肥胖对雄性生殖影响的机制研究

Obesity is a disease induced by disorder of lipid metabolism in human body. The epidemiological investigation revealed that the male infertility was correlated with obesity, and animal experiments also demonstrated the fact that obesity can lead to male infertility as well as the changes of epigenetic modification. Interestingly, our results showed that the protein levels of both ERp57 and ACTRT2 in the spermatozoa from obese infertile male with asthenozoospermia declined significantly. Thus, our research program will be focused on the following; 1) To demonstrate the correlation between the level declines of ERp57 and ACTRT2 and asthenozoospermia induced by obesity via the protein level detection of these two kinds of protein from the spermatozoa in clinics. We also want to investigate the correlation between the obese asthenozoospermia and the changes of sperm epigenetic modification, such as DNA methylation and histone methylation, acetylation, ubiquitination and phosphorylation, etc. 2) To establish the model of male obese mice and to probe the levels of ERp57 and ACTRT2 or other similar proteins such as cellular skeleton protein X in the spermatozoa. 3) To construct the conditional knockout mice responding to ERp57 and ACTRT2 or Protein X genes and then, to detect the sperm capability of fertility and the histological changes of tissues in male reproductive system , furthermore, to determine the biological function of these proteins for male reproduction. 4) To probe the changes of epigenetic modification in spermatozoa from obese mice model and its male offspring. In conclusion, the aim for this program is to systematically elucidate the mechanism of the obese effects on male reproduction and moreover, it also will provide reliable theoretical bases and experimental data for the disease diagnosis and treatment clinically.

肥胖症是一种由体内脂类代谢紊乱引发的疾病。流行病学调查发现：肥胖与男性不育症发病显著相关，动物实验也证实肥胖可致雄性生育率下降且伴有表观遗传修饰的改变。我们在前期研究中发现：肥胖型弱精症不育患者其精子ERp57和ACTRT2含量显著下降。本课题将通过1）临床大规模检测肥胖型弱精症精子ERp57和ACTRT2含量及精子DNA甲基化和组蛋白甲基化、乙酰化、泛素化和磷酸化变化，证实这两种蛋白或精子表观遗传修饰改变与该病的相关性；2）构建雄性肥胖小鼠模型，检测其精子ERp57和ACTRT2或类似骨架蛋白X变化；3）构建睾丸ERp57或ACTRT2或蛋白X条件性基因敲除小鼠，检测其精子受精功能及生殖系统组织学变化并探索该类蛋白在雄性生殖中的作用；4）检测肥胖模型小鼠及子代精子DNA和组蛋白的表观遗传修饰变化。这将为系统阐明肥胖对雄性生殖的影响机制及临床对该病的诊治提供可靠的理论基础和充分的实验依据。

肥胖是一类由饮食结构改变和机体代谢异常引起的综合代谢性疾病。随着肥胖人口的迅速增加，其已成为世界范围内威胁人类健康的主要病因之一。目前，肥胖对生殖健康的危害得到了广泛的重视，但其中的机制尚有待深入探索。过去研究中，我们从临床和基础两方面长期关注肥胖影响精子质量的分子机制，并推测：肥胖可以诱发生殖系统慢性炎症反应，并通过炎症信号影响精子发生、成熟等过程，甚至可通过表观遗传修饰影响下一代健康。在本课题研究中，我们（1）通过炎症因子和炎症信号分子的相关检测，明确肥胖可以导致（雄性和雌性）生殖系统局部慢性炎症，进而影响生殖系统细胞功能，如血睾屏障、子宫内膜容受性等；（2）通过蛋白组学技术分析肥胖精子蛋白组成的变化，通过线粒体功能分析和氧化应激检测，探索肥胖影响精子发生，干扰精子质量的可能机制；（3）通过脐带血细胞非编码RNA测序和DNA甲基化测序，探索母体肥胖对子代表观遗传修饰的影响；（4）通过构建生殖细胞特异的条件性基因敲除小鼠，探索氧化应激效应分子内质网蛋白ERp57在精子发生中的作用。我们的研究结果为探索肥胖影响生殖健康的分子机制提供了重要的理论基础和可靠的实验依据。