Paternal obesity-induced changes in sperm chromatin accessibility and have mild effect on offspring metabolic health

The increasing global burden of metabolic disorders including obesity and diabetes necessitates a comprehensive understanding of their etiology, which not only encompasses genetic and environmental factors but also parental influence. Recent evidence has unveiled paternal obesity as a contributing factor to offspring's metabolic health via sperm epigenetic modifications. In this study, we investigated the impact of a Western diet-induced obesity in C57BL/6 male mice on sperm chromatin accessibility and the subsequent metabolic health of their progeny. Utilizing Assay for Transposase-Accessible Chromatin with sequencing, we discovered 450 regions with differential accessibility in sperm from obese fathers, implicating key developmental and metabolic pathways. Contrary to expectations, these epigenetic alterations in sperm were not predictive of long-term metabolic disorders in offspring, who exhibited only mild transient metabolic changes early in life. Both male and female F1 progeny showed no enduring predisposition to obesity or diabetes. These results underscore the biological resilience of offspring to paternal epigenetic inheritance, suggesting a complex interplay between inherited epigenetic modifications and the offspring's own developmental compensatory mechanisms. This study calls for further research into the biological processes that confer this resilience, which could inform interventional strategies to combat the heritability of metabolic diseases. Using a diet-induced obesity model in male mice, we examined changes in sperm chromatin accessibility through Assay for Transposase-Accessible Chromatin with sequencing (ATAC-seq) between F0 Western diet fed male mice (6 months duration) and a control group of F0 Chow diet fed male male. We then assessed the effects of these epigenetic alterations on the metabolic health of F1 offspring through various physiological metabolic tests.

全球代谢紊乱（包括肥胖与糖尿病）的负担日益加重，亟需全面阐明其病因学机制——该机制不仅涵盖遗传与环境因素，还涉及亲代影响。近期研究证据表明，父系肥胖可通过精子表观遗传修饰，对子代代谢健康产生不良影响。本研究以C57BL/6雄性小鼠为模型，探究西式饮食诱导肥胖对其精子染色质可及性以及子代代谢健康的影响。本研究借助转座酶可及性测序测定（Assay for Transposase-Accessible Chromatin with sequencing，以下简称ATAC-seq），在肥胖父鼠的精子中发现了450个差异可及区域，这些区域涉及关键发育与代谢通路。与预期相悖的是，精子中的这些表观遗传改变并不能预测子代的长期代谢紊乱：子代仅在生命早期出现轻度一过性代谢变化，且雌雄F1代小鼠均未表现出肥胖或糖尿病的持久易感倾向。上述结果凸显了子代对父系表观遗传传递的生物学韧性，提示遗传获得的表观遗传修饰与子代自身发育代偿机制间存在复杂互作。本研究呼吁针对介导这一韧性的生物学过程开展进一步研究，该成果可为对抗代谢疾病的遗传可遗传性提供干预策略。本研究利用雄性小鼠饮食诱导肥胖模型，通过ATAC-seq检测了喂食西式饮食（造模时长6个月）的F0代雄性小鼠与喂食常规饲料（Chow diet）的对照组F0代雄性小鼠的精子染色质可及性变化；随后通过多项生理代谢检测，评估了这些表观遗传改变对F1子代代谢健康的影响。