Liu Hongling, Ma Zhiyuan, Zhang Tao, Yu Nanyang, Su Guanyong, Giesy John P, Yu Hongxia
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China.
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210023, China; Toxicology Centre and Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada; School of Biological Sciences, University of Hong Kong, China.
Chemosphere. 2018 Jan;190:243-252. doi: 10.1016/j.chemosphere.2017.09.137. Epub 2017 Sep 29.
In silico and in vivo approaches were combined in an aggregate exposure pathway (AEP) to assess accumulation and effects of waterborne exposures of early life stages of zebrafish (Danio rerio) to tetrabromobisphenol A (TBBPA). Three metabolites, two of which were isomers, were detected in fish. Two additional metabolites were detected in the exposure solution. Based on kinetics modeling, proportions of TBBPA that were bioaccumulated and metabolized were 19.33% and 8.88%, respectively. Effects of TBBPA and its metabolites were predicted by use of in silico, surflex-Dock simulations that they were capable of interacting with ThRα and activating associated signaling pathways. TBBPA had a greater toxic contribution than its metabolites did when we evaluated the toxicity of these substances based on the toxicity unit method. The half of the internal lethal dose (ILD) was 18.33 μg TBBPA/g at 74 hpf. This finding was further confirmed by changes in expressions of ThRα and other NRs as well as associated genes in their signal pathways. Specifically, exposure to 1.6 × 10, 3.3 × 10 or 6.5 × 10 μg TBBPA/L significantly down-regulated expression of ThRα and associated genes, ncor, c1d, ncoa2, ncoa3, and ncoa4, in the AR pathway and of er2a and er2b genes in the ER pathway.
将计算机模拟和体内实验方法结合在一个累积暴露途径（AEP）中，以评估斑马鱼（Danio rerio）幼鱼通过水体接触四溴双酚A（TBBPA）的累积情况和影响。在鱼体内检测到三种代谢物，其中两种是异构体。在暴露溶液中还检测到另外两种代谢物。基于动力学模型，生物累积和代谢的TBBPA比例分别为19.33%和8.88%。通过计算机模拟Surflex-Dock预测TBBPA及其代谢物的影响，它们能够与甲状腺激素受体α（ThRα）相互作用并激活相关信号通路。当我们基于毒性单位法评估这些物质的毒性时，TBBPA的毒性贡献比其代谢物更大。在74小时胚胎期（hpf）时，半数致死剂量（ILD）的一半为18.33μg TBBPA/g。甲状腺激素受体α和其他核受体（NRs）及其信号通路中相关基因表达的变化进一步证实了这一发现。具体而言，暴露于1.6×10、3.3×10或6.5×10μg TBBPA/L会显著下调AR途径中ThRα和相关基因ncor、c1d、ncoa2、ncoa3和ncoa4以及ER途径中er2a和er2b基因的表达。
