Toluene diisocyanate exposure and autotaxin–lysophosphatidic acid signalling
(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.
(Less)
- author
- Broström, Julia M. LU ; Ghalali, Aram ; Zheng, Huiyuan ; Högberg, Johan ; Stenius, Ulla ; Littorin, Margareta LU ; Tinnerberg, Håkan LU and Broberg, Karin LU
- organization
- publishing date
- 2018-09-15
- 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
-
- pmid:29940203
- 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
- 2024-08-05 19:56:33
@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}}, keywords = {{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}}, doi = {{10.1016/j.taap.2018.06.019}}, volume = {{355}}, year = {{2018}}, }