短链氯化石蜡对大鼠呼吸系统的毒性作用及分子机制研究

Short chain chlorinated paraffins (SCCPs) are candidates soon to be included in the Stockholm Convention as persistent organic pollutants (POPs), yet their toxic effects and relevant mechanisms are still under debate. Specifically, studies are urgently needed to explore the relationship between the varying carbon chain length and chlorine content of SCCPs and their bioaccumulation and toxicity. In this project, chloroalkanes with different carbon chain lengths and chlorine contents will be synthesized and employed as standard compounds to develop the qualitative and quantitate analytical methods for SCCPs, by using gas chromatography− high resolution mass spectrometer (GC-HRMS). Furthermore, individual and combined exposure experiments will be performed in rats to compare the bioaccumulation, metabolism and transformation behaviors of diverse SCCPs isomers. By using human bronchial epithelial cells and primary pulmonary cells, airway tissues from rats, and rats, we aim to illustrate the possible molecular mechanisms of the SCCPs-caused toxic effects to different tissues and organs (in particular lung) and to establish dose-effect and structure-effect relationships of SCCPs-related toxicities. These results will ultimately provide critical information for evaluating the toxicology and ecological risks of SCCPs, as well as for adjusting and optimizing the industrial process of chlorinated paraffin production.

短链氯化石蜡（SCCPs），作为即将列入斯德哥尔摩公约新增POPs名单的一类污染物，其毒性效应与致毒机制仍然存在较大争论。SCCPs的生物累积性和毒性大小与化合物的碳链长度和氯含量之间的相关性仍需更多的科学实验加以证明。本项目将通过合成不同碳链长度和氯取代量的氯化烷烃单体，作为SCCPs的标准品，建立SCCPs气相色谱-高分辨磁质谱的定性/定量分析方法；选择大鼠作为活体动物模型，开展单一和复合暴露实验，比较研究SCCPs同系物在大鼠体内的生物累积/代谢和生物转化规律；结合人支气管上皮细胞株、原代培养肺上皮细胞、大鼠气道组织及大鼠活体暴露实验模型，研究并揭示SCCPs对生物体各组织器官尤其是肺部毒性作用的分子作用机制，阐明SCCPs造成生物体毒性作用的剂量-效应曲线和构效关系，最终为SCCPs的生态风险评估和氯化石蜡产品升级和技术革新提供科学依据。

工业短链氯化石蜡（SCCP）产品成分复杂，其理化性质和毒性效应、环境转化和生物转化程度与SCCP的结构密切相关。SCCP已被列入持久性有机污染物名单，其毒性效应与致毒机制仍然存在较大争论。本项目中，合成了不同碳链长度和氯取代量的氯化烷烃单体，作为SCCP的标准品，建立了SCCP气相色谱-高分辨磁质谱的定性/定量分析方法，并开展离体实验评估了SCCP单品的毒性效应。在此基础上，开展了工业品SCCP暴露大鼠的胆汁重吸收研究工作，揭示了SCCP在大鼠体内的分布及代谢/转化规律。为探究不同组分SCCP工业产品（镇洋-52、开普-52）是否具有不同的健康效应，项目中以不同的方式（灌胃、滴鼻）暴露小鼠后比较了两种SCCP工业品对小鼠尤其是对呼吸系统的毒性效应差异，并进一步利用离体暴露实验验证。此外，从宏观脏器水平（肺脏器系数和肺组织体积）、功能水平（肺功能）、微观组织水平（组织病理学和胶原纤维增生）以及分子水平（肺泡表面活性蛋白）四个方面深入研究了溴化阻燃剂三-（2,3）二溴丙基异氰脲酸酯（TBC）的毒性效应，为深入评估SCCP的呼吸毒性效应提供了模型和方法。