Engineering Research Center of Groundwater Pollution Control and Remediation, Ministry of Education, College of Water Sciences, Beijing Normal University, Beijing, 100875, China.
Engineering Research Center of Groundwater Pollution Control and Remediation, Ministry of Education, College of Water Sciences, Beijing Normal University, Beijing, 100875, China.
Chemosphere. 2020 Oct;256:127066. doi: 10.1016/j.chemosphere.2020.127066. Epub 2020 May 13.
Tri(1,3-dichloropropyl) phosphate (TDCPP) potentially damages the thyroid system in humans and animals. However, knowledge of its toxic effects and underlying mechanisms is limited. The present study was conducted to determine the thyroid hormone-disrupting effects of TDCPP and its major metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP) in rat pituitary cell lines (GH3). TDCPP and BDCPP, that mimic the thyroid hormone (TH), promoted GH3 cell proliferation and modulated the progression of the cell cycle at 20 and 200 μmol/L, respectively. Similar to T3, TDCPP and BDCPP also significantly upregulated c-fos and downregulated Tshβ gene expression. Although the binding affinity of these chemicals for thyroid receptor β (TRβ) was not measured, significant competition between these chemicals to bind to the membrane thyroid hormone receptor (integrin αβ) was found, suggesting that TDCPP and BDCPP were strongly bound to integrin αβ. Results from a molecular docking analysis provided further evidence of strong binding affinities of TDCPP and BDCPP for integrin αβ, and the ligand binding site of Arg-Gly-Asp (RGD) was identified. Real-time PCR also supported the supposition that, after binding to integrin αβ, TDCPP and BDCPP may induce the activation of the extracellular signal-regulated protein kinase (ERK1/2) signal transduction pathway. Taken together, our data suggest that TDCPP and BDCPP have the ability to mimic THs and that the underlying mechanism might be associated with their interactions with integrin αβ and the activation of the ERK1/2 pathway, providing new insight into the mechanism of TDCPP- and BDCPP-induced cytotoxicity.
磷酸三（1,3-二氯丙基）酯（TDCPP）可能会对人类和动物的甲状腺系统造成损害。然而，其毒性作用和潜在机制的知识有限。本研究旨在确定 TDCPP 及其主要代谢物双（1,3-二氯-2-丙基）磷酸酯（BDCPP）对大鼠垂体细胞系（GH3）的甲状腺激素干扰作用。TDCPP 和 BDCPP 模拟甲状腺激素（TH），分别在 20 和 200 μmol/L 时促进 GH3 细胞增殖并调节细胞周期进程。与 T3 相似，TDCPP 和 BDCPP 还显著上调了 c-fos 并下调了 Tshβ 基因的表达。尽管这些化学物质与甲状腺受体 β（TRβ）的结合亲和力未被测量，但发现这些化学物质与膜甲状腺激素受体（整合素 αβ）之间存在显著的竞争，表明 TDCPP 和 BDCPP 与整合素 αβ 强烈结合。分子对接分析的结果进一步提供了 TDCPP 和 BDCPP 与整合素 αβ 具有强烈结合亲和力的证据，并确定了配体结合位点为 Arg-Gly-Asp（RGD）。实时 PCR 也支持了这样的假设，即在与整合素 αβ 结合后，TDCPP 和 BDCPP 可能会诱导细胞外信号调节蛋白激酶（ERK1/2）信号转导途径的激活。综上所述，我们的数据表明 TDCPP 和 BDCPP 具有模拟 TH 的能力，其潜在机制可能与它们与整合素 αβ 的相互作用以及 ERK1/2 途径的激活有关，为 TDCPP 和 BDCPP 诱导细胞毒性的机制提供了新的见解。
