ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
Paternal Obesity-Induced H3K27me3 Elevation Leads to MANF-Mediated Transgenerational Metabolic Dysfunction in Female Offspring.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
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Who cites it
7 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Global research trends on the impact of obesity on male infertility: a bibliometric analysis.Frontiers in nutrition · 2026Pooled it
- Parental microbiome programming of early-life neurodevelopment: multi-niche contributions through the microbiome-gut-brain axis.Gut microbes · 2026Review
- Paternal Caffeine Exposure Programs Offspring Stress Vulnerability via Sperm Dlk1-Dio3 Imprinting-Directed Remodeling of a Novel Neural Circuit.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Paternal Sertoli cell-derived extracellular vesicles transfer mtDNA and microRNA cargo to trigger germ cell oxidative stress and induce metabolic risks in offspring.Cell communication and signaling : CCS · 2026Article
- Obesity in reproduction: Mechanisms from fertilization to post‑uterine development (Review).International journal of molecular medicine · 2025Review
- Targeted Degradation of sGRP78 Alleviates the Immunosuppressive Tumor Microenvironment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Paternal Obesity-Induced H3K27me3 Elevation Leads to MANF-Mediated Transgenerational Metabolic Dysfunction in Female Offspring.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
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Authors and funding
14 authors.
Funding
Abstract
Paternal lifestyle and environmental exposures can alter epigenetic changes in sperm and play a critical role in the offspring's future health, yet the underlying mechanisms remain elusive. The present study established a model of paternal obesity and found that the increased levels of H3K27me3 in sperm persist into the 8-cell embryo stage, resulting in a transgenerational decrease of Manf, which causes endoplasmic reticulum stress and activates the GRP78-PERK-EIF2α-ATF4-CHOP axis. This consequently leads to impaired glucose metabolism and apoptosis in the liver of female offspring. Based on these findings, the F0 mice are treated with 3-deazaneplanocin A, an EZH2 inhibitor, which successfully prevented metabolic dysfunction in F0 mice of the high-fat diet (HFD) group. Meanwhile, intravenous injection of recombinant human MANF in F1 female offspring can successfully rescue the metabolic dysfunction in the HFD-F1 group. These results demonstrate that paternal obesity triggers transgenerational metabolic dysfunction through sperm H3K27me3-dependent epigenetic regulation. The present study also identifies the H3K27me3-MANF pathway as a potentially preventive and therapeutic strategy for diabetes, although further studies are needed to validate its clinical applicability.
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