title: Adjuvant Effect of an Alternative Plasticizer, Diisopropyl Adipate, on a Contact Hypersensitivity Mouse Model: Link with Sensory Ion Channel TRPA1 Activation.
abstract: Due to health concerns about phthalate esters, the use of alternative plasticizers is being considered. Phthalate esters enhance skin sensitization to fluorescein isothiocyanate (FITC) in mouse models. We have demonstrated that phthalate esters stimulate transient receptor potential ankyrin 1 (TRPA1) cation channels expressed on sensory neurons. We also found a correlation between TRPA1 activation and the enhancing effect on FITC-induced contact hypersensitivity (CHS) when testing various types of phthalate esters. Here we investigated the effects of an alternative plasticizer, diisopropyl adipate (DIA). Activation of TRPA1 by DIA was demonstrated by calcium mobilization using Chinese hamster ovary cells expressing TRPA1 in vitro. The effect of DIA was inhibited by a TRPA1-specific antagonist, HC-030031. The presence of DIA or dibutyl phthalate (DBP; positive control) during skin sensitization of BALB/c mice to FITC augmented the CHS response, as revealed by the level of ear-swelling. The enhancing effect of DIA was inhibited by in vivo pretreatment with HC-030031. FITC-presenting CD11c(+) dendritic cell (DC)-trafficking to draining lymph nodes was facilitated both by DIA and by DBP. DBP and DIA were similarly active in the enhancement of interferon-γ production by draining lymph nodes, but the effect on interleukin-4 production was weaker with DIA. Overall, DIA activated TRPA1 and enhanced FITC-induced CHS, as DBP did. The adjuvant effects of adipate esters may need to be considered because they are used as ingredients in cosmetics and drug formulations topically applied to the skin.
authors.affiliation: Laboratory of Microbiology and Immunology, School of Pharmaceutical Sciences, University of Shizuoka.
authors.forename: Kohta
authors.initials: K
authors.lastname: Kurohane
authors.forename: Ayako
authors.initials: A
authors.lastname: Kimura
authors.forename: Rie
authors.initials: R
authors.lastname: Terasawa
authors.forename: Yurina
authors.initials: Y
authors.lastname: Sahara
authors.forename: Kamiyu
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Wakana
authors.initials: W
authors.lastname: Suzuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Imai
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000272:Adipates / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003412:Cricetulus; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D003877:Dermatitis, Contact / Q000209:etiology / Q000276:immunology*; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008807:Mice, Inbred BALB C; D010968:Plasticizers / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D000272:Adipates; D000276:Adjuvants, Immunologic; D016207:Cytokines; D010968:Plasticizers; D011687:Purines; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D016650:Fluorescein-5-isothiocyanate; C048852:diisopropyl adipate; D002118:Calcium