Adjuvant effects of inhaled mono-2-ethylhexyl phthalate in BALB/cJ mice.
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.
Hansen
Jitka Stilund
JS
Airway Allergy and Irritation Group, National Research Centre for the Working Environment, Lersø Parkallé 105, DK-2100 Copenhagen, Denmark. jitkastilund.hansen@fhi.no
Larsen
Søren Thor
ST
Poulsen
Lars K
LK
Nielsen
Gunnar Damgård
GD
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
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