Structure-Oriented Research on the Antiestrogenic Effect of Organophosphate Esters and the Potential Mechanism

Organophosphate esters (OPEs) can exhibit various toxicities including endocrine disruption activity. Unfortunately, the low-dose endocrine-disrupting effects mediated by estrogen receptors (ERs) are commonly underestimated for OPEs and their metabolites. Here, structure-oriented research was perfor...

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Bibliographic Details
Published inEnvironmental science & technology Vol. 54; no. 22; pp. 14525 - 14534
Main Authors Li, Juan, Cao, Huiming, Mu, Yunsong, Qu, Guangbo, Zhang, Aiqian, Fu, Jianjie, Jiang, Guibin
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 17.11.2020
Subjects
Biological Assay
China
Disruption
Ecotoxicology and Public Health
Eigenvalues
Endocrine disruptors
Environmental Monitoring
Esters
Estrogen receptors
Estrogens
Flame Retardants
Hydrophobicity
Metabolites
Molecular docking
Molecular Docking Simulation
Organophosphates
Organophosphates - toxicity
Phosphate esters
Statistical analysis
Toxicity
Tricresyl phosphate
Xenoestrogens
China
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Summary:Organophosphate esters (OPEs) can exhibit various toxicities including endocrine disruption activity. Unfortunately, the low-dose endocrine-disrupting effects mediated by estrogen receptors (ERs) are commonly underestimated for OPEs and their metabolites. Here, structure-oriented research was performed to investigate the estrogenic/antiestrogenic effect of 13 OPEs (including three metabolites) and the potential mechanism. All of the OPEs exerted antiestrogenic activities in both E-screen and MVLN assays. OPEs with bulky substituents, such as phenyl rings (triphenyl phosphate (TPP), tricresyl phosphate (TCP), diphenylphosphoryl chloride, and diphenylphosphite) or relatively long alkyl chains (dibutylbutylphosphonate (DBBP)), exerted relatively strong ER antagonism potency at micromolar concentrations. The established quantitative structure–activity relationship indicated that the antiestrogenic activities of the OPEs mainly depended on the volume, leading eigenvalue, and hydrophobicity of the molecule. Molecular docking revealed that the three OPEs with the bulkiest substituents on the phosphate ester group (TPP, TCP, and DBBP) have a similar interaction mode to the classical ER antagonist 4-hydroxytamoxifen. The correlation between the antiestrogenic activity and the corresponding ER binding affinity was statistically significant, strongly suggesting that the OPEs possess the classical antagonism mechanism of interfering with the positioning of helix 12 in the ER.
ISSN:0013-936X
1520-5851
DOI:10.1021/acs.est.0c04376