic syndrome-like phenotypes, including obesity and impaired insulin sensitivity. Concurrently, these manipulated offspring displayed neurobehavioral abnormalities characterized by heightened anxiety-like and aggressive behaviors, accompanied by hippocampal transcriptomic alterations. Taken together, our findings demonstrate that sperm 28S-rsRNAs contribute to paternal immune activation-mediated programming of offspring behavioral and metabolic phenotypes and provide mechanistic insights into environment-germline interactions.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41536523","pmcid":"PMC12797211","openalex_id":null,"authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"32573315","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"32372965","title":null}],"total_grants":2,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":null,"license":"https://creativecommons.org/licenses/by/4.0/","oa_locations":[{"url":"https://academic.oup.com/pnasnexus/article-pdf/5/1/pgaf381/66336855/pgaf381.pdf","host_type":"publisher"},{"url":"https://europepmc.org/articles/PMC12797211","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12797211?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":[],"mesh_terms":[],"keywords":["Sperm","Behavior","Intergenerational Effect","Paternal Immune Activation","28S-rsrnas"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-15T04:42:21.890312Z","pmid":null,"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":[]}