Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; School of Public Health, Qingdao University, Qingdao 266000, China.
Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
Ecotoxicol Environ Saf. 2022 Jan 1;229:113069. doi: 10.1016/j.ecoenv.2021.113069. Epub 2021 Dec 8.
As the typical aryl-organophosphate flame retardants (OPFRs), triphenyl phosphate (TPhP) and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) were reported to be estrogen disruptors. However, estrogen receptor α (ERα) binding experiments could not explain their biological effects. In this study, their action on ERα, G protein-coupled estrogen receptor (GPER) and the synthesis of 17β-estradiol (E2) were investigated using in vitro assays and molecular docking. The results showed that TPhP acted as an ERα agonist and recruited steroid receptor co-activator 1 (SRC1) and 3 (SRC3), which was found for the first time. Unlike TPhP, TDCIPP acted as an ERα antagonist. However, both TPhP and TDCIPP activated the estrogen pathway by GPER in SKBR3 cells which were lack of ERα. Although molecular docking results revealed that both TPhP and TDCIPP could dock into ERα and GPER, their substituent groups and combination mode might affect the receptor activation. In addition, by using estrogen biosynthesis assay in H295R cells, both of TPhP and TDCIPP were found to promote E2 synthesis and E2/T ratio involving their different alteration on levels of progesterone, testosterone and estrone, and expression of various key genes. Our data proposed estrogen-disrupting mechanism frameworks of TPhP and TDCIPP. Moreover, our results will contribute to future construction of adverse outcome pathway (AOP) framework of endocrine disruptors.
作为典型的芳基有机磷酸酯阻燃剂（OPFRs），磷酸三苯酯（TPhP）和磷酸三（1,3-二氯-2-丙基）酯（TDCIPP）被报道为雌激素干扰物。然而，雌激素受体α（ERα）结合实验无法解释它们的生物学效应。在这项研究中，使用体外测定和分子对接研究了它们对 ERα、G 蛋白偶联雌激素受体（GPER）和 17β-雌二醇（E2）合成的作用。结果表明，TPhP 作为 ERα 激动剂起作用，并招募了类固醇受体共激活因子 1（SRC1）和 3（SRC3），这是首次发现。与 TPhP 不同，TDCIPP 作为 ERα 拮抗剂起作用。然而，TPhP 和 TDCIPP 均可通过缺乏 ERα 的 SKBR3 细胞中的 GPER 激活雌激素途径。尽管分子对接结果表明 TPhP 和 TDCIPP 均可与 ERα 和 GPER 结合，但它们的取代基基团和结合方式可能会影响受体的激活。此外，通过在 H295R 细胞中进行雌激素生物合成测定，发现 TPhP 和 TDCIPP 均可促进 E2 合成和 E2/T 比值，涉及它们对孕酮、睾酮和雌酮水平以及各种关键基因表达的不同改变。我们的数据提出了 TPhP 和 TDCIPP 的雌激素干扰机制框架。此外，我们的结果将有助于未来构建内分泌干扰物的不良结局途径（AOP）框架。
