Broström Julia M, Ghalali Aram, Zheng Huiyuan, Högberg Johan, Stenius Ulla, Littorin Margareta, Tinnerberg Håkan, Broberg Karin
Division of Occupational and Environmental Medicine, Lund University, SE 221 85 Lund, Sweden.
Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE171 77 Stockholm, Sweden.
Toxicol Appl Pharmacol. 2018 Sep 15;355:43-51. doi: 10.1016/j.taap.2018.06.019. Epub 2018 Jun 22.
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.
甲苯二异氰酸酯（TDI）是一种用于制造塑料的活性化学品。接触TDI会对工人健康产生不利影响，导致职业性哮喘，但个体易感性存在差异。我们最近提出，由自分泌运动因子（ATX）及其产物溶血磷脂酸（LPA）介导的信号传导在TDI毒性中发挥作用。在此，我们对118名接触TDI的工人进行了基因分型，检测了编码参与ATX-LPA信号传导的蛋白质的基因中的六个单核苷酸多态性（SNP）：嘌呤能受体P2X7（P2RX7）、CC基序趋化因子配体2（CCL2）、白细胞介素1β（IL1B）和小窝蛋白1（CAV1）。两个P2RX7 SNP（rs208294和rs2230911）显著改变了TDI暴露生物标志物（尿2,4-甲苯二胺）与血浆LPA之间的关联；两个IL1B SNP（rs16944和rs1143634）则没有。CAV1 rs3807989改变了这种关联，但效果无统计学意义（p = 0.05 - 0.09）。在体外，接触TDI的支气管上皮细胞（16HBE14o-）迅速释放ATX和IL-1β。P2X7抑制剂减弱了这两种反应，但共聚焦显微镜显示ATX和IL-1β的定位不重叠，并且CAV1的下调抑制了ATX反应，但不影响IL-1β反应。这项研究表明，P2X7对于TDI诱导的ATX-LPA信号传导至关重要，而该信号传导被P2RX7中的基因变异所改变。此外，我们的数据表明，TDI诱导的ATX和IL-1β反应是独立发生的。
