Cresyl diphenyl phosphate (CDP), a novel organophosphate ester (OPE), has been increasingly detected in various environmental and human samples. However, its toxicity, mechanisms, and health risks remain largely unknown. In this work, we investigated CDP-induced hepatic steatosis through Liver X Receptor α (LXRα) pathway across the molecular interactions, signaling pathways, cell functions, animal effects, and population risks, and compared them to triphenyl phosphate (TPHP) and tricresyl phosphate (TCRP). Receptor binding results showed that all three OPEs bound to LXRα directly in the order of TCRP > CDP > TPHP. Docking results suggested that the three aryl groups played an essential role in the binding of these chemicals to LXRα. They also activated LXRα-mediated lipogenesis pathway and promoted lipid accumulation in HepG2 cells. The intracellular concentration and LXRα-bound concentration of the chemicals in HepG2 cells followed a consistent order of CDP > TCRP > TPHP. In mice, exposure to CDP activated LXRα-mediated de novo lipogenesis pathway, leading to hepatic steatosis. Risk assessment results suggested that few populations (5.38 %) face a LXRα-mediated hepatic steatosis risk from CDP exposure. Collectively, our results demonstrate that CDP could bind to LXRα, activate the subsequent de novo lipogenesis pathway, inducing hepatic steatosis, and increasing adverse health risks.

中文翻译：

---

甲酚基二苯基磷酸酯（一种新型有机磷酸酯）通过直接与肝脏 X 受体结合诱导肝脂肪变性α：从分子作用到风险评估


甲酚基二苯基磷酸酯 （CDP） 是一种新型有机磷酸酯 （OPE），已越来越多地在各种环境和人类样品中检测到。然而，它的毒性、机制和健康风险在很大程度上仍然未知。在这项工作中，我们研究了 CDP 通过肝脏 X 受体 α （LXRα） 通路诱导的肝脂肪变性在分子相互作用、信号通路、细胞功能、动物影响和群体风险方面，并将它们与磷酸三苯酯 （TPHP） 和磷酸三甲苯酯 （TCRP） 进行了比较。受体结合结果显示，所有三种 OPE 都按照 TCRP > CDP > TPHP 的顺序直接与 LXRα 结合。对接结果表明，三个芳基在这些化学物质与 LXRα 的结合中起着至关重要的作用。它们还激活 LXRα 介导的脂肪生成途径并促进 HepG2 细胞中的脂质积累。HepG2 细胞中化学物质的细胞内浓度和 LXRα 结合浓度遵循 CDP > TCRP > TPHP 的一致顺序。在小鼠中，暴露于 CDP 会激活 LXRα 介导的新生脂肪生成途径，导致肝脂肪变性。风险评估结果表明，很少有人群 （5.38%） 面临 CDP 暴露的 LXRα 介导的肝脂肪变性风险。总的来说，我们的结果表明 CDP 可以与 LXRα 结合，激活随后的从头脂肪生成途径，诱导肝脂肪变性，并增加不良健康风险。