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Toluene diisocyanate exposure and autotaxin–lysophosphatidic acid signalling

Broström, Julia M. LU ; Ghalali, Aram; Zheng, Huiyuan; Högberg, Johan; Stenius, Ulla; Littorin, Margareta LU ; Tinnerberg, Håkan LU and Broberg, Karin LU (2018) In Toxicology and Applied Pharmacology 355. p.43-51
Abstract

Toluene diisocyanate (TDI) is a reactive chemical used in manufacturing plastics. TDI exposure adversely affects workers' health, causing occupational asthma, but individuals differ in susceptibility. We recently suggested a role for signalling mediated by the enzyme autotaxin (ATX) and its product, lysophosphatidic acid (LPA), in TDI toxicity. Here we genotyped 118 TDI-exposed workers for six single-nucleotide polymorphisms (SNPs) in genes encoding proteins implicated in ATX–LPA signalling: purinergic receptor P2X7 (P2RX7), C–C motif chemokine ligand 2 (CCL2), interleukin 1β (IL1B), and caveolin 1 (CAV1). Two P2RX7 SNPs (rs208294 and rs2230911) significantly modified the associations between a biomarker of TDI exposure (urinary... (More)

Toluene diisocyanate (TDI) is a reactive chemical used in manufacturing plastics. TDI exposure adversely affects workers' health, causing occupational asthma, but individuals differ in susceptibility. We recently suggested a role for signalling mediated by the enzyme autotaxin (ATX) and its product, lysophosphatidic acid (LPA), in TDI toxicity. Here we genotyped 118 TDI-exposed workers for six single-nucleotide polymorphisms (SNPs) in genes encoding proteins implicated in ATX–LPA signalling: purinergic receptor P2X7 (P2RX7), C–C motif chemokine ligand 2 (CCL2), interleukin 1β (IL1B), and caveolin 1 (CAV1). Two P2RX7 SNPs (rs208294 and rs2230911) significantly modified the associations between a biomarker of TDI exposure (urinary 2,4-toluene diamine) and plasma LPA; two IL1B SNPs (rs16944 and rs1143634) did not. CAV1 rs3807989 modified the associations, but the effect was not statistically significant (p = 0.05–0.09). In vitro, TDI-exposed bronchial epithelial cells (16HBE14o-) rapidly released ATX and IL-1β. P2X7 inhibitors attenuated both responses, but confocal microscopy showed non-overlapping localizations of ATX and IL-1β, and down-regulation of CAV1 inhibited the ATX response but not the IL-1β response. This study indicates that P2X7 is pivotal for TDI-induced ATX–LPA signalling, which was modified by genetic variation in P2RX7. Furthermore, our data suggest that the TDI-induced ATX and IL-1β responses occur independently.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Autotaxin, Genetic Susceptibility, Interleukin 1β, Isocyanate, Lysophosphatidic Acid, Purinergic Receptors, Respiratory Sensitizer, Toluene Diisocyanate
in
Toxicology and Applied Pharmacology
volume
355
pages
9 pages
publisher
Academic Press
external identifiers
  • scopus:85049109890
ISSN
0041-008X
DOI
10.1016/j.taap.2018.06.019
language
English
LU publication?
yes
id
50678126-5d73-44d2-a0ed-179527de67a0
date added to LUP
2018-07-09 10:56:31
date last changed
2018-07-10 03:00:04
@article{50678126-5d73-44d2-a0ed-179527de67a0,
  abstract     = {<p>Toluene diisocyanate (TDI) is a reactive chemical used in manufacturing plastics. TDI exposure adversely affects workers' health, causing occupational asthma, but individuals differ in susceptibility. We recently suggested a role for signalling mediated by the enzyme autotaxin (ATX) and its product, lysophosphatidic acid (LPA), in TDI toxicity. Here we genotyped 118 TDI-exposed workers for six single-nucleotide polymorphisms (SNPs) in genes encoding proteins implicated in ATX–LPA signalling: purinergic receptor P2X7 (P2RX7), C–C motif chemokine ligand 2 (CCL2), interleukin 1β (IL1B), and caveolin 1 (CAV1). Two P2RX7 SNPs (rs208294 and rs2230911) significantly modified the associations between a biomarker of TDI exposure (urinary 2,4-toluene diamine) and plasma LPA; two IL1B SNPs (rs16944 and rs1143634) did not. CAV1 rs3807989 modified the associations, but the effect was not statistically significant (p = 0.05–0.09). In vitro, TDI-exposed bronchial epithelial cells (16HBE14o-) rapidly released ATX and IL-1β. P2X7 inhibitors attenuated both responses, but confocal microscopy showed non-overlapping localizations of ATX and IL-1β, and down-regulation of CAV1 inhibited the ATX response but not the IL-1β response. This study indicates that P2X7 is pivotal for TDI-induced ATX–LPA signalling, which was modified by genetic variation in P2RX7. Furthermore, our data suggest that the TDI-induced ATX and IL-1β responses occur independently.</p>},
  author       = {Broström, Julia M. and Ghalali, Aram and Zheng, Huiyuan and Högberg, Johan and Stenius, Ulla and Littorin, Margareta and Tinnerberg, Håkan and Broberg, Karin},
  issn         = {0041-008X},
  keyword      = {Autotaxin,Genetic Susceptibility,Interleukin 1β,Isocyanate,Lysophosphatidic Acid,Purinergic Receptors,Respiratory Sensitizer,Toluene Diisocyanate},
  language     = {eng},
  month        = {09},
  pages        = {43--51},
  publisher    = {Academic Press},
  series       = {Toxicology and Applied Pharmacology},
  title        = {Toluene diisocyanate exposure and autotaxin–lysophosphatidic acid signalling},
  url          = {http://dx.doi.org/10.1016/j.taap.2018.06.019},
  volume       = {355},
  year         = {2018},
}