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Using a paternal preconception caffeine exposure (PPCE) rat model with in vitro fertilization to exclude maternal confounders, we uncover a novel pathway linking sperm epigenetics to offspring HPA axis hyperresponsivity. By elevating paternal corticosterone, PPCE induces hypomethylation at the intergenic differentially methylated region (IG\u2010DMR) within sperm Dlk1\u2010Dio3 domain. This epigenetic alteration evades postfertilization reprogramming, persists in offspring hippocampus, and derepresses the maternally expressed miRNA cluster, causing posttranscriptional downregulation of glutaminase (GLS). Hippocampal GLS deficiency impairs glutamatergic neurotransmission in a novel circuit: ventral hippocampal CA1 glutamatergic neurons (vCA1\n                    <jats:sup>Glu<\/jats:sup>\n                    ) \u2192 piriform cortex \u03b3\u2010aminobutyric acid\u2010ergic neurons (Pir\n                    <jats:sup>GABA<\/jats:sup>\n                    ) \u2192 paraventricular nucleus corticotropin\u2010releasing hormone neurons (PVN\n                    <jats:sup>CRH<\/jats:sup>\n                    ). Chemogenetic activation of this circuit rescues HPA axis hyperresponsivity and affective phenotypes. Clinically, sperm IG\u2010DMR hypomethylation correlates with elevated plasma cortisol in prospective fathers. Importantly, paternal folic acid supplementation prevents these epigenetic alterations and restores offspring stress homeostasis. Our study delineates an intergenerational mechanism and identifies a potentially translatable prenatal intervention strategy.\n                  <\/jats:p>","DOI":"10.1002\/advs.75380","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T08:07:46Z","timestamp":1777536466000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Paternal Caffeine Exposure Programs Offspring Stress Vulnerability via Sperm Dlk1\u2010Dio3 Imprinting\u2010Directed Remodeling of a Novel Neural Circuit"],"prefix":"10.1002","volume":"13","author":[{"given":"Mengxi","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Obstetrics School of Pharmaceutical Sciences Zhongnan Hospital of Wuhan University Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaole","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics School of 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