期刊
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
卷 208, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ecoenv.2020.111390
关键词
BDE-47; Nuclear receptors; Molecular simulation; RXR alpha; Cytotoxicity
资金
- National Natural Science Foundation of China, China [21677103]
- Sanming Project of Medicine in Shenzhen, China [SZSM201811070]
- Shenzhen Science and Technology Innovation Commission, China [JCYJ20170413102320786]
This study evaluated the toxic effects of BDE-47 on nuclear receptors (NRs) in human neuroblastoma cells, finding that BDE-47 can activate multiple NRs and disrupt interactions among them, especially RXR alpha. This discovery provides a better understanding of the mechanisms underlying toxic effects and intermolecular interactions induced by BDE-47.
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 timeand 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 (RXR alpha), 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 PPAR gamma > PXR > TR beta > RXR alpha 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 RXR alpha and the NRs was PXR > TR beta > PPAR gamma. Further analysis of the interaction between BDE-47 and dimerized-NRs, the affinity order was RXR alpha > TR beta > PXR > PPAR gamma via Glide. The results of this study demonstrated that BDE-47 interfered the cross-talk among NRs, especially the promiscuous RXR alpha, 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据