Toluene diisocyanate exposure and autotaxin–lysophosphatidic acid signalling

• Published in: Toxicology and applied pharmacology Vol. 355; pp. 43 - 51
• Main Authors: Broström, Julia M., Ghalali, Aram, Zheng, Huiyuan, Högberg, Johan, Stenius, Ulla, Littorin, Margareta, Tinnerberg, Håkan, Broberg, Karin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2018
• Subjects: Adolescent; Adult; Arbetsmedicin och miljömedicin; Autotaxin; Biomarkers; Caveolin 1 - drug effects; Caveolin 1 - genetics; Cell Line; Chemical Industry; Environmental Health and Occupational Health; Female; Genetic Susceptibility; Genotype; Health Sciences; Humans; Hälsovetenskap; Interleukin 1β; Isocyanate; Lysophosphatidic Acid; Lysophospholipids - metabolism; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Middle Aged; Occupational Exposure - adverse effects; Phosphoric Diester Hydrolases - drug effects; Phosphoric Diester Hydrolases - genetics; Polymorphism, Single Nucleotide - genetics; Purinergic Receptors; Receptors, Purinergic P2X7 - drug effects; Receptors, Purinergic P2X7 - genetics; Respiratory Sensitizer; RNA, Small Interfering - pharmacology; Signal Transduction - drug effects; Signal Transduction - genetics; Toluene 2,4-Diisocyanate - toxicity; Toluene Diisocyanate; Young Adult; Respiratory Sensitizer; Isocyanate; Autotaxin; Lysophosphatidic Acid; Purinergic Receptors; Interleukin 1β; Toluene Diisocyanate; Genetic Susceptibility
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2018.06.019

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), CC 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. •Toluene diisocyanate (TDI) causes airway symptoms including asthma.•SNPs in the P2RX7 gene modified the LPA response of TDI in TDI workers.•TDI induced ATX–LPA signalling via P2X7 receptor.•TDI-induced ATX and IL-1β responses occur independently.•TDI seems to be toxic via ATX-LPA signalling.