碘代消毒副产物内分泌干扰效应的分子模拟及QSAR研究

With the promotion of new technologies for drinking water disinfection, iodinated disinfection byproducts (I-DBPs) highlighted the environmental and health risk. Although carcinogenic and mutagenic effects of I-DBPs have received extensive attention, the latest research began to focus on endocrine disrupting effects. However, studies on effect identification, toxic mechanism and risk assessment are still lacking, meanwhile the mixed state of I-DBPs is a major bottleneck problem for toxicological testing. This Project herein is to explore molecular mechanism of endocrine disrupting effect through the nuclear hormone receptor-mediated pathway using a method combined theoretical calculation with toxicological testing. We simulated the binding modes of I-DBPs with major human hormone receptors to find the influence of I-DBPs to multilevel structure of these receptors; then molecular dynamics simulation was performed to simulate the interacting / dissociation process with cofactors and DNA, identifying structure-activity relationships of estrogenic/anti-estrogenic activities through the conformation of H12 helical; finally, three-dimensional QSAR models that can reflect toxic mechanism were established to predict the endocrine disrupting activities of I-DBPs. The QSAR models were also validated by data from modern molecular biological technology. These findings will provide a useful supplement to traditional toxicology at the laboratory, and provide a scientific basis for ensuring the water environment security and health risk assessments.

随着新型饮用水消毒技术的推广，碘代消毒副产物（I-DBPs）引发的环境和健康问题凸显。I-DBPs的致癌和致突变效应已受到广泛关注，最新的研究发现存在内分泌干扰效应，然而其效应表征、致毒机理和风险评估等方面尚不清楚。因I-DBPs多以混合物存在，成为毒理测试的瓶颈。项目拟采用理论计算与毒理试验相结合的手段，探明I-DBPs引发内分泌干扰效应相关受体介导通路的微观分子机制。研究I-DBPs与人体内主要激素受体的微观结合模式，揭示I-DBPs对受体多级结构的影响规律；利用分子动力学方法动态模拟复合物与辅因子、DNA的结合/解离过程，通过H12螺旋的空间构象识别不同I-DBPs的拟/抗激素效应；最后基于毒理机制建立三维QSAR模型，并结合分子生物学测试结果对模型进行校验，实现对I-DBPs类激素活性的准确预测。成果为传统毒理学提供有益补充，为水环境安全保障和健康风险评估提供科学依据。

随着我国对饮用水消毒副产物控制标准的日益严格，新型碘代消毒副产物（I-DBPs）的内分泌效应开始受到关注，但致毒机理尚不明确。尤其对那些容易受海水入侵影响的淡水水源地，辖区内生活饮用水处理厂已有的处理工艺导致I-DBPs的产生，对水生态系统和人体健康构成潜在风险。本项目采用毒性测试、计算机建模和大数据分析相结合的手段，揭示了I-DBPs及其前提物质和代谢产物诱发内分泌干扰效应的微观分子机制，识别I-DBPs引起的H12螺旋变化和拟/抗激素效应分子机制，构建多维QSAR毒性预测模型；建立基于内分泌干扰效应靶标受体结构特征和诱导契合柔性结合模式的虚拟高通量筛选技术，获得具有潜在内分泌干扰效应的前体物质；开展实际水环境中卤代消毒副产物的生态风险评估研究，识别出高风险副产物的结构特征，为现有饮用水消毒工艺的改进提供科学依据。截止目前已发表高水平研究论文10篇（第一标注4篇），其中SCI收录7篇，国内核心期刊3篇。授权美国专利1项，国内发明专利4项。项目组成员参加国内外相关学术会议并作口头报告12人次，培养研究生2名。依托项目建立的I-DBPs毒性定量预测方法及相关基础数据，应用于我国新型污染物环境基准与标准的制修订工作中，直接服务于国家环境管理和风险防控。项目支出与预算基本相符，经费结余0万元。