Introduction and Objective: Type 1 diabetes (T1D) can impact reproductive health in males. Given the potential impact of environmental stimuli, including hyperglycemia, on epigenetic marks, we assessed DNA methylation (DNAm) in sperm from men with T1D.Methods: We recruited 29 weight and age-matched men, 19 with T1D and 10 normoglycemic controls (CON). Samples were collected at baseline and after 3 months. We analyzed reproductive hormones, sperm quality, and sperm DNA methylation (Infinium MethylationEPIC), analyzed using SeSAMe pipeline.Results: Men with T1D had higher levels of luteinizing hormone (LH) (46%, p=0.03) and sex hormone binding globulin (SHBG) (91%, p=0.01), but similar testosterone levels and sperm quality vs. CON. Sperm DNAm remained stable in repeated samples over 3-months in both T1D and CON. Of the 755,827 CpG on the array, 97,723 (12.9%) were differentially methylated (FDR<0.05) in men with T1D vs. CON, adjusted for BMI; DNAm at these sites was increased in 91.7% and reduced in 8.3%. Differential methylation was attenuated after adjustment for HbA1c, suggesting glucose impact on methylation. Ontology analysis of differentially methylated loci revealed annotation to genes regulating helper T cell differentiation, natural killer cell chemotaxis, lysine deacetylation and lipoprotein lipase activity. Among differentially methylated sites, methylation was increased at multiple CpG sites within the human leukocyte antigen (HLA) complex, including HLA-DQA2, DQB2, DRA, DRB1, DPA1, DMB, and C (FDR<0.05).Conclusion: Men with T1D exhibited significantly higher levels of DNA methylation in sperm vs. CON. Whether differential DNA methylation in sperm could alter early post-fertilization phenotypes in offspring and contribute to disease risk remains unknown. Given the association between HLA genotype and T1D risk, ongoing analysis will determine whether differentially methylated loci within the HLA complex are associated with specific HLA risk alleles.
R. Ferraz-Bannitz: None. B. Ozturk: None. V. Efthymiou: None. H. Wang: None. A. Cruz: None. C.J. Cummings: None. J. Patel: None. H. Pan: None. J. Dreyfuss: None. E.M. Isganaitis: None. M. Patti: Research Support; Dexcom, Inc. Other Relationship; Recordati, Fractyl Health, Inc. Consultant; Spruce Biosciences, Premier, Cello, Alpha sight, Boxer Capital. Other Relationship; Amylyx.
Beatson FoundationIacocca Foundation
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