Evaluation of the Estrogenic/Antiestrogenic Activities of Perfluoroalkyl Substances and Their Interactions with the Human Estrogen Receptor by Combining In Vitro Assays and In Silico Modeling
Evaluation of the Estrogenic/Antiestrogenic Activities of Perfluoroalkyl Substances and Their Interactions with the Human Estrogen Receptor by Combining In Vitro Assays and In Silico Modeling
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通过结合体外测定和计算机模拟评估全氟烷基物质的雌激素/抗雌激素活性及其与人类雌激素受体的相互作用。
DOI：
10.1021/acs.est.0c03468
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发表时间：
2020-11-17
影响因子：
11.4
通讯作者：
Fu, Jianjie
中科院分区：
文献类型：
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作者：
Li, Juan;Cao, Huiming;Fu, Jianjie
全氟烷基物质（PFASs）的潜在雌激素活性是有争议的。本研究采用体外实验和计算机模拟相结合的方法，研究了PFASs的雌激素/抗雌激素活性，并探讨了PFASs与雌激素受体（ER）的相互作用模式。我们发现三种PFAS（全氟丁酸、全氟丁烷磺酸和全氟戊酸）通过抑制荧光素酶活性发挥抗雌激素作用，而全氟己烷磺酸（PFHxS）和全氟辛烷磺酸（PFOS）通过诱导荧光素酶活性发挥雌激素作用。当共暴露于17β-雌二醇（E2）时，所有检测的PFAS均减弱E2刺激的荧光素酶活性;出乎意料的是，每种PFAS均能进一步减弱ICI 182，780和E2共处理产生的荧光素酶活性，最低有效浓度与人血清中的浓度相当。PFHxS和PFOS显著诱导TFF 1基因表达;此外，所有PFASs均抑制E2诱导的TFF 1和EGR 3基因表达。此外，盲对接分析的结果表明，与ER表面辅激活因子结合区的相互作用应被视为PFAS发挥雌激素和抗雌激素活性的途径。最后，我们揭示了影响PFAS抗雌激素活性的关键分子特性，即零级分子连接性指数（MCI）（0χ）。
The potential estrogenic activities of perfluoroalkyl substances (PFASs) are controversial. Here, we investigated the estrogenic/antiestrogenic activities of PFASs and explored the corresponding interaction mode of PFASs with the estrogen receptor (ER) by combining in vitro assays and in silico modeling. We found that three PFASs (perfluorobutanoic acid, perfluorobutane sulfonate, and perfluoropentanoic acid) exerted antiestrogenic effects by inhibiting luciferase activity, whereas perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) exerted estrogenic effects by inducing luciferase activity. When coexposed to 17β-estradiol (E2), all tested PFASs attenuated the E2-stimulated luciferase activity; unexpectedly, each PFAS could further attenuate the luciferase activity generated by the cotreatment with ICI 182,780 and E2, with a minimal effective concentration comparable to that found in human serum. PFHxS and PFOS significantly induced the gene expression of TFF1; additionally, all PFASs inhibited the E2-induced gene expression of TFF1 and EGR3. Furthermore, the results of the blind docking analyses suggested that the interaction with the coactivator-binding region on the ER surface should be included as a pathway through which PFASs exert estrogenic and antiestrogenic activities. Finally, we revealed the critical molecular property of the zero-order molecular connectivity index (MCI) (0χ) that affects the antiestrogenic activity of PFASs.