title: Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms.
abstract: 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.
authors.affiliation: Division of Occupational and Environmental Medicine, Lund University, SE 221 85 Lund, Sweden.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Broström
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 Stockholm, Sweden.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Ye
authors.affiliation: Division of Occupational and Environmental Medicine, Lund University, SE 221 85 Lund, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Axmon
authors.affiliation: Division of Occupational and Environmental Medicine, Lund University, SE 221 85 Lund, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Littorin
authors.affiliation: Division of Occupational and Environmental Medicine, Lund University, SE 221 85 Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Tinnerberg
authors.affiliation: Division of Occupational and Environmental Medicine, Lund University, SE 221 85 Lund, Sweden.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Lindh
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 Stockholm, Sweden.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 Stockholm, Sweden.
authors.forename: Aram
authors.initials: A
authors.lastname: Ghalali
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 Stockholm, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Stenius
authors.affiliation: Division of Occupational and Environmental Medicine, Lund University, SE 221 85 Lund, Sweden.
authors.forename: Bo A G
authors.initials: BA
authors.lastname: Jönsson
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE 171 77 Stockholm, Sweden. Electronic address: johan.hogberg@ki.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Högberg
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged; D009784:Occupational Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism; D016273:Occupational Exposure / Q000009:adverse effects; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis*; D034622:RNA Interference; D058848:Receptors, Purinergic P2X4 / Q000187:drug effects / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D013548:Sweden; D013997:Time Factors; D014051:Toluene 2,4-Diisocyanate / Q000009:adverse effects*; D014162:Transfection; D015854:Up-Regulation; D055815:Young Adult; D000099189:Lysophospholipase D
chemical_list: D015415:Biomarkers; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; D014051:Toluene 2,4-Diisocyanate; D000099189:Lysophospholipase D; C546468:P2RX7 protein, human; C032881:lysophosphatidic acid
keywords: Autotaxin-lysophosphatidic acid axis; Exposure biomarker; Microvesicles; Purinergic receptors; Respiratory sensitizer; Toluene diisocyanate toxicity