In vitro and in silico assessment of endocrine disrupting effects of food contaminants through pregnane X receptor.

Yuan Liang, Qiuyan Jiang, Yiyao Gong, Yifan Yu, Haoyang Zou, Jingqi Zhao, Tiehua Zhang, Jie Zhang

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2023 May

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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. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Yuan Liang, Qiuyan Jiang, Yiyao Gong, Yifan Yu, Haoyang Zou, Jingqi Zhao, Tiehua Zhang, Jie Zhang. In vitro and in silico assessment of endocrine disrupting effects of food contaminants through pregnane X receptor. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2023 May;175:113711