title: Activation of the Endoperoxide Ascaridole Modulates Its Sensitizing Capacity.
abstract: The monoterpene ascaridole, a fairly stable endoperoxide found in essential oils such as tea tree oil can provoke allergic contact dermatitis which has been evidenced under patch test conditions. However, concomitantly we observed irritative skin reactions that demand further data underlining the sensitization potential of ascaridole. Here, we studied the effects of ascaridole on dendritic cell (DC) activation and protein reactivity, 2 key steps of chemical-induced skin sensitization. Treatment of human monocyte-derived DC with ascaridole found support for full DC maturation, a capability of sensitizers but not irritants. It induced significant upregulation of the expression of the costimulatory molecules CD86, CD80, CD40, and the adhesion molecule CD54 in a time-dependent manner. Maturation was accompanied by release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-8. Similar to other chemical skin sensitizers including hydroperoxides, we observed a certain reactivity of ascaridole toward cysteine- but not lysine-containing peptides. During recent years, evidence accumulated for a radical mechanism as trigger for protein reactivity of peroxides. Treatment of the fairly stable endoperoxide ascaridole with iron as radical inducer ("activated ascaridole") resulted in cysteine peptide reactivity exceeding by far that of ascaridole itself. Furthermore, activated ascaridole showed increased potential for induction of the Nrf2 target gene heme oxygenase 1 and upregulation of CD86 and CD54 on THP-1 cells, an established DC surrogate. These results indicate that radical formation could be involved in the steps leading to skin sensitization induced by the endoperoxide ascaridole.
authors.affiliation: *Department of Environmental Toxicology, University Trier, 54296 Trier, Germany and.
authors.forename: Nora L
authors.initials: NL
authors.lastname: Krutz
authors.affiliation: *Department of Environmental Toxicology, University Trier, 54296 Trier, Germany and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hennen
authors.affiliation: *Department of Environmental Toxicology, University Trier, 54296 Trier, Germany and.
authors.forename: Corinna
authors.initials: C
authors.lastname: Korb
authors.affiliation: *Department of Environmental Toxicology, University Trier, 54296 Trier, Germany and.
authors.forename: Mario T
authors.initials: MT
authors.lastname: Schellenberger
authors.affiliation: Central Product Safety Department, The Procter & Gamble Company, Mason Business Center, 8700 Mason Montgomery Road, Cincinnati, OH.
authors.forename: G Frank
authors.initials: GF
authors.lastname: Gerberick
authors.affiliation: *Department of Environmental Toxicology, University Trier, 54296 Trier, Germany and bloemeke@uni-trier.de.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Blömeke
mesh_terms: D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D002460:Cell Line; D000081005:Cyclohexane Monoterpenes; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells; D017449:Dermatitis, Allergic Contact / Q000209:etiology*; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D039821:Monoterpenes / Q000009:adverse effects*; D010545:Peroxides / Q000009:adverse effects*; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D000081005:Cyclohexane Monoterpenes; D016207:Cytokines; D039821:Monoterpenes; D010545:Peroxides; D018799:Intercellular Adhesion Molecule-1; C043372:ascaridole
keywords: THP-1; ascaridole; endoperoxide; monocyte-derived dendritic cells (MoDC); skin sensitization; terpene