基于生态毒理效应及机制的多氟代二苯并对二噁英(PFDD)的结构-活性研究

Polyfluorinated dibenzo-p-dioxins (PFDDs) have 76 congeners. They are a class of compounds structurally similar to polychlorinated dibenzo-p-dioxin (PCDDs), and are highly stable and difficult to be degraded as other organofluorine compounds. They have been detected in environmental samples including gas samples and chemical product. In the present study, over 20 types of PFDDs are synthesized and their environment-related properties such as oxidative stress, effects on the metal balance in biological tissue, DNA damage, endocrine disruption and aryl hydrocarbon receptor (AhR) activation effect are determined. The toxicological effect of PFDDs are compared with that of PCDDs and PBDDs, and the molecular mechanism which results in the toxic differences is explored. By means of molecular docking, a model revealing the interaction means between PFDDs and biological hormone receptor/AhR is established, and the interaction mechanisms between PFDDs and receptors are stated at a micro level. Consequently, the mechanisms resulting to the endocrine disruption and AhR activation are proposed preliminarily. These investigations will give fundamental supports for the further study on the environmental migration, transformation and toxic mechanism of PFDDs, and it may support theoretical basis for the ecoenvironmental risk assessment.

多氟代二苯并对二噁英(PFDDs)有76种系列化合物，结构与二噁英类似，具有有机氟化物的稳定性高、难降解等特征，在垃圾焚烧的烟气、化工产品中已有检出。本研究以PFDDs为研究对象，拟合成20余种结构上有代表性的PFDDs异构体，测定它们对生物体的氧化应激效应、对组织痕量金属平衡的影响、对DNA损伤、内分泌干扰效应和激活芳香烃受体效应等环境相关性质，比较PFDDs的毒理效应与氯代、溴代二苯并对二噁英的毒性效应的变化规律的异同，并研究它们毒性差异的分子基础，采用分子对接方法研究PFDDs分子与生物激素受体和芳香烃受体(AhR)蛋白相互作用方式的模型，从微观水平上解释配体-受体相互作用的机理，从而初步提出PFDDs内分泌干扰效应和激活芳香烃受体效应的致毒机制。本研究将为研究PFDDs在环境中的的迁移、转化及其致毒机理提供基础信息，为这类化合物的环境生态风险评价提供理论依据。

多氟代二苯并对二噁英(PFDDs)有76种系列化合物，结构与二噁英类似，具有稳定性高、难降解等特征，在垃圾焚烧的烟气、化工产品中已有检出。首先，本研究合成了22种结构上具有代表性的PFDDs异构体，并通过核磁共振氢谱和气质联用对合成的PFDDs进行了结构鉴定。其次，针对具有代表性的PFDDs，分别研究了它们对水生生物锦鲫鱼体肝脏的氧化应激效应、小鼠肝脏脱乙基酶(EROD)的诱导作用、离体大鼠肝癌细胞株H4IIE的细胞毒性和AhR受体效应、以及对斑马鱼胚胎的急性毒性。结果表明：（1）与对照组相比，一些PFDDs暴露组鱼体肝脏中超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、非酶抗氧化剂还原型谷胱甘肽(GSH)含量和谷胱甘肽S-转移酶(GST)活性受到显著抑制，而脂质过氧化产物丙二醛(MDA)含量普遍升高，表明PFDDs暴露导致机体受到过多氧自由基的攻击，使机体细胞产生氧化应激和损伤。（2）雄性小鼠注射染毒PFDDs后，不同浓度的PFDDs（1,8-di-FDD, 1,3,8-tri-FDD, 1,3,6,8-tetra-FDD, 2,3,7,8-tetra-FDD和1,2,3,4,5,6,7,8-octa-FDD）对小鼠肝脏EROD活性均有一定的诱导作用，同时在实验过程中测定体重和器官的重量变化，发现各种PFDDs都表现出显著的抑制小鼠生长的趋势。肝脏作为生物体的解毒器官，占身体的比重随着毒性物质剂量的增加而变大，其中最显著的是1,2,3,4,5,6,7,8-FDD。而肾脏和脾脏作为生物体的产尿和造血器官肾脏萎缩比较严重的是2,3,7,8-FDDs和1,8-FDDs，而脾脏在染毒1,8-FDDs和1,3,8-FDDs后变化更明显。（3）PFDDs化合物的细胞毒性、AhR受体效应和斑马鱼胚胎研究表明PFDDs暴露组具有轻微的细胞毒性（p>0.05），同时，14种PFDDs所诱导的AhR活性不到TCDD的10 %。另外，我们还进一步初步研究了PFDDs部分理化性质的定量构效关系，比如：由•OH引发的大气氧化降解机理的模拟计算研究；18个PFDDs在有机溶剂中的降解动力学及其降解机理；共存物质对UV/Fe(Ⅱ)/PMS体系光解OFDD速度的影响等。本研究为研究PFDDs在环境中的的迁移、转化及其致毒机理提供了基础信息，为这类化合物的环境生态风险评价提供理论依据。