In vitro and in silico assessment of endocrine disrupting effects of food contaminants through pregnane X receptor. (May 2023)

• Record Type: Journal Article
• Authors: Liang, Yuan; Jiang, Qiuyan; Gong, Yiyao; Yu, Yifan; Zou, Haoyang; Zhao, Jingqi; Zhang, Tiehua; Zhang, Jie
• Is Part Of: Food and chemical toxicology. Volume 175(2023)
• Publication Date: 2023-05
• Subjects: Risk assessment -- Endocrine disrupting effects -- Food contaminants pregnane X receptor (PXR); Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2023.113711
• Languages: English
• ISSNs: 0278-6915

Abstract

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. Highlights: PXR binding affinities of food contaminants were determined by TR-FRET assays. PXR agonist activities of these compounds were confirmed by reporter gene assays. These compounds interfered with the expressions of PXR and its related genes. Structural basis of their PXR binding capacities was explored by computer simulation. These compounds might exhibit endocrine disrupting effects via PXR.