PMID- 26072274
OWN - NLM
STAT- MEDLINE
DCOM- 20151116
LR  - 20190522
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 287
IP  - 3
DP  - 2015 Sep 15
TI  - Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and 
      its association with airways symptoms.
PG  - 222-31
LID - S0041-008X(15)30013-2 [pii]
LID - 10.1016/j.taap.2015.06.006 [doi]
AB  - Diisocyanates are industrial chemicals which have a wide range of applications in 
      developed and developing countries. They are notorious lung toxicants and 
      respiratory sensitizers. However, the mechanisms behind their adverse effects are 
      not adequately characterized. Autotaxin (ATX) is an enzyme producing 
      lysophosphatidic acid (LPA), and the ATX-LPA axis has been implicated in lung 
      related inflammatory conditions and diseases, including allergic asthma, but not 
      to toxicity of environmental low-molecular-weight chemicals. We investigated 
      effects of toluene diisocyanate (TDI) on ATX induction in human lung epithelial 
      cell models, and we correlated LPA-levels in plasma to biomarkers of TDI exposure 
      in urine collected from workers exposed to <5ppb (parts per billion). Information 
      on workers' symptoms was collected through interviews. One nanomolar TDI robustly 
      induced ATX release within 10min in vitro. A P2X7- and P2X4-dependent 
      microvesicle formation was implicated in a rapid ATX release and a subsequent 
      protein synthesis. Co-localization between purinergic receptors and ATX was 
      documented by immunofluorescence and confocal microscopy. The release was 
      modulated by monocyte chemoattractant protein-1 (MCP-1) and by extracellular ATP. 
      In workers, we found a dose-response relationship between TDI exposure biomarkers 
      in urine and LPA levels in plasma. Among symptomatic workers reporting 
      "sneezing", the LPA levels were higher than among non-symptomatic workers. This 
      is the first report indicating induction of the ATX-LPA axis by an environmental 
      low-molecular-weight chemical, and our data suggest a role for the ATX-LPA axis 
      in TDI toxicity.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Brostrom, Julia M
AU  - Brostrom JM
AD  - Division of Occupational and Environmental Medicine, Lund University, SE 221 85 
      Lund, Sweden.
FAU - Ye, Zhi-Wei
AU  - Ye ZW
AD  - Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 
      Stockholm, Sweden.
FAU - Axmon, Anna
AU  - Axmon A
AD  - Division of Occupational and Environmental Medicine, Lund University, SE 221 85 
      Lund, Sweden.
FAU - Littorin, Margareta
AU  - Littorin M
AD  - Division of Occupational and Environmental Medicine, Lund University, SE 221 85 
      Lund, Sweden.
FAU - Tinnerberg, Hakan
AU  - Tinnerberg H
AD  - Division of Occupational and Environmental Medicine, Lund University, SE 221 85 
      Lund, Sweden.
FAU - Lindh, Christian H
AU  - Lindh CH
AD  - Division of Occupational and Environmental Medicine, Lund University, SE 221 85 
      Lund, Sweden.
FAU - Zheng, Huiyuan
AU  - Zheng H
AD  - Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 
      Stockholm, Sweden.
FAU - Ghalali, Aram
AU  - Ghalali A
AD  - Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 
      Stockholm, Sweden.
FAU - Stenius, Ulla
AU  - Stenius U
AD  - Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 
      Stockholm, Sweden.
FAU - Jonsson, Bo A G
AU  - Jonsson BA
AD  - Division of Occupational and Environmental Medicine, Lund University, SE 221 85 
      Lund, Sweden.
FAU - Hogberg, Johan
AU  - Hogberg J
AD  - Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 
      Stockholm, Sweden. Electronic address: johan.hogberg@ki.se.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20150611
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Biomarkers)
RN  - 0 (Lysophospholipids)
RN  - 0 (P2RX7 protein, human)
RN  - 0 (Receptors, Purinergic P2X4)
RN  - 0 (Receptors, Purinergic P2X7)
RN  - 17X7AFZ1GH (Toluene 2,4-Diisocyanate)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
RN  - EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase)
RN  - PG6M3969SG (lysophosphatidic acid)
SB  - IM
MH  - Adult
MH  - Biomarkers/blood/urine
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Induction
MH  - Epithelial Cells/drug effects/metabolism
MH  - Female
MH  - Humans
MH  - Lung/*drug effects/enzymology/physiopathology
MH  - Lung Diseases/*chemically induced/diagnosis/metabolism
MH  - Lysophospholipids/blood/*metabolism/urine
MH  - Male
MH  - Middle Aged
MH  - Occupational Diseases/*chemically induced/diagnosis/metabolism
MH  - Occupational Exposure/adverse effects
MH  - Phosphoric Diester Hydrolases/*biosynthesis
MH  - RNA Interference
MH  - Receptors, Purinergic P2X4/drug effects/metabolism
MH  - Receptors, Purinergic P2X7/drug effects/metabolism
MH  - Risk Assessment
MH  - Signal Transduction/drug effects
MH  - Sweden
MH  - Time Factors
MH  - Toluene 2,4-Diisocyanate/*adverse effects
MH  - Transfection
MH  - Up-Regulation
MH  - Young Adult
OTO - NOTNLM
OT  - Autotaxin-lysophosphatidic acid axis
OT  - Exposure biomarker
OT  - Microvesicles
OT  - Purinergic receptors
OT  - Respiratory sensitizer
OT  - Toluene diisocyanate toxicity
EDAT- 2015/06/15 06:00
MHDA- 2015/11/17 06:00
CRDT- 2015/06/15 06:00
PHST- 2015/03/10 00:00 [received]
PHST- 2015/06/02 00:00 [revised]
PHST- 2015/06/05 00:00 [accepted]
PHST- 2015/06/15 06:00 [entrez]
PHST- 2015/06/15 06:00 [pubmed]
PHST- 2015/11/17 06:00 [medline]
AID - S0041-008X(15)30013-2 [pii]
AID - 10.1016/j.taap.2015.06.006 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2015 Sep 15;287(3):222-31. doi: 
      10.1016/j.taap.2015.06.006. Epub 2015 Jun 11.