title: Glyphosate-rich air samples induce IL-33, TSLP and generate IL-13 dependent airway inflammation.
abstract: Several low weight molecules have often been implicated in the induction of occupational asthma. Glyphosate, a small molecule herbicide, is widely used in the world. There is a controversy regarding a role of glyphosate in developing asthma and rhinitis among farmers, the mechanism of which is unexplored. The aim of this study was to explore the mechanisms of glyphosate induced pulmonary pathology by utilizing murine models and real environmental samples. C57BL/6, TLR4-/-, and IL-13-/- mice inhaled extracts of glyphosate-rich air samples collected on farms during spraying of herbicides or inhaled different doses of glyphosate and ovalbumin. The cellular response, humoral response, and lung function of exposed mice were evaluated. Exposure to glyphosate-rich air samples as well as glyphosate alone to the lungs increased: eosinophil and neutrophil counts, mast cell degranulation, and production of IL-33, TSLP, IL-13, and IL-5. In contrast, in vivo systemic IL-4 production was not increased. Co-administration of ovalbumin with glyphosate did not substantially change the inflammatory immune response. However, IL-13-deficiency resulted in diminished inflammatory response but did not have a significant effect on airway resistance upon methacholine challenge after 7 or 21 days of glyphosate exposure. Glyphosate-rich farm air samples as well as glyphosate alone were found to induce pulmonary IL-13-dependent inflammation and promote Th2 type cytokines, but not IL-4 for glyphosate alone. This study, for the first time, provides evidence for the mechanism of glyphosate-induced occupational lung disease.
authors.affiliation: Department of Environmental Health, College of Medicine, University of Cincinnati, OH 45267, USA.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Marat
authors.initials: M
authors.lastname: Khodoun
authors.affiliation: Department of Environmental Health, College of Medicine, University of Cincinnati, OH 45267, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Kettleson
authors.affiliation: Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: McKnight
authors.affiliation: Department of Environmental Health, College of Medicine, University of Cincinnati, OH 45267, USA.
authors.forename: Tiina
authors.initials: T
authors.lastname: Reponen
authors.affiliation: Department of Environmental Health, College of Medicine, University of Cincinnati, OH 45267, USA.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Grinshpun
authors.affiliation: Department of Environmental Health, College of Medicine, University of Cincinnati, OH 45267, USA; Department of Environmental Health Sciences, Jiann-Ping Hsu College of Public Health, Georgia Southern University, Statesboro, GA 30460, USA. Electronic address: aadhikari@georgiasouthern.edu.
authors.forename: Atin
authors.initials: A
authors.lastname: Adhikari
mesh_terms: D000382:Agricultural Workers' Diseases / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D000393:Air Pollutants / Q000633:toxicity*; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism*; D019570:Inhalation Exposure; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018570:Risk Assessment; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin; D000097797:Glyphosate
chemical_list: D000393:Air Pollutants; D016207:Cytokines; D005998:Glycine; D006540:Herbicides; D018836:Inflammation Mediators; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D051197:Toll-Like Receptor 4; D000094632:Thymic Stromal Lymphopoietin; D000097797:Glyphosate; C506535:Il33 protein, mouse; C493487:Tlr4 protein, mouse
keywords: Asthma; Immunotoxicology; Innate immunity; Lung disease; Occupational health; Pesticide