Academic journal article Environmental Health Perspectives

Effects of Diisononyl Phthalate on Atopic Dermatitis in Vivo and Immunologic Responses in Vitro

Academic journal article Environmental Health Perspectives

Effects of Diisononyl Phthalate on Atopic Dermatitis in Vivo and Immunologic Responses in Vitro

Article excerpt

BACKGROUND: Diisononyl phthalate (DINP), a principal plasticizer in many polyvinyl chloride products, has been shown to have an adjuvant effect on immunoglobulin (Ig) production in mice. However, the effects of DINP on allergic diseases have not been fully elucidated.

OBJECTIVES: In the present study we investigated the effects of DINP on atopic dermatitis (AD)-like skin lesions induced by Dermatophagoides Pteronyssinus (Dp) in atopic-prone NC/Nga mice.

METHODS: Mice were injected intradermally with Dp on their ears and were exposed to DINP (0, 0.15, 1.5, 15, or 150 mg/kg/day) intraperitoneally. We evaluated clinical scores, ear thickening, histologic findings, protein expression of cytokines/chemokines in the ear, and serum levels of Ig and histamine. Furthermore, we investigated the effects of DINP on bone-marrow-derived dendritic cells (BMDCs) or splenocytes in vitro. After exposure to DINP (0-100 [micro]M), cells were evaluated for phenotype and function.

RESULTS: DINP aggravated AD-like skin lesions related to Dp. The aggravation was consistent with eosinophilic inflammation, mast cell degranulation, and thymic stromal lymphopoietin (TSLP) expression in the ear. DINP enhanced the expression of cell surface activation markers on BMDCs and their production of TARC/CCL17 (thymus- and activation-regulated chemokine) and MDC/CCL22 (macrophage-derived chemokine), as well as their capacity to stimulate Dp-specific T-cell proliferation. DINP also enhanced interleukin-4 production and Dp-stimulated proliferation of splenocytes.

CONCLUSIONS: DINP can aggravate AD-like skin lesions related to Dp. The mechanisms of the aggravation might be mediated, at least partly, through the TSLP-related activation of dendritic cells and by direct or indirect activation of the immune cells.

KEY WORDS: antigen-presenting activity, atopic dermatitis, bone-marrow--derived dendritic cells, chemokines, diisononyl phthalate, eosinophils, mast cells, splenocytes. Environ Health Perspect 118:472-478 (2010). doi:10.1289/ehp.0901255 [Online 19 November 2009]


Phthalate esters, ubiquitously used as plasticizers in many polyvinyl chloride (PVC) products, have become widespread in the environment (Peijnenburg et al. 2008). Diisononyl phthalate (DINP) is used in flooring, wire and cable, dip coating, coated fabrics, tubing, shoes, sealants, and artificial leather, and humans may be exposed to DINP by the oral, dermal, and inhalation routes (Kavlock et al. 2002). It has been expected that general population exposure to DINP would not exceed levels of di-(2-ethylhexyl) phthalate (DEHP) (Kavlock et al. 2002), which are estimated at 3-30 [micro]g/kg body weight/day (Doull et al. 1999). Plasticizcrs, including DINP, are not covalently bound to the plastics and can migrate into saliva and be swallowed (Earls et al. 2003; Kavlock et al. 2002). Thus, children may be exposed to higher levels of DINP than are adults because infants and small children mouth toys and other ankles containing DINP (Babich et al. 2004; Kavlock et al. 2002).

Several epidemiologic studies have suggested that exposure to phthalate esters may be associated with development of asthma, wheezing, and allergic symptoms (Bornehag et al. 2004; Jaakkola et al. 1999, 2004, 2006). Bornehag et al. (2004) revealed the positive association between allergic asthma in children and phthalate esters in house dust. Thus, it is possible that phthalate esters in the environment may also be associated with development of the other allergic diseases such as atopic dermatitis (AD).

In our previous studies, DEHP enhanced AD-like skin lesions in atopic-prone NC/Nga mice at hundreds-fold lower levels than the no observed adverse effect level (NOAEL) determined from histologic changes in the liver of rodents (Takano et al. 2006; Yanagisawa et al. 2008). The enhancing effects of DEHP paralleled the infiltration of eosinophils, mast cell degranulation, and the expression of proinflammatory proteins in inflamed skin. …

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