PMID- 28903487
OWN - NLM
STAT- MEDLINE
DCOM- 20180619
LR  - 20200930
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 159
IP  - 1
DP  - 2017 Sep 1
TI  - From the Cover: Arsenic Induces Hippocampal Neuronal Apoptosis and Cognitive 
      Impairments via an Up-Regulated BMP2/Smad-Dependent Reduced BDNF/TrkB Signaling 
      in Rats.
PG  - 137-158
LID - 10.1093/toxsci/kfx124 [doi]
AB  - Arsenic promotes hippocampal neuronal damage inducing cognitive impairments. 
      However, mechanism arbitrating arsenic-mediated cognitive deficits remains 
      less-known. Here, we identified that chronic exposure to environmentally relevant 
      doses of arsenic increased apoptosis, characterized by caspase-3 activation, 
      poly(ADP-ribose) polymerase cleavage and Terminal deoxynucleotidyl transferase 
      dUTP nick-end labeling of rat hippocampal neurons, marked by NeuN. Investigating 
      apoptotic mechanism through invivo and invitro studies revealed that arsenic 
      promoted bone morphogenetic protein-2 (BMP2) expression, supported by increased 
      BMP-receptor2 (BMPR2) and p-Smad1/5 in hippocampal neurons. BMP2-silencing and 
      treatment with BMP antagonist, noggin, attenuated the arsenic-induced apoptosis 
      and loss in hippocampal neurons. We then investigated whether BMP2/Smad signaling 
      stimulated neuronal apoptosis independently or required other intermediate 
      pathways. We hypothesized participation of brain-derived neurotrophic factor 
      (BDNF) that promotes neuronal survival. We identified an arsenic-mediated 
      attenuation of BDNF-dependent TrkB signaling, and observed that co-treatment with 
      recombinant-BDNF reinstated BDNF/TrkB and reduced neuronal apoptosis. To probe 
      whether BMP2/Smad and BDNF/TrkB pathways could be linked, we co-treated arsenic 
      with noggin or recombinant BDNF. We detected a noggin-mediated restored 
      BDNF/TrkB, while recombinant-BDNF failed to affect BMP2/Smad signaling. In 
      addition, we found that TrkB-inhibitor, K252a, nullified noggin-induced 
      protection, proving the necessity of a downstream reduced BDNF/TrKB signaling for 
      BMP2/Smad-mediated apoptosis in arsenic-treated neurons. We further related our 
      observations with cognitive performances, and detected noggin-mediated 
      restoration of transfer latency time and learning-memory ability for passive 
      avoidance and Y-Maze tests respectively in arsenic-treated rats. Overall, our 
      study proves that arsenic promotes hippocampal neuronal apoptosis through an 
      up-regulated BMP2/Smad-dependent attenuation of BDNF/TrkB pathway, inducing 
      cognitive deficits.
CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the Society 
      of Toxicology. All rights reserved. For Permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Pandey, Rukmani
AU  - Pandey R
AD  - Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, 
      India.
AD  - Developmental Toxicology Laboratory, Systems Toxicology and Health Risk 
      Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 
      Lucknow 226001, India.
FAU - Rai, Vipin
AU  - Rai V
AD  - Developmental Toxicology Laboratory, Systems Toxicology and Health Risk 
      Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 
      Lucknow 226001, India.
FAU - Mishra, Juhi
AU  - Mishra J
AD  - Developmental Toxicology Laboratory, Systems Toxicology and Health Risk 
      Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 
      Lucknow 226001, India.
AD  - Babu Banarasi Das University, Lucknow 226028, India.
FAU - Mandrah, Kapil
AU  - Mandrah K
AD  - Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, 
      India.
AD  - Analytical Chemistry Laboratory and Regulatory Toxicology Group, CSIR-IITR, 
      Lucknow, India.
FAU - Kumar Roy, Somendu
AU  - Kumar Roy S
AD  - Analytical Chemistry Laboratory and Regulatory Toxicology Group, CSIR-IITR, 
      Lucknow, India.
FAU - Bandyopadhyay, Sanghamitra
AU  - Bandyopadhyay S
AD  - Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, 
      India.
AD  - Developmental Toxicology Laboratory, Systems Toxicology and Health Risk 
      Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 
      Lucknow 226001, India.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Bmp2 protein, rat)
RN  - 0 (Bone Morphogenetic Protein 2)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Smad Proteins)
RN  - EC 2.7.10.1 (Ntrk2 protein, rat)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - N712M78A8G (Arsenic)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Arsenic/*toxicity
MH  - Bone Morphogenetic Protein 2/*metabolism
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Cells, Cultured
MH  - Cognition Disorders/*chemically induced
MH  - Female
MH  - Hippocampus/*drug effects/pathology
MH  - Neurons/*drug effects/pathology
MH  - Pregnancy
MH  - Rats
MH  - Rats, Wistar
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptor, trkB/*metabolism
MH  - *Signal Transduction
MH  - Smad Proteins/*metabolism
MH  - Up-Regulation
OTO - NOTNLM
OT  - arsenic
OT  - attenuated neurotrophin
OT  - increased BMP
OT  - memory deficits
OT  - neuronal loss
EDAT- 2017/09/15 06:00
MHDA- 2018/06/21 06:00
CRDT- 2017/09/15 06:00
PHST- 2017/09/15 06:00 [entrez]
PHST- 2017/09/15 06:00 [pubmed]
PHST- 2018/06/21 06:00 [medline]
AID - 3869069 [pii]
AID - 10.1093/toxsci/kfx124 [doi]
PST - ppublish
SO  - Toxicol Sci. 2017 Sep 1;159(1):137-158. doi: 10.1093/toxsci/kfx124.