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Aims/hypothesis <p>Disorders of the reproductive system, including hypogonadism and reduced fertility, are an under-recognized complication of diabetes. Based on experimental data in mice, hyperglycemia and obesity may modify epigenetic marks in sperm and impact health and development of offspring, but data are more limited in humans. Thus, we sought to study the impact of type 2 diabetes and glycemic control on sperm quality and DNA methylation.</p> Methods <p>In this prospective cohort study, we recruited 40 men with BMI greater than 25&#xa0;kg/m<sup>2</sup> including 18 with type 2 diabetes, 6 with prediabetes, and 16 normoglycemic controls. Assessments were repeated after 3&#xa0;months in 9 men with type 2 diabetes and 7 controls. We analyzed reproductive hormones, sperm concentration and motility, and sperm DNA methylation (MethylationEPIC BeadChip).</p> Results <p>Men with type 2 diabetes had higher levels of follicle-stimulating hormone (FSH), but similar testosterone levels and sperm quality as controls. Sperm DNA methylation was stable with repeat sampling at 3&#xa0;months in men with and without type 2 diabetes. We identified differential methylation at 655 of 745,804 CpG sites in men with type 2 diabetes versus controls (FDR &lt; 0.05). Of these, 96.5% showed higher methylation in type 2 diabetes, with a mean difference in DNA methylation (beta value, β) of 0.16 ± 0.004 (16 ± 0.4%). Ontology analysis of differentially methylated loci revealed annotation to genes regulating synaptic signaling, actin, cAMP-dependent pathways, and G protein-coupled&#xa0;receptor pathways. 24% of probes differentially regulated in men with type 2 diabetes versus control overlapped with probes associated with HbA1c, suggesting additional factors beyond glycemic control contributed to diabetes-associated differences in DNA methylation.</p> Conclusions/interpretation <p>Men with type 2 diabetes showed higher DNA methylation levels in sperm relative to normoglycemic controls with similar BMI. Whether these differences are reversible with glucose-lowering treatment or may contribute to post-fertilization transcriptional regulation warrants further investigation.</p> Trial registration <p>NCT03860558</p>

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Type 2 diabetes impacts DNA methylation in human sperm

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月20日

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  • Lei Su,
  • Jonathan M. Dreyfuss,
  • Rafael Ferraz Bannitz,
  • Danielle Wolfs,
  • Georgia Hansbury,
  • Lauren Richardson,
  • Charnice Charmant,
  • Jay Patel,
  • Elizabeth S. Ginsburg,
  • Catherine Racowsky,
  • Ruby Fore,
  • Vissarion Efthymiou,
  • Jessica Desmond,
  • Allison Goldfine,
  • Anne Ferguson-Smith,
  • Hui Pan,
  • Marie-France Hivert,
  • Elvira Isganaitis,
  • Mary Elizabeth Patti

摘要

Aims/hypothesis

Disorders of the reproductive system, including hypogonadism and reduced fertility, are an under-recognized complication of diabetes. Based on experimental data in mice, hyperglycemia and obesity may modify epigenetic marks in sperm and impact health and development of offspring, but data are more limited in humans. Thus, we sought to study the impact of type 2 diabetes and glycemic control on sperm quality and DNA methylation.

Methods

In this prospective cohort study, we recruited 40 men with BMI greater than 25 kg/m2 including 18 with type 2 diabetes, 6 with prediabetes, and 16 normoglycemic controls. Assessments were repeated after 3 months in 9 men with type 2 diabetes and 7 controls. We analyzed reproductive hormones, sperm concentration and motility, and sperm DNA methylation (MethylationEPIC BeadChip).

Results

Men with type 2 diabetes had higher levels of follicle-stimulating hormone (FSH), but similar testosterone levels and sperm quality as controls. Sperm DNA methylation was stable with repeat sampling at 3 months in men with and without type 2 diabetes. We identified differential methylation at 655 of 745,804 CpG sites in men with type 2 diabetes versus controls (FDR < 0.05). Of these, 96.5% showed higher methylation in type 2 diabetes, with a mean difference in DNA methylation (beta value, β) of 0.16 ± 0.004 (16 ± 0.4%). Ontology analysis of differentially methylated loci revealed annotation to genes regulating synaptic signaling, actin, cAMP-dependent pathways, and G protein-coupled receptor pathways. 24% of probes differentially regulated in men with type 2 diabetes versus control overlapped with probes associated with HbA1c, suggesting additional factors beyond glycemic control contributed to diabetes-associated differences in DNA methylation.

Conclusions/interpretation

Men with type 2 diabetes showed higher DNA methylation levels in sperm relative to normoglycemic controls with similar BMI. Whether these differences are reversible with glucose-lowering treatment or may contribute to post-fertilization transcriptional regulation warrants further investigation.

Trial registration

NCT03860558