TY - JOUR
T1 - Effects of HO-/MeO-PBDEs on androgen receptor
T2 - In vitro investigation and helix 12-involved MD simulation
AU - Wang, Xiaoxiang
AU - Yang, Huaiyu
AU - Hu, Xinxin
AU - Zhang, Xiaowei
AU - Zhang, Qiansen
AU - Jiang, Hualiang
AU - Shi, Wei
AU - Yu, Hongxia
PY - 2013/10/15
Y1 - 2013/10/15
N2 - Hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) have received increasing attention for their potential endocrine disrupting activities and widely environmental distribution. However, little information is available for the anti-androgenic activities, and the molecular mechanism of interactions with androgen receptor (AR) is not fully understood. In the present study, cell line assay and computational simulation were integrated to systematically explore the molecular mechanism of interactions between chemicals and AR. The metabolites with similar molecular structures exhibited different anti-androgenic activity while none of them showed androgenic activity. According to the multisystem molecular dynamics simulation, minute differences in the structure of ligands induced dramatic different conformational transition of AR-ligand binding domain (LBD). The Helix12 (H12) component of active ligands occupied AR-LBD could become stable, but this component continued to fluctuate in inactive ligands occupied AR-LBD. Settling time and reposition of H12 obtained in dynamics process are important factors governing anti-androgenic activities. The related settling times were characteristic of anti-androgenic potencies of the tested chemicals. Overall, in our study, the stable reposition of H12 is characterized as a computational mark for identifying AR antagonists from PBDE metabolites, or even other various environmental pollutants.
AB - Hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) have received increasing attention for their potential endocrine disrupting activities and widely environmental distribution. However, little information is available for the anti-androgenic activities, and the molecular mechanism of interactions with androgen receptor (AR) is not fully understood. In the present study, cell line assay and computational simulation were integrated to systematically explore the molecular mechanism of interactions between chemicals and AR. The metabolites with similar molecular structures exhibited different anti-androgenic activity while none of them showed androgenic activity. According to the multisystem molecular dynamics simulation, minute differences in the structure of ligands induced dramatic different conformational transition of AR-ligand binding domain (LBD). The Helix12 (H12) component of active ligands occupied AR-LBD could become stable, but this component continued to fluctuate in inactive ligands occupied AR-LBD. Settling time and reposition of H12 obtained in dynamics process are important factors governing anti-androgenic activities. The related settling times were characteristic of anti-androgenic potencies of the tested chemicals. Overall, in our study, the stable reposition of H12 is characterized as a computational mark for identifying AR antagonists from PBDE metabolites, or even other various environmental pollutants.
UR - https://www.scopus.com/pages/publications/84886896376
U2 - 10.1021/es4029364
DO - 10.1021/es4029364
M3 - 文章
C2 - 24044724
AN - SCOPUS:84886896376
SN - 0013-936X
VL - 47
SP - 11802
EP - 11809
JO - Environmental Science and Technology
JF - Environmental Science and Technology
IS - 20
ER -