Paternal Obesity-Induced H3K27me3 Elevation Leads to MANF-Mediated Transgenerational Metabolic Dysfunction in Female Offspring.

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, intraveno

SUBMITTER: Shi Y 

PROVIDER: S-EPMC12021121 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature