Wang Li, Zhou Lantian, Liu Longyu, Yang Yu, Zhao Qiang
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Sci Total Environ. 2023 Jun 10;876:162734. doi: 10.1016/j.scitotenv.2023.162734. Epub 2023 Mar 11.
DDT and its transformation products (DDTs) are frequently detected in environmental and biological media. Research suggests that DDT and its primary metabolites (DDD and DDE) could induce estrogenic effects by disturbing estrogen receptor (ER) pathways. However, the estrogenic effects of DDT high-order transformation products, and the exact mechanisms underlying the differences of responses in DDT and its metabolites (or transformation products) still remain unknown. Here, besides DDT, DDD and DDE, we selected two DDT high-order transformation products, 2,2-bis(4-chlorophenyl) ethanol (p,p'-DDOH) and 4,4'-dichlorobenzophenone (p,p'-DCBP). We aim to explore and reveal the relation between DDTs activity and their estrogenic effects by receptor binding, transcriptional activity, and ER-mediated pathways. Fluorescence assays showed that the tested 8 DDTs bound to the two isoforms (ERα and ERβ) of ER directly. Among them, p,p'-DDOH exhibited the highest binding affinity, with IC values of 0.43 μM and 0.97 μM to ERα and ERβ, respectively. Eight DDTs showed different agonistic activity toward ER pathways, with p,p'-DDOH exhibiting the strongest potency. In silico studies revealed that the eight DDTs bound to either ERα or ERβ in a similar manner to 17β-estradiol, in which specific polar and non-polar interactions and water-mediated hydrogen bonds were involved. Furthermore, we found that 8 DDTs (0.0008-5 μM) showed distinct pro-proliferative effects on MCF-7 cells in an ER-dependent manner. Overall, our results revealed not only for the first time the estrogenic effects of two DDT high-order transformation products by acting on ER-mediated pathways, but also the molecular basis for differential activity of 8 DDTs.
滴滴涕及其转化产物（滴滴涕类）经常在环境和生物介质中被检测到。研究表明，滴滴涕及其主要代谢物（滴滴滴和滴滴伊）可通过干扰雌激素受体（ER）途径诱导雌激素效应。然而，滴滴涕高阶转化产物的雌激素效应，以及滴滴涕及其代谢物（或转化产物）反应差异的具体机制仍然未知。在此，除了滴滴涕、滴滴滴和滴滴伊之外，我们还选择了两种滴滴涕高阶转化产物，2,2-双（4-氯苯基）乙醇（p,p'-DDOH）和4,4'-二氯二苯甲酮（p,p'-DCBP）。我们旨在通过受体结合、转录活性和ER介导的途径来探索和揭示滴滴涕类活性与其雌激素效应之间的关系。荧光分析表明，所测试的8种滴滴涕类直接与ER的两种亚型（ERα和ERβ）结合。其中，p,p'-DDOH表现出最高的结合亲和力，对ERα和ERβ的IC值分别为0.43 μM和0.97 μM。8种滴滴涕类对ER途径表现出不同的激动活性，p,p'-DDOH的效力最强。计算机模拟研究表明，这8种滴滴涕类与ERα或ERβ的结合方式与17β-雌二醇相似，其中涉及特定的极性和非极性相互作用以及水介导的氢键。此外，我们发现8种滴滴涕类（0.0008 - 5 μM）以ER依赖的方式对MCF-7细胞表现出明显的促增殖作用。总体而言，我们的结果不仅首次揭示了两种滴滴涕高阶转化产物通过作用于ER介导的途径产生的雌激素效应，还揭示了8种滴滴涕类差异活性的分子基础。
