Structures of Endocrine-Disrupting Chemicals Correlate with the Activation of 12 Classic Nuclear Receptors

2021 ◽  
Author(s):  
Haoyue Tan ◽  
Qinchang Chen ◽  
Huixiao Hong ◽  
Emilio Benfenati ◽  
Giuseppina C. Gini ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Endocrine Disrupting Chemicals ◽  
Endocrine Disrupting

scholarly journals Virtual screening of potentially endocrine-disrupting chemicals against nuclear receptors and its application to identify PPARγ-bound fatty acids

2020 ◽  
Author(s):  
Chaitanya K. Jaladanki ◽  
Yang He ◽  
Li Na Zhao ◽  
Sebastian Maurer-Stroh ◽  
Lit-Hsin Loo ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Virtual Screening ◽  
Nuclear Receptors ◽  
Endocrine Disrupting Chemicals ◽  
Screening Method ◽  
The Body ◽  
Cyclopropane Fatty Acid ◽  
Peroxisome Proliferator ◽  
Endocrine Disrupting ◽  
Multiple Structures

Abstract Nuclear receptors (NRs) are key regulators of energy homeostasis, body development, and sexual reproduction. Xenobiotics binding to NRs may disrupt natural hormonal systems and induce undesired adverse effects in the body. However, many chemicals of concerns have limited or no experimental data on their potential or lack-of-potential endocrine-disrupting effects. Here, we propose a virtual screening method based on molecular docking for predicting potential endocrine-disrupting chemicals (EDCs) that bind to NRs. For 12 NRs, we systematically analyzed how multiple crystal structures can be used to distinguish actives and inactives found in previous high-throughput experiments. Our method is based on (i) consensus docking scores from multiple structures at a single functional state (agonist-bound or antagonist-bound), (ii) multiple functional states (agonist-bound and antagonist-bound), and (iii) multiple pockets (orthosteric site and alternative sites) of these NRs. We found that the consensus enrichment from multiple structures is better than or comparable to the best enrichment from a single structure. The discriminating power of this consensus strategy was further enhanced by a chemical similarity-weighted scoring scheme, yielding better or comparable enrichment for all studied NRs. Applying this optimized method, we screened 252 fatty acids against peroxisome proliferator-activated receptor gamma (PPARγ) and successfully identified 3 previously unknown fatty acids with Kd = 100–250 μM including two furan fatty acids: furannonanoic acid (FNA) and furanundecanoic acid (FUA), and one cyclopropane fatty acid: phytomonic acid (PTA). These results suggested that the proposed method can be used to rapidly screen and prioritize potential EDCs for further experimental evaluations.

scholarly journals New Modes of Action for Endocrine-Disrupting Chemicals

2006 ◽  
Vol 20 (3) ◽  
pp. 475-482 ◽  
Author(s):  
Michelle M. Tabb ◽  
Bruce Blumberg
Keyword(s):  
Steroid Hormones ◽  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Methylation Status ◽  
Endocrine Disrupting Chemicals ◽  
Steroid Hormone Receptors ◽  
Protein Kinase Activity ◽  
Naturally Occurring ◽  
Endocrine Disrupting ◽  
Xenobiotic Chemicals

Abstract Endocrine-disrupting chemicals (EDC) are commonly considered to be compounds that mimic or block the transcriptional activation elicited by naturally circulating steroid hormones by binding to steroid hormone receptors. For example, the Food Quality Protection Act of 1996 defines EDC as those, that “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate.” The definition of EDC was later expanded to include those that act on the estrogen, androgen, and thyroid hormone receptors. In this minireview, we discuss new avenues through which xenobiotic chemicals influence these and other hormone-dependent signaling pathways. EDC can increase or block the metabolism of naturally occurring steroid hormones and other xenobiotic chemicals by activating or antagonizing nuclear hormone receptors. EDC affect the transcriptional activity of nuclear receptors by modulating proteasome-mediated degradation of nuclear receptors and their coregulators. Xenobiotics and environmental contaminants can act as hormone sensitizers by inhibiting histone deacetylase activity and stimulating mitogen-activated protein kinase activity. Some endocrine disrupters can have genome-wide effects on DNA methylation status. Others can modulate lipid metabolism and adipogenesis, perhaps contributing to the current epidemic of obesity. Additional elucidation of these new modes of endocrine disruption will be key in understanding the nature of xenobiotic effects on the endocrine system.

scholarly journals Correlation of Endocrine Disrupting Chemicals Serum Levels and White Blood Cells Gene Expression of Nuclear Receptors in a Population of Infertile Women

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Donatella Caserta ◽  
Francesca Ciardo ◽  
Giulia Bordi ◽  
Cristiana Guerranti ◽  
Emiliano Fanello ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptors ◽  
Limit Of Detection ◽  
Biological Effects ◽  
White Blood Cells ◽  
Endocrine Disrupting Chemicals ◽  
Internal Exposure ◽  
Infertile Women ◽  
Significant Difference ◽  
Endocrine Disrupting

Significant evidence supports that many endocrine disrupting chemicals could affect female reproductive health. Aim of this study was to compare the internal exposure to bisphenol A (BPA), perfluorooctane sulphonate (PFOS), perfluorooctanoic acid (PFOA), monoethylhexyl phthalate (MEHP), and di(2-ethylhexyl) phthalate (DEHP) in serum samples of 111 infertile women and 44 fertile women. Levels of gene expression of nuclear receptors (ERα, ERβ, AR, AhR, PXR, and PPARγ) were also analyzed as biomarkers of effective dose. The percentage of women with BPA concentrations above the limit of detection was significantly higher in infertile women than in controls. No statistically significant difference was found with regard to PFOS, PFOA, MEHP and DEHP. Infertile patients showed gene expression levels of ERα, ERβ, AR, and PXR significantly higher than controls. In infertile women, a positive association was found between BPA and MEHP levels and ERα, ERβ, AR, AhR, and PXR expression. PFOS concentration positively correlated with AR and PXR expression. PFOA levels negatively correlated with AhR expression. No correlation was found between DEHP levels and all evaluated nuclear receptors. This study underlines the need to provide special attention to substances that are still widely present in the environment and to integrate exposure measurements with relevant indicators of biological effects.

scholarly journals Potential roles of nuclear receptors in mediating neurodevelopmental toxicity of known endocrine‐disrupting chemicals in ascidian embryos

2019 ◽  
Vol 86 (10) ◽  
pp. 1333-1347 ◽  
Author(s):  
Isa D. L. Gomes ◽  
Ievgeniia Gazo ◽  
Lydia Besnardeau ◽  
Céline Hebras ◽  
Alex McDougall ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Endocrine Disrupting Chemicals ◽  
Neurodevelopmental Toxicity ◽  
Endocrine Disrupting ◽  
Ascidian Embryos

scholarly journals Allosteric binding on nuclear receptors: Insights on screening of non-competitive endocrine-disrupting chemicals

2022 ◽  
Vol 159 ◽  
pp. 107009
Author(s):  
Chi Zhang ◽  
Jinqiu Wu ◽  
Qinchang Chen ◽  
Haoyue Tan ◽  
Fuyan Huang ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Endocrine Disrupting Chemicals ◽  
Endocrine Disrupting

scholarly journals Predicting Potential Endocrine Disrupting Chemicals Binding to Estrogen Receptor α (ERα) Using a Pipeline Combining Structure-Based and Ligand-Based in Silico Methods

2021 ◽  
Vol 22 (6) ◽  
pp. 2846
Author(s):  
Asma Sellami ◽  
Matthieu Montes ◽  
Nathalie Lagarde
Keyword(s):  
Estrogen Receptors ◽  
Nuclear Receptors ◽  
Environmental Protection Agency ◽  
Glucocorticoid Receptors ◽  
Estrogenic Activity ◽  
Endocrine Disrupting Chemicals ◽  
Peroxisome Proliferator ◽  
Consensus Protocol ◽  
Endocrine Disrupting ◽  
Pharmacophore Models

The estrogen receptors α (ERα) are transcription factors involved in several physiological processes belonging to the nuclear receptors (NRs) protein family. Besides the endogenous ligands, several other chemicals are able to bind to those receptors. Among them are endocrine disrupting chemicals (EDCs) that can trigger toxicological pathways. Many studies have focused on predicting EDCs based on their ability to bind NRs; mainly, estrogen receptors (ER), thyroid hormones receptors (TR), androgen receptors (AR), glucocorticoid receptors (GR), and peroxisome proliferator-activated receptors gamma (PPARγ). In this work, we suggest a pipeline designed for the prediction of ERα binding activity. The flagged compounds can be further explored using experimental techniques to assess their potential to be EDCs. The pipeline is a combination of structure based (docking and pharmacophore models) and ligand based (pharmacophore models) methods. The models have been constructed using the Environmental Protection Agency (EPA) data encompassing a large number of structurally diverse compounds. A validation step was then achieved using two external databases: the NR-DBIND (Nuclear Receptors DataBase Including Negative Data) and the EADB (Estrogenic Activity DataBase). Different combination protocols were explored. Results showed that the combination of models performed better than each model taken individually. The consensus protocol that reached values of 0.81 and 0.54 for sensitivity and specificity, respectively, was the best suited for our toxicological study. Insights and recommendations were drawn to alleviate the screening quality of other projects focusing on ERα binding predictions.

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