农药混合暴露对精子发生的影响及其机制研究

Infertility is a major global problem in the field of reproductive health. Environmental factor (especially mixed pesticide)-induced spermatogenesis failure and male infertility have caused widespread concern. Previous studies are limited in studying only one or a class of pesticides, the understanding regarding internal exposure levels and toxic activities of mixed pesticides as well as underlying mechanisms is scarce. This project will use a newly established method for the determination of 276 kinds of pesticides and their metabolites in human serum in a large sample set of spermatogenesis failure cases and matched fertile controls, and the seminal plasma of these subjects will be analyzed using metabolomics analysis. The relationship of key mixed pesticides-key disrupted metabolism-spermatogenesis failure will be established in humans. Then, we will establish a mouse model with key mixed pesticide exposure according to the actual exposure levels of pesticides in the population, with or without the corresponding key metabolic intervention. The testicular key metabolic enzyme gene expression and activity as well as key metabolites will be monitored, and spermatogenesis-related results will be collected to verify the effects of key mixed pesticide exposure on spermatogenesis, and to reveal the role of key metabolism plays in mixed pesticide-induced spermatogenesis failure. The project will provide a key technical approach for the risk assessment of mixed pesticides, and will provide scientific basis for prevention, diagnosis and treatment of spermatogenesis failure and male infertility, and will improve human life quality and enhance reproductive health.

不孕不育是全球性生殖健康领域亟待解决的重大科学问题。环境因素，尤其是农药混合暴露所致生精障碍和男性不育已引起普遍关注。既往研究多限于某一或某类农药暴露的影响，对混合农药内暴露水平、毒作用方式及机制知之甚少。本项目拟基于大样本生精障碍病例和匹配的正常生育对照，采用新建立的常用276种农药及其代谢产物的方法检测农药内暴露谱，并对精浆采用代谢组学方法分析，在人群中筛选出关键农药混合暴露-关键代谢-生精障碍的关联。建立符合人群实际暴露水平的关键农药混合暴露的小鼠模型，对关键代谢进行干预，检测睾丸关键代谢酶基因表达和活性及关键代谢物，观察精子生成相关指标，确认关键农药混合暴露对精子发生的影响及关键代谢在其中发挥的作用。本研究可为农药混合暴露风险评估提供关键技术手段，为生精障碍和男性不育的预防、诊断和治疗提供科学依据，为提高人口质量，促进人类生殖健康作出贡献。

不孕不育是全球性生殖健康领域亟待解决的重大科学问题。农药混合暴露所致生精障碍和男性不育已引起普遍关注。目前，对混合农药内暴露水平、毒作用方式及机制知之甚少。本项目采用新建立的方法检测农药内暴露谱，并对精浆采用代谢组学方法分析，在人群中筛选出关键农药混合暴露（α-六六六和双苯酰草胺）-关键代谢（乙酰肉碱）-生精障碍的关联。建立符合人群实际暴露水平的α-六六六（α.HCH）和双苯酰草胺（diphenamid）混合暴露的小鼠模型，对乙酰肉碱代谢进行干预，观察精子生成相关指标，发现乙酰肉碱和相关的糖和脂代谢为diphenamid和α.HCH混合暴露致精子生成障碍的关键代谢，关键中介代谢物为两种内源性糖类6-磷酸甘露糖和山梨糖醇。本研究为农药混合暴露风险评估提供关键技术手段，为生精障碍和男性不育的预防、诊断和治疗提供新的科学依据。