邻苯二甲酸苄基酯暴露与男性生殖健康的相关性及其分子机理研究

项目名称： 邻苯二甲酸苄基酯暴露与男性生殖健康的相关性及其分子机理研究

项目编号： No.21477127

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 化学工业

项目作者： 张红霞

作者单位： 中国科学院动物研究所

项目金额： 88万元

中文摘要： 邻苯二甲酸丁基苄酯（BBP）作为增塑剂应用于化工、装修材料、食品包装等中，在环境介质及人体中广泛检出。我们的前期研究发现我国男性人群尿液中BBP的代谢物－邻苯二甲酸苄酯(MBzP)的水平与精子质量和数量呈负相关性。动物实验也发现BBP或MBzP具有明显的生殖毒性，但其机制尚未明确。本项目拟通过大样本量分析，揭示我国典型地区生育期男性尿液中PAEs暴露水平（特别是MBzP）与男性生殖健康的关联；进一步用MBzP暴露小鼠，通过交叉哺育实验，研究子宫暴露或母乳暴露对子代雄性生殖系统的影响，找到其敏感的暴露时期；通过成年小鼠体内、体外暴露实验，运用蛋白质组学、RNA干扰等技术手段，阐明MBzP对成年雄性生殖毒性效应及机制，明确PPAR?在MBzP诱导的生殖毒性中的作用；为正确评估BBP及其代谢物MBzP对男性生殖健康的影响提供科学依据。

中文关键词： 邻苯二甲酸苄基酯（MBzP）；男性生殖健康；交叉哺育；分子机制；RNA干扰

英文摘要： Butyl benzyl phthalate (BBP) is one member of phthalates (PAEs), which are used as plasticizers, solvents and stabilizers in industry, medicine, building and consumer products. The widespread use of PAEs contributes to their omnipresent detection in the environment and human beings. PAEs can be transferred from maternal blood into the developing fetus via placenta and into neonates via breast milk. The possibility of PAEs entering into the biological system has generated concern about their reproductive and developmental toxic potential in humans. BBP and its metabolite (mono-benzyl phthalate (MBzP)) has been reported to induce a decrease in testis size, sperm production and mobility, morphological changes, embryolethality and malformations in mice, but its mechanism has not been clarified. Although preliminary, our study analyzed urinary phthalate metabolites from 511 mans with subfertile problems and found that the urinary MBzP levels were negatively correlated with the sperm concentration, sperm count, acrosomal enzyme and morphologically normal rate. This suggested that BBP and MBzP had a potential threat to the human reproductive health. Some reports showed that the urinary MBzP levels were significantly higher in children compared to adolescents and adults. The usage of BBP in baby products has been limited in US and other countries, but not yet limited in China. In our present program, firstly, we will collect 1200 urine samples from the males who were members of subfertile couples in China, analyze 14 phthalate metabolite concentrations using UPLC-MS/MS and determine serum hormon levels, the sperm production and qualities. The aim is to investigate the general concentrations of phthalate exposures in China and to evaluate correlations between phthalate metabolite concentrations with male reproductive parameters. This study will also help scientists plan and conduct research on exposure and health effects. In addition, we will establish a cross-foster animal model to study whether prenatal or postnatal exposure to MBzP alone can disturb the male reproductive function in mouse pups, and if so, which kind of exposure is a major cause. Besides, the mechanisms of action by which MBzP interferes with male reproductive system in mouse pups were also investigated. Moreover, we will establish a subchronic MBzP exposure model to adult male mouse, find the key proteins and pathways in mouse testis targeted by MBzP using proteomic technology. Furthermore, we will use in vitro exposure model through preparing primary Sertoli cells and Leydig cells, inhibiting PPARα expression by RNAi technology to further explore the mechanism of MBzP induced structural and functional damage to mouse testis and the roles of PPARα in MBzP induced male reproductive toxicity. We hope that this study will help scientist to evaluate the adverse effect of BBP to human health, and help government to draft related policy about BBP usage.

英文关键词： mono-benzyl phthalate (MBzP);male reproductive health;cross-foster;molecular mechanism;RNAi