Paternal Diet-Induced Obesity Retards Early Mouse Embryo Development, Mitochondrial Activity and Pregnancy Health

Worldwide, 48% of adult males are overweight or obese. An association between infertility and excessive body weight is now accepted, although focus remains primarily on females. It has been shown that parental obesity results in compromised embryo development, disproportionate changes in embryo metabolism and reduced blastocyst cell number. The aim of this study was to determine whether paternal obesity has negative effects on the resultant embryo. Specifically, using in vitro fertilisation (IVF), we wanted to isolate the functional effects of obesity on sperm by examining the subsequent embryo both pre- and post-implantation. Epididymal sperm was collected from age matched normal and obese C57BL/6 mice and cryopreserved for subsequent IVF with oocytes collected from Swiss females (normal diet/weight). Obesity was induced in male mice by feeding a high fat diet of 22% fat for 10 weeks. Resultant embryos were cultured individually and development monitored using time-lapse microscopy. Paternal obesity resulted in a significant delay in preimplantation embryo development as early as syngamy (P<0.05). Metabolic parameters were measured across key developmental stages, demonstrating significant reduction in mitochondrial membrane potential (P<0.01). Blastocysts were stained to determine trophectoderm (TE) and inner cell mass (ICM) cell numbers, revealing significant differences in the ratio of cell allocation to TE and ICM lineages (P<0.01). Functional studies examining blastocyst attachment, growth and implantation demonstrated that blastocysts derived from sperm of obese males displayed significantly reduced outgrowth on fibronectin in vitro (P<0.05) and retarded fetal development in vivo following embryo transfer (P<0.05). Taken together, these data clearly demonstrate that paternal obesity has significant negative effects on the embryo at a variety of key early developmental stages, resulting in delayed development, reduced placental size and smaller offspring.

全球范围内，48%的成年男性处于超重或肥胖状态。目前学界已公认不育与体重超标存在关联，但过往研究的焦点主要集中于女性群体。已有研究证实，父母一方肥胖会导致胚胎发育受损、胚胎代谢异常失衡以及囊胚细胞数量减少。本研究旨在探究父本肥胖是否会对后续胚胎产生负面影响。具体而言，我们借助体外受精（in vitro fertilisation, IVF）技术，通过检测植入前后的胚胎，以分离肥胖对精子的功能性影响。研究人员通过饲喂脂肪占比22%的高脂饲料10周，诱导雄性C57BL/6小鼠发生肥胖，并选取同龄、体重正常的同品系小鼠作为对照。从两组小鼠的附睾中采集精子并冷冻保存，用于后续与瑞士雌性小鼠（正常饮食、体重正常）采集的卵母细胞进行体外受精。所得胚胎进行单独培养，并利用延时显微镜（time-lapse microscopy）监测其发育进程。结果显示，父本肥胖会在合子期（syngamy）就显著延缓胚胎的植入前发育（P<0.05）。研究人员在关键发育阶段检测了代谢参数，发现线粒体膜电位（mitochondrial membrane potential）显著降低（P<0.01）。通过染色技术检测囊胚的滋养外胚层（trophectoderm, TE）与内细胞团（inner cell mass, ICM）细胞数量，结果显示两者的细胞分配比例存在显著差异（P<0.01）。针对囊胚附着、生长与植入的功能研究表明，源自肥胖雄性精子的囊胚在体外纤连蛋白（fibronectin）基质上的贴附生长能力显著降低（P<0.05），且胚胎移植后体内胎儿发育迟缓（P<0.05）。综合来看，本研究数据清晰证实，父本肥胖会在多个关键早期发育阶段对胚胎产生显著负面影响，具体表现为发育延迟、胎盘尺寸减小以及后代体型偏小。