Abstract：
As a promiscuous xenobiotic receptor, pregnane X receptor (PXR) has been confirmed to participate in numerous physiological process. In addition to the conventional estrogen/androgen receptor, PXR also serves as an alternative target for environmental chemical contaminants. In this work, the PXR-mediated endocrine disrupting effects of typical food contaminants were explored. Firstly, the time-resolved fluorescence resonance energy transfer assays confirmed the PXR binding affinities of 2,2\',4,4\',5,5\'-hexachlorobiphenyl, bis(2-ethylhexyl) phthalate, dibutyl phthalate, chlorpyrifos, bisphenol A, and zearalenone, with IC50 values ranging from 1.88 to 4284.00 nM. Then their PXR agonist activities were assessed by PXR-mediated CYP3A4 reporter gene assays. Subsequently, the regulation of gene expressions of PXR and its targets CYP3A4, UGT1A1, and MDR1 by these compounds was further investigated. Intriguingly, all the tested compounds interfered with these gene expressions, confirming their endocrine disrupting effects via PXR-mediated signaling. The compound-PXR-LBD binding interactions were explored by molecular docking and molecular dynamics simulations to unravel the structural basis of their PXR binding capacities. The weak intermolecular interactions are key players in stabilizing these compound-PXR-LBD complexes. During the simulation process, 2,2\',4,4\',5,5\'-hexachlorobiphenyl remained stable while the other 5 compounds underwent relatively severe disturbances. In conclusion, these food contaminants might exhibit endocrine disrupting effects via PXR.
摘要：
作为一种混杂的异种生物受体，孕烷X受体（PXR）已被证实参与许多生理过程。除了常规的雌激素/雄激素受体，PXR还作为环境化学污染物的替代目标。在这项工作中,探讨了PXR介导的典型食品污染物的内分泌干扰作用。首先,时间分辨荧光共振能量转移试验证实了2,2'的PXR结合亲和力，4,4\'，5,5'-六氯联苯，邻苯二甲酸二(2-乙基己基)酯,邻苯二甲酸二丁酯,毒死蜱,双酚A,和玉米赤霉烯酮,IC50值范围为1.88至4284.00nM。然后通过PXR介导的CYP3A4报告基因测定来评估它们的PXR激动剂活性。随后，进一步研究了这些化合物对PXR及其靶标CYP3A4，UGT1A1和MDR1的基因表达的调控。有趣的是，所有测试的化合物都干扰了这些基因的表达，证实它们通过PXR介导的信号传导的内分泌干扰作用。通过分子对接和分子动力学模拟探索化合物-PXR-LBD结合相互作用，以揭示其PXR结合能力的结构基础。弱的分子间相互作用是稳定这些化合物-PXR-LBD复合物的关键因素。在模拟过程中,2,2\'，4,4\'，5,5'-六氯联苯保持稳定，而其他5种化合物则受到相对严重的干扰。总之,这些食物污染物可能通过PXR表现出内分泌干扰作用。
