1135-P: Type 2 Diabetes Modulates DNA Methylation in Human Sperm

Paternal obesity and diabetes are associated with cardiometabolic risk in offspring. To test the hypothesis that paternal metabolism could exert these effects via modulation of the sperm epigenome, we collected motile sperm at two study visits 3 months apart in men with and without T2D (NCT03860558). Sperm DNA methylation was quantified in 32 samples using the Infinium MethylationEPIC array. HbA1c was higher in men with T2D vs. controls (7.6±1.1% vs. 5.2±0.2%, n=9 vs. 7, p 0.2), including sites annotated to SLFN5, MMAA, and LOC101927829. All 7 sites were hypermethylated in T2D, with mean difference in beta of 26.4%. Paired analysis between study visits for individual participants revealed no significant CpG, indicating stability of sperm methylation over time. Genes annotated to differentially methylated CpG at both study visits (n=89, nominal p In summary, DNA methylation is altered in motile sperm from men with T2D, with hypermethylation at significant CpG sites. These alterations may reflect differential transcriptional regulation at developmentally important loci, and should be investigated as potential contributors to the impact of paternal metabolism on offspring. Disclosure L. Su: None. D. Wolfs: None. M. Hivert: None. J. Patel: None. L. Richardson: None. C. O. Charmant: None. E. M. Isganaitis: None. M. Patti: Consultant; Self; Cello Health, Fractyl Laboratories, Inc., MBX, Poxel SA, WGBH, Other Relationship; Self; Xeris Pharmaceuticals, Inc., Research Support; Self; Dexcom, Inc. Funding National Institutes of Health (R21HD091974)