2型糖尿病会影响人类精子中的DNA甲基化。
Type 2 diabetes impacts DNA methylation in human sperm.
作者信息
Su Lei, Dreyfuss Jonathan M, Ferraz Bannitz Rafael, Wolfs Danielle, Hansbury Georgia, Richardson Lauren, Charmant Charnice, Patel Jay, Ginsburg Elizabeth S, Racowsky Catherine, Fore Ruby, Efthymiou Vissarion, Desmond Jessica, Goldfine Allison, Ferguson-Smith Anne, Pan Hui, Hivert Marie-France, Isganaitis Elvira, Patti Mary Elizabeth
机构信息
Research Division, Harvard Medical School, Joslin Diabetes Center, 1 Joslin Place, Boston, MA, 02215, USA.
Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
出版信息
Clin Epigenetics. 2025 Mar 20;17(1):49. doi: 10.1186/s13148-025-01853-9.
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/m 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.
目的/假设：生殖系统疾病，包括性腺功能减退和生育力降低，是糖尿病一种未得到充分认识的并发症。基于小鼠实验数据，高血糖和肥胖可能改变精子中的表观遗传标记，并影响后代的健康和发育，但人类相关数据较为有限。因此，我们试图研究2型糖尿病和血糖控制对精子质量和DNA甲基化的影响。
方法
在这项前瞻性队列研究中，我们招募了40名体重指数（BMI）大于25kg/m²的男性，其中18名患有2型糖尿病，6名患有糖尿病前期，16名作为血糖正常对照。9名2型糖尿病男性和7名对照在3个月后重复进行评估。我们分析了生殖激素、精子浓度和活力以及精子DNA甲基化（MethylationEPIC BeadChip）。
结果
2型糖尿病男性的促卵泡激素（FSH）水平较高，但睾酮水平和精子质量与对照相似。在有和没有2型糖尿病的男性中，精子DNA甲基化在3个月重复采样时保持稳定。我们在2型糖尿病男性与对照的745,804个CpG位点中的655个位点鉴定出差异甲基化（错误发现率<0.05）。其中，96.5%在2型糖尿病中表现出更高的甲基化，DNA甲基化的平均差异（β值，β）为0.16±0.004（16±0.4%）。差异甲基化位点的本体分析显示与调节突触信号、肌动蛋白、cAMP依赖性途径和G蛋白偶联受体途径的基因相关。2型糖尿病男性与对照中差异调节的探针有24%与糖化血红蛋白（HbA1c）相关探针重叠，表明除血糖控制外的其他因素导致了糖尿病相关的DNA甲基化差异。
结论/解读：与BMI相似的血糖正常对照相比，2型糖尿病男性精子中的DNA甲基化水平更高。这些差异是否可通过降糖治疗逆转或是否可能影响受精后的转录调控值得进一步研究。
试验注册
NCT03860558。
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