父代肥胖影响精子Tet3介导的子代小鼠自闭症样行为的机制研究

自闭症发病率逐年上升，但发病机制尚不明确。发育源性成人疾病学说将发病起源追溯至胎儿、胚胎甚至是配子时期的环境暴露。我们前期研究初步发现高脂饮食诱导的父代肥胖可导致子代小鼠出现自闭症样行为，自闭症关键基因mGluR5和Gria2在肥胖父代精子和子代大脑内侧前额叶皮层中均呈高甲基化状态，DNA去甲基化关键酶Tet3在肥胖父代精子中表达下调，提示父代肥胖可能通过抑制精子Tet3表达，导致精子中自闭症靶基因甲基化升高并遗传给子代，影响其在子代靶器官中表达，从而导致子代小鼠出现自闭症样行为。本项目拟在前期研究基础上，利用行为学测试、突触结构功能检测、体外细胞实验、精子特异性Tet3敲除和过表达小鼠、父代和子代拯救干预等研究，进一步明确父代肥胖导致子代自闭症样行为，阐明其表观遗传学机制并探索可能的拯救干预手段，揭示配子源性自闭症发病新机制，为临床早期筛查和干预提供潜在分子靶标和理论基础。

The incidence of autism is increasing year by year, but the pathogenesis is still unclear. The theory of developmental origins of adult diseases traces the origin of adult diseases back to environmental exposure during fetal, embryonic and even gamete stages. Our preliminary study found that paternal obesity induced by a high-fat diet can lead to autistic-like behaviors in offspring mice. The key genes of autism, mGluR5 and Gria2, were hypermethylated in both obese paternal sperm and medial prefrontal cortex of offspring brain. The expression of Tet3, a key DNA demethylation enzyme, was down-regulated in obese paternal sperm. It is suggested that paternal obesity may increase the methylation of autism target genes by inhibiting Tet3 expression in sperm, which is then passed on to offspring, affecting their expressions in the target organ of offspring, thus leading to autistic-like behaviors in offspring mice. This project is based on the previous research, using behavioral tests, synaptic structure and function tests, in vitro cell experiments, sperm-specific Tet3 knockout and overexpression mice, paternal and offspring rescue interventions, to further clarify that paternal obesity leads to autistic-like behaviors in offspring, elucidate the epigenetic mechanism, and explore possible rescue interventions. This project will reveal the new pathogenesis of gamete origin of autism and provide potential molecular targets and theoretical basis for early clinical screening and intervention.