CAS Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research (YIC), Chinese Academy of Sciences (CAS); Shandong Key Laboratory of Coastal Environmental Processes, YICCAS, Yantai, 264003, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
Yantai Yuhuangding Hosp, Dept Western Med, Yuhuangdingdong Rd 20, Yantai, 264000, Shandong, PR China.
Chemosphere. 2022 Jan;287(Pt 4):132419. doi: 10.1016/j.chemosphere.2021.132419. Epub 2021 Sep 29.
Endocrine-disrupting chemicals can interfere with hormone action via various pathways, thereby increasing the risk of adverse health outcomes. Organophosphorus ester (OPEs) retardants, a group of new emerging endocrine disruption chemicals, have been referred to as metabolism disruptors and reported to induce chronic health problems. However, the toxicity pathways were mainly focused on nuclear receptor signaling pathways. Significantly, the membrane receptor pathway (such as G protein-coupled estrogen receptor 1 (GPER) signaling pathway) had been gradually realized as the important role in respond more effective to lipid metabolism disorder than traditional nuclear receptors, whereas the detailed mechanism was unclear yet. Therefore, this study innovatively integrated the bibliometric analysis, in silico and in vitro approach to develop toxicity pathways for the mechanism interpretation. Bibliometric analysis found that the typical OPEs - triphenyl phosphate was a major concern of lipid metabolism abnormality. Results verified that TPP could damage the structures of cell membranes and exert an agonistic effect of GPER as the molecular initiating event. Then, the activated GPER could trigger the PI3K-Akt/NCOR1 and mTOR/S6K2/PPARα transduction pathways as key event 1 (KE1) and affect the process of lipid metabolism and synthesis (CPT1A, CPT2, SREBF2 and SCD) as KE2. As a result, these alterations led to lipid accumulation as adverse effect at cellular-levels. Furthermore, the potential outcomes (such as immunity damage, weight change and steatohepatitis) at high biological levels were expanded. These findings improved knowledge to deeply understand toxicity pathways of phosphorus flame retardants and then provided a theoretical basis for risk assessments.
内分泌干扰化学物质可以通过多种途径干扰激素作用，从而增加不良健康结果的风险。有机磷酯 (OPE) 阻燃剂是一组新出现的内分泌干扰化学物质，被称为代谢干扰物，并被报道会导致慢性健康问题。然而，毒性途径主要集中在核受体信号通路。值得注意的是，膜受体途径（如 G 蛋白偶联雌激素受体 1 (GPER) 信号通路）已逐渐被认为在应对脂质代谢紊乱方面比传统核受体更有效，而其详细机制尚不清楚。因此，本研究创新性地整合了文献计量分析、计算和体外方法，以开发毒性途径来解释其机制。文献计量分析发现，典型的 OPEs-三苯基磷酸酯是脂质代谢异常的主要关注点。结果证实，TPP 可以破坏细胞膜的结构，并作为分子起始事件发挥 GPER 的激动作用。然后，激活的 GPER 可以作为关键事件 1 (KE1) 触发 PI3K-Akt/NCOR1 和 mTOR/S6K2/PPARα 转导途径，并影响脂质代谢和合成过程 (CPT1A、CPT2、SREBF2 和 SCD) 作为 KE2。结果，这些变化导致细胞水平的脂质积累作为不良影响。此外，还扩展了高生物学水平的潜在结果（如免疫损伤、体重变化和脂肪性肝炎）。这些发现提高了对磷系阻燃剂毒性途径的认识，为风险评估提供了理论依据。
