Interaction of BDE-47 with nuclear receptors (NRs) based on the cytotoxicity: In vitro investigation and molecular interaction
Polybrominated diphenyl ethers (PBDEs) are endocrine-disrupting chemicals that possess neuroendocrine and reproductive toxicity to humans and disturb thyroid hormone homeostasis, neurobehavior, and development. The most predominant congener of PBDEs in humans and other organisms is 2,2′,4,4′-tetrabr...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651320312276 |
| _version_ | 1819276676522049536 |
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| author | Jiayi Song Yunxiu Li Chunyan Zhao Qunfang Zhou Jianqing Zhang |
| author_facet | Jiayi Song Yunxiu Li Chunyan Zhao Qunfang Zhou Jianqing Zhang |
| author_sort | Jiayi Song |
| collection | DOAJ |
| description | Polybrominated diphenyl ethers (PBDEs) are endocrine-disrupting chemicals that possess neuroendocrine and reproductive toxicity to humans and disturb thyroid hormone homeostasis, neurobehavior, and development. The most predominant congener of PBDEs in humans and other organisms is 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47); however, the molecular mechanisms underlying its cytotoxicity remain largely unknown. Here, we evaluated the toxic effect and underlying mechanism of nuclear receptors (NRs) induced by BDE-47 in SK-N-SH human neuroblastoma cells. The CCK-8 cell viability assay showed that the proliferation of human SK-N-SH cells exposed to BDE-47 was significantly inhibited in time- and dose-dependent manners, and flow cytometry showed that cell cycle was arrested at the S phase after BDE-47 exposure. Moreover, compared with the control group, the expression of retinoic acid receptor alpha (RXRα), pregnane X receptor (PXR), thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors (PPARs) at the mRNA and protein levels was significantly increased, as determined by quantitative PCR and western blot analysis, demonstrating that BDE-47 activated the NRs in vitro. Moreover, BDE-47 could bind to all four NRs in the affinity order of PPARγ > PXR > TRβ > RXRα under molecular dynamics. Because RXR is the promiscuous dimerization partner for a large number of NRs, ZDock was used to calculate its interaction with other three NRs. Taking the number of hydrogen bonds and ZDock scores into account, the rank of docking ability between RXRα and the NRs was PXR > TRβ > PPARγ. Further analysis of the interaction between BDE-47 and dimerized-NRs, the affinity order was RXRα > TRβ > PXR > PPARγ via Glide. The results of this study demonstrated that BDE-47 interfered the cross-talk among NRs, especially the promiscuous RXRα, which might be critical for the harmonized re-adjustment of cytotoxicity and biological regulation. Our findings provide a better understanding of the mechanisms underlying toxic effects and intermolecular interaction induced by BDE-47. |
| first_indexed | 2024-12-23T23:44:00Z |
| format | Article |
| id | doaj.art-5422c048015c4517b16f1064d4433145 |
| institution | Directory Open Access Journal |
| issn | 0147-6513 |
| language | English |
| last_indexed | 2024-12-23T23:44:00Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj.art-5422c048015c4517b16f1064d44331452022-12-21T17:25:34ZengElsevierEcotoxicology and Environmental Safety0147-65132021-01-01208111390Interaction of BDE-47 with nuclear receptors (NRs) based on the cytotoxicity: In vitro investigation and molecular interactionJiayi Song0Yunxiu Li1Chunyan Zhao2Qunfang Zhou3Jianqing Zhang4POPs Lab, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, ChinaPOPs Lab, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, ChinaSchool of Pharmacy, Lanzhou University, Lanzhou 730000, ChinaState Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, ChinaPOPs Lab, Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China; Correspondence to: Shenzhen Center for Disease Control and Prevention, No. 8 Longyuan Road, Shenzhen 518055, Guangdong, China.Polybrominated diphenyl ethers (PBDEs) are endocrine-disrupting chemicals that possess neuroendocrine and reproductive toxicity to humans and disturb thyroid hormone homeostasis, neurobehavior, and development. The most predominant congener of PBDEs in humans and other organisms is 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47); however, the molecular mechanisms underlying its cytotoxicity remain largely unknown. Here, we evaluated the toxic effect and underlying mechanism of nuclear receptors (NRs) induced by BDE-47 in SK-N-SH human neuroblastoma cells. The CCK-8 cell viability assay showed that the proliferation of human SK-N-SH cells exposed to BDE-47 was significantly inhibited in time- and dose-dependent manners, and flow cytometry showed that cell cycle was arrested at the S phase after BDE-47 exposure. Moreover, compared with the control group, the expression of retinoic acid receptor alpha (RXRα), pregnane X receptor (PXR), thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors (PPARs) at the mRNA and protein levels was significantly increased, as determined by quantitative PCR and western blot analysis, demonstrating that BDE-47 activated the NRs in vitro. Moreover, BDE-47 could bind to all four NRs in the affinity order of PPARγ > PXR > TRβ > RXRα under molecular dynamics. Because RXR is the promiscuous dimerization partner for a large number of NRs, ZDock was used to calculate its interaction with other three NRs. Taking the number of hydrogen bonds and ZDock scores into account, the rank of docking ability between RXRα and the NRs was PXR > TRβ > PPARγ. Further analysis of the interaction between BDE-47 and dimerized-NRs, the affinity order was RXRα > TRβ > PXR > PPARγ via Glide. The results of this study demonstrated that BDE-47 interfered the cross-talk among NRs, especially the promiscuous RXRα, which might be critical for the harmonized re-adjustment of cytotoxicity and biological regulation. Our findings provide a better understanding of the mechanisms underlying toxic effects and intermolecular interaction induced by BDE-47.http://www.sciencedirect.com/science/article/pii/S0147651320312276BDE-47Nuclear receptorsMolecular simulationRXRαCytotoxicity |
| spellingShingle | Jiayi Song Yunxiu Li Chunyan Zhao Qunfang Zhou Jianqing Zhang Interaction of BDE-47 with nuclear receptors (NRs) based on the cytotoxicity: In vitro investigation and molecular interaction Ecotoxicology and Environmental Safety BDE-47 Nuclear receptors Molecular simulation RXRα Cytotoxicity |
| title | Interaction of BDE-47 with nuclear receptors (NRs) based on the cytotoxicity: In vitro investigation and molecular interaction |
| title_full | Interaction of BDE-47 with nuclear receptors (NRs) based on the cytotoxicity: In vitro investigation and molecular interaction |
| title_fullStr | Interaction of BDE-47 with nuclear receptors (NRs) based on the cytotoxicity: In vitro investigation and molecular interaction |
| title_full_unstemmed | Interaction of BDE-47 with nuclear receptors (NRs) based on the cytotoxicity: In vitro investigation and molecular interaction |
| title_short | Interaction of BDE-47 with nuclear receptors (NRs) based on the cytotoxicity: In vitro investigation and molecular interaction |
| title_sort | interaction of bde 47 with nuclear receptors nrs based on the cytotoxicity in vitro investigation and molecular interaction |
| topic | BDE-47 Nuclear receptors Molecular simulation RXRα Cytotoxicity |
| url | http://www.sciencedirect.com/science/article/pii/S0147651320312276 |
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