NP在学龄期儿童的体内暴露水平及NP影响哮喘发作的机制研究

The prevalence of asthma and asthma-related symptoms has increased dramatically over the last decade in China and western industrial countries．Genetic and environmental factors have a significant joint impact on asthma attack. Nonylphenol (NP) is an endocrine disrupting chemicals (EDC) with estrogenic activity. Prior studies testified that EDC exposure can increase the risk of asthma attack, however, whether exposure to NP would increase the risk of asthma attack has not been elucidated. Our previous studies demonstrated that exposure to NP can inhibit immune function in male offspring rats, but it was unclear whether exposure to NP has adverse effects on asthma attack and its potential mechanism, especially, NP exposure time is limited into critical window. The mechanism of NP's immunotoxicity is complicated, which has not been interpreted by molecular biological experiments in vivo. Our project plans to carry out a detection on NP concentration in blood and urine among school-age children at first, which clarifies the internal exposure levels of NP in high risk population as well as the main risk factors associated with NP exposure. Secondly, our project intends to use an animal model to address the adverse effects of perinatal NP exposure on asthma attack in pups. Then, we assess the airway responsiveness and inflammation of pups, and examine relative cytokine expressions in phosphoinositide 3-kinase (PI3K)/Akt pathway in pups' lung tissues. Finally, we plan to perform molecular biology tests to detect the mRNA expression lever of NGF in the mast cells of lung tissue by using RT-PCR test to explore whether NP may trigger NGF pathway and contribute to asthma.

居民哮喘及其相关过敏疾患发病率日益增高。哮喘是遗传和环境共同作用引起的复杂疾病，环境内分泌干扰物暴露是其不可忽视的危险因素之一。壬基酚(NP)是具有拟雌激素样作用的环境内分泌干扰物，以往研究显示：环境内分泌干扰物暴露可增强哮喘发作强度，但未见NP暴露与哮喘发作的关联研究。研究证实，NP暴露对机体免疫功能有抑制作用，关于NP暴露是否影响哮喘发作及可能机制，特别是敏感窗口期暴露的影响，目前尚未阐明。NP对机体的免疫毒性机制复杂，还未见通过体内生物分子实验验证机理的研究。本课题拟测定学龄期儿童血液和尿液中NP的浓度，揭示高暴露人群NP的体内暴露水平及NP 暴露与主要危险因素之间的关系。建立哮喘动物模型，阐明NP围产期染毒对仔鼠哮喘发作强度的影响, 分析PI3K/Akt信号通路在NP毒效应中的作用机制。并检验NP致小鼠肺组织肥大细胞中NGF mRNA表达水平的变化，来探索NP的免疫毒性。

项目按合同计划超额完成预期目标。居民哮喘及其相关过敏疾患发病率日益增高。哮喘是遗传和环境共同作用引起的复杂疾病，环境内分泌干扰物暴露是其不可忽视的危险因素之一。壬基酚(NP)是具有拟雌激素样作用的环境内分泌干扰物，关于NP暴露是否影响哮喘发作及可能机制，特别是敏感窗口期暴露的影响，目前尚未阐明。NP对机体的免疫毒性机制复杂，还未见通过体内生物分子实验验证机理的研究。本课题分3个部分：①率先监测遵义地区环境中河流、水生动物和自来水中壬基酚污染水平，分析环境中NP的污染状况。②首次对黔北地区遵义市5-14岁儿童血清中壬基酚（NP)、双酚 A（BPA)和邻苯二甲酸二甲酯（DMP）三种环境内分泌干扰物（EDCs）的暴露水平进行评估，揭示学龄期儿童体内NP、BPA和DMP暴露水平与主要危险因素之间及与肝功能指标间的关系。③率先研究围产期母鼠暴露壬基酚对仔鼠肺部炎症损伤的影响，探索围产期母鼠暴露NP是否诱导仔鼠肺组织损伤；最后阐明围产期母鼠暴露壬基酚对OVA诱导哮喘仔鼠气道炎症作用，研究在呼吸系统发育的关键时期暴露NP对OVA诱导哮喘仔鼠气道炎症的影响。本项目探讨NP在学龄期儿童的体内暴露水平及NP影响哮喘发作的机制研究，为决策者制定我国NP 暴露标准提供科学依据。. 合同计划发表学术论文6-8 篇，其中SCI 收录2-4 篇，申请人俞捷实际以第一作者或通讯作者发表核心期刊论文9篇，其中SCI收录4篇，北图核心期刊论文5篇。获批2 项发明专利、19项实用新型专利授权和1项专利成果转让。俞捷研究成果分获2016年贵州省科技进步三等奖、2019年贵州省医学科技成果二等奖及2016年贵州省高校优秀自然科学研究成果三等奖各1项。俞捷2018年分别入选贵州省高层次创新型人才“百层次”人才，贵州省高校科技拔尖人才。