PMID- 37330034
OWN - NLM
STAT- MEDLINE
DCOM- 20230807
LR  - 20230808
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 494
DP  - 2023 Aug 1
TI  - BDE209-promoted Dio2 degradation in H4 glioma cells through the autophagy 
      pathway, resulting in hypothyroidism and leading to neurotoxicity.
PG  - 153581
LID - S0300-483X(23)00167-1 [pii]
LID - 10.1016/j.tox.2023.153581 [doi]
AB  - Decabromodiphenyl ether (BDE209), the homologue with the highest number of 
      brominates in polybrominated diphenyl ethers (PBDEs), is one of the most 
      widespread environmental persistent organic pollutants (POPs) due to its mass 
      production and extensive application in recent decades. BDE209 is neurotoxic, 
      possibly related to its interference with the thyroid hormone (TH) system. 
      However, the underlying molecular mechanisms of BDE209-induced TH interference 
      and neurobehavioral disorders remains unknown. Here, we explored how BDE209 
      manipulated the major enzyme, human type II iodothyronine deiodinase (Dio2), that 
      is most important in regulating local cerebral TH equilibrium by neuroglial 
      cells, using an in vitro model of human glioma H4 cells. Clonogenic cell survival 
      assay and LC/MS/MS analysis showed that BDE209 could induce chronic neurotoxicity 
      by inducing TH interference. Co-IP assay, RT-qPCR and confocal assay identified 
      that BDE209 destroyed the stability of Dio2 without affecting its expression, and 
      promoted its binding to p62, thereby enhancing its autophagic degradation, thus 
      causing TH metabolism disorder and neurotoxicity. Furthermore, molecular docking 
      studies predicted that BDE209 could effectively suppress Dio2 activity by 
      competing with tetraiodothyronine (T4). Collectively, our study demonstrates that 
      BDE209-induced Dio2 degradation and loss of its enzymatic activity in neuroglial 
      cells are the fundamental pathogenic basis for BDE209-mediated cerebral TH 
      disequilibrium and neurotoxicity, providing a target of interest for further 
      investigation using glial/neuronal cell co-culture system and in vivo models.
CI  - Copyright (c) 2023 Elsevier B.V. All rights reserved.
FAU - Liu, Min
AU  - Liu M
AD  - Department of Environmental Health and Toxicology, School of Public Health, 
      Dalian Medical University, Dalian 116044, China; Neurology Department, Dalian 
      University Affiliated Xinhua Hospital, Dalian 116021, China.
FAU - Yu, Zhenlong
AU  - Yu Z
AD  - College of Pharmacy, Dalian Medical University, Dalian 116044, China.
FAU - Yang, Fangyu
AU  - Yang F
AD  - General Hospital of Northern Theater Command (General Hospital of Shenyang 
      Military Command), Department of Neurosurgery, Shenyang, China.
FAU - Zhao, Zikuang
AU  - Zhao Z
AD  - School of Pharmacy, Hangzhou Normal University, Hangzhou 116000, China.
FAU - Zhou, Meirong
AU  - Zhou M
AD  - College of Pharmacy, Dalian Medical University, Dalian 116044, China.
FAU - Wang, Chao
AU  - Wang C
AD  - College of Pharmacy, Dalian Medical University, Dalian 116044, China.
FAU - Zhang, Baojing
AU  - Zhang B
AD  - College of Pharmacy, Dalian Medical University, Dalian 116044, China.
FAU - Liang, Guobiao
AU  - Liang G
AD  - General Hospital of Northern Theater Command (General Hospital of Shenyang 
      Military Command), Department of Neurosurgery, Shenyang, China. Electronic 
      address: liangguobiao6708@vip.163.com.
FAU - Liu, Xiaohui
AU  - Liu X
AD  - Department of Environmental Health and Toxicology, School of Public Health, 
      Dalian Medical University, Dalian 116044, China.
FAU - Shao, Jing
AU  - Shao J
AD  - Department of Environmental Health and Toxicology, School of Public Health, 
      Dalian Medical University, Dalian 116044, China; Liaoning Key Laboratory of 
      Hematopoietic Stem Cell Transplantation and Translational Medicine; Liaoning 
      Medical Center for Hematopoietic Stem Cell Transplantation; Dalian Key Laboratory 
      of Hematology; Diamond Bay Institute of Hematology; Second Hospital of Dalian 
      Medical University, Dalian 116027, China. Electronic address: 
      jshao@u.washington.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230616
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - EC 1.11.1.8 (Iodide Peroxidase)
RN  - 0 (Thyroid Hormones)
RN  - 0 (Halogenated Diphenyl Ethers)
SB  - IM
MH  - Humans
MH  - Iodide Peroxidase/genetics
MH  - Molecular Docking Simulation
MH  - Tandem Mass Spectrometry
MH  - Thyroid Hormones
MH  - *Hypothyroidism
MH  - *Glioma
MH  - Autophagy
MH  - Halogenated Diphenyl Ethers/chemistry
OTO - NOTNLM
OT  - Autophagy
OT  - Decabromodiphenyl ether (BDE209)
OT  - Human type II iodothyronine deiodinase (Dio2)
OT  - Thyroid hormone
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/06/18 01:07
MHDA- 2023/08/07 06:41
CRDT- 2023/06/17 19:15
PHST- 2023/02/20 00:00 [received]
PHST- 2023/06/07 00:00 [revised]
PHST- 2023/06/15 00:00 [accepted]
PHST- 2023/08/07 06:41 [medline]
PHST- 2023/06/18 01:07 [pubmed]
PHST- 2023/06/17 19:15 [entrez]
AID - S0300-483X(23)00167-1 [pii]
AID - 10.1016/j.tox.2023.153581 [doi]
PST - ppublish
SO  - Toxicology. 2023 Aug 1;494:153581. doi: 10.1016/j.tox.2023.153581. Epub 2023 Jun 
      16.