title: Adjuvant effects of inhaled mono-2-ethylhexyl phthalate in BALB/cJ mice.
abstract: Phthalates, including di(2-ethylhexyl) phthalate (DEHP), are widely used and have been linked with the development of wheezing and asthma. The main metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP), was investigated for adjuvant effects in a mouse inhalation model. BALB/cJ mice were exposed to aerosols of 0.03 or 0.4 mg/m(3) MEHP 5 days/week for 2 weeks and thereafter weekly for 12 weeks together with a low dose of ovalbumin (OVA) as a model allergen. Mice exposed to OVA alone or OVA+Al(OH)(3) served as negative and positive controls, respectively. Finally, all groups were exposed to a nebulized 1% OVA solution on 3 consecutive days to investigate the development of an inflammatory response. Serum, bronchoalveolar lavage (BAL) fluid, and draining lymph nodes were collected 24h later. In the OVA+Al(OH)(3) group, significantly increased levels of OVA-specific IgE and IgG1 in serum as well as of eosinophils in BAL fluid were observed. OVA-specific IgG1 production in both MEHP groups was significantly increased. OVA-specific IgE and IgG2a were not increased significantly. A dose-dependent increase in inflammatory cells was observed in BAL fluid, leading to significantly higher lymphocyte and eosinophil numbers in the OVA+0.4 mg/m(3) MEHP group. Ex vivo cytokine secretion by cultures of draining lymph nodes suggested a T(H)2 profile of MEHP. In conclusion, MEHP acted as a T(H)2 adjuvant after inhalation. However, it is suggested that the inflammation in the MEHP groups was primarily mediated by an IgG1-dependent mechanism. To address implications for humans, a margin-of-exposure was estimated based on the lack of significant effects on IgE production and inflammation after exposures to 0.03 mg/m(3) MEHP observed in the present study and estimated human exposure levels.
authors.affiliation: Airway Allergy and Irritation Group, National Research Centre for the Working Environment, Lersø Parkallé 105, DK-2100 Copenhagen, Denmark. jitkastilund.hansen@fhi.no
authors.forename: Jitka Stilund
authors.initials: JS
authors.lastname: Hansen
authors.forename: Søren Thor
authors.initials: ST
authors.lastname: Larsen
authors.forename: Lars K
authors.initials: LK
authors.lastname: Poulsen
authors.forename: Gunnar Damgård
authors.initials: GD
authors.lastname: Nielsen
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000633:toxicity*; D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000633:toxicity; D005260:Female; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D012119:Respiration / Q000187:drug effects; D012129:Respiratory Function Tests
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; D007074:Immunoglobulin G; D007378:Interleukins; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate