An exploration of the estrogen receptor transcription activity of capsaicin analogues via an integrated approach based on in silico prediction and in vitro assays

Li, Juan; Ma, Ding; Lin, Yuan; Fu, Jianjie; Zhang, Aiqian

doi:10.1016/j.toxlet.2014.04.007

Cited by 8 publications

(7 citation statements)

References 37 publications

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“…Finally, only molecular connectivity indices (MCIs) and solvation connectivity indices of the tested compounds were included. The effect of the structural characteristics on cell proliferation was explored by a simplified QSAR model established using the logistic modeling method. , The relationship between the biological activity data and molecular structure descriptors was obtained by the stepwise linear regression method with a confidence interval of 95%. Considering that the test set used in the present study was too small to be divided into two parts for the robustness testing of the QSAR model, full sets of data were adopted for the regression analysis with no compulsory estimation of the degree of freedom .…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the Estrogenic/Antiestrogenic Activities of Perfluoroalkyl Substances and Their Interactions with the Human Estrogen Receptor by Combining In Vitro Assays and In Silico Modeling

Cao

Feng

et al. 2020

Environ. Sci. Technol.

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The potential estrogenic activities of perfluoroalkyl substances (PFASs) are controversial. Here, we investigated the estrogenic/antiestrogenic activities of PFASs and explored the corresponding interaction mode of PFASs with the estrogen receptor (ER) by combining in vitro assays and in silico modeling. We found that three PFASs (perfluorobutanoic acid, perfluorobutane sulfonate, and perfluoropentanoic acid) exerted antiestrogenic effects by inhibiting luciferase activity, whereas perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) exerted estrogenic effects by inducing luciferase activity. When coexposed to 17β-estradiol (E2), all tested PFASs attenuated the E2-stimulated luciferase activity; unexpectedly, each PFAS could further attenuate the luciferase activity generated by the cotreatment with ICI 182,780 and E2, with a minimal effective concentration comparable to that found in human serum. PFHxS and PFOS significantly induced the gene expression of TFF1; additionally, all PFASs inhibited the E2-induced gene expression of TFF1 and EGR3. Furthermore, the results of the blind docking analyses suggested that the interaction with the coactivator-binding region on the ER surface should be included as a pathway through which PFASs exert estrogenic and antiestrogenic activities. Finally, we revealed the critical molecular property of the zero-order molecular connectivity index (MCI) (0χ) that affects the antiestrogenic activity of PFASs.

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Section: Methodsmentioning

confidence: 99%

Evaluation of the Estrogenic/Antiestrogenic Activities of Perfluoroalkyl Substances and Their Interactions with the Human Estrogen Receptor by Combining In Vitro Assays and In Silico Modeling

Cao

Feng

et al. 2020

Environ. Sci. Technol.

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“…The details of the process of QSAR development and statistical significance verification can be found in our previous studies (see the Supporting Information). , …”

Section: Methodsmentioning

confidence: 99%

“…According to the 21st century toxic testing report, in vitro assays combined with in silico models are highly recommended for toxicity exploration of environmental pollutants . In particular, molecular docking, quantitative structure–activity relationship (QSAR) prediction models, and well-designed in vitro experiments have been successfully applied to determine and predict the molecular structural properties that mainly contribute to the interaction between compounds and nuclear receptor proteins. − In the present study, to determine the estrogenic-like and/or antiestrogenic effects of 13 OPEs (including three metabolites) with different substituent groups, including phenyl rings, halogenated alkyl chains, and alkyl chains, we performed a comprehensive study by combining three in vitro methods that are specific to human breast tissue: E-screen assay, MVLN assay, and detection of estrogen-responsive genes in MCF-7 cells. Furthermore, a QSAR model was developed to identify and describe the structural features that contribute to the ability of the 13 analytes to interact with hERα.…”

Section: Introductionmentioning

confidence: 99%

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

Cao

et al. 2020

Environ. Sci. Technol.

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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.

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“…Several of the treatments (OHT and OHT + BNF) significantly reduced both Vtg gene and protein expression in a similar manner, illustrating the close coherence between the gene and protein responses of this estrogenic biomarker . The wellcharacterised anti-estrogen OHT competitively bind to the ER and act as a partial ERantagonist (Macgregor and Jordan, 1998;Li et al, 2014) and agonist (Wu et al, 2005) in different in vivo and in vitro assays from mammals and in fish. The present study concluded that OHT alone did not significantly induce any of the ER-target genes (er-α, zrp, vtg-1) ( Supplementary Fig.…”

Section: Er Signallingmentioning

confidence: 99%

Characterizing combined effects of antiestrogenic chemicals on vitellogenin production in rainbow trout (Oncorhynchus mykiss) hepatocytes

Hultman

Petersen

Tollefsen

2017

Journal of Toxicology and Environmental Health, Part A

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Fish are exposed to a complex mixture of endocrine disrupting compounds (EDC), some of which display antiestrogenic activity leading to suppression of estrogen receptor (ER)- mediated reproductive processes. Although the main mode of action (MoA) of these antiestrogens is to directly interfere with natural ligand binding of the ER, several other MoA have been proposed. The aim of the present study was to characterize single and combined antiestrogenic effects of the aryl hydrocarbon receptor (AhR)-agonist β-naphthoflavone (BNF) and ER-antagonist 4-hydroxytamoxifen (OHT) on vitellogenin (Vtg) protein using primary rainbow trout (Oncorhynchus mykiss) hepatocytes. Supporting transcriptional analysis of ER-responsive genes (estrogen receptor-α (er-α), vitellogenin-1 (vtg-1), eggshell zona radiata protein (zrp)) and AhR-mediated genes (aryl hydrocarbon receptor-2β, cytochrome p450-1a (cyp1a)) was performed by qPCR to characterize the antiestrogenic influence on ER- and AhR-mediated responses. Data demonstrated that both BNF and OHT significantly reduced 17β-estradiol (E2)-induced Vtg protein expression in a concentration responsive manner, whereas exposure to a mixture of these produced an additive antiestrogenic effect. The results observed at the protein level were further supported by transcriptional analysis of ER-responsive genes (er-α, vtg-1, zrp), where only E2-induced vtg-1 gene expression was significantly decreased by OHT and the mixture of OHT and BNF. E2-induced er-α and zrp gene expression was not markedly altered. The significant reduction of E2-induced vtg-1 gene expression by OHT suggested that the antiestrogenic effect of this compound may be associated with ER signaling pathway. Specific genes involved in putative AhR-ER cross-talk were also investigated, however none were directly associated with the compound anti-estrogenic MoA. Although the MoA of the single compounds and mixture were not completely characterized, the present study enhanced our knowledge of the combined toxicity mediated by antiestrogens acting through different MoA.

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An exploration of the estrogen receptor transcription activity of capsaicin analogues via an integrated approach based on in silico prediction and in vitro assays

Cited by 8 publications

References 37 publications

Evaluation of the Estrogenic/Antiestrogenic Activities of Perfluoroalkyl Substances and Their Interactions with the Human Estrogen Receptor by Combining In Vitro Assays and In Silico Modeling

Evaluation of the Estrogenic/Antiestrogenic Activities of Perfluoroalkyl Substances and Their Interactions with the Human Estrogen Receptor by Combining In Vitro Assays and In Silico Modeling

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

Characterizing combined effects of antiestrogenic chemicals on vitellogenin production in rainbow trout (Oncorhynchus mykiss) hepatocytes

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