Bisphenol A (BPA) is used in various areas of daily life as a major component of plastic products. However, it is also known as a strong endocrine disruptor that affects the human immune system. Studies have indicated that BPA possibly exacerbates allergic diseases such as atopic dermatitis and asthma. The main aim of this study was to elucidate whether BPA is directly involved in the exacerbation of allergic inflammation. Initially, in vivo experiments with mouse models of allergic inflammation induced by Th2 type hapten toluene-2, 4-diisocyanate (TDI) was performed. Mice were subjected to oral administration of BPA 48, 24, and 4 h before challenge with TDI. Dermal challenge of TDI onto the ear auricle was performed for the allergic dermatitis model, and intratracheal challenge of TDI was performed for the allergic airway inflammation model. In the allergic dermatitis model, ear-swelling response was significantly downregulated by high doses of BPA. The opposite reaction was observed in the allergic airway inflammation model, including significant exacerbation of red coloration in the lung, local cytokine levels, and total IgE levels in serum by BPA administration. To confirm the in vivo results, in vitro experiments with human epidermal keratinocytes (HEKs) and bronchial epithelial (BEAS-2B) cells were carried out. Significant enhancement of cytokine release from BEAS-2B cells but not HEKs in the BPA-treated group supported the in vivo observations. Our results imply that exposure to BPA directly exacerbates allergic airway inflammation but not allergic dermatitis.

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The aryl hydrocarbon receptor (AhR) is a ligand‐dependent transcription factor that binds to various environmental chemicals and contributes to numerous toxicological effects. However, the direct effects of AhR on the development of allergic diseases are not fully understood. The main aim of this study was to elucidate the action of AhR in the development of cutaneous allergies. Initially, the potential for a direct relationship between AhR and the immune cells was investigated in vitro, using murine bone marrow‐derived dendritic cells, human epidermal keratinocytes, and the mixed leukocyte reaction assay. Benzo[a]pyrene (BaP) and 6‐formylindolo[3,2‐b]carbazole were used as selective ligands for the AhR. Pretreatment with BaP and/or 6‐formylindolo[3,2‐b]carbazole significantly induced cytokine release by activated keratinocytes and T‐cell proliferation, whereas interleukin‐12 production in bone marrow‐derived dendritic cells was reduced by AhR activation. To confirm the in vitro results, in vivo experiments were also performed in T‐helper (Th)2‐type hapten toluene‐2,4‐diisocyanate‐ and Th1‐type hapten dinitrochlorobenzene‐induced mouse models of allergic dermatitis. Mice were orally administered BaP at 48, 24 and 4 hours before the final allergen challenge. In the Th2 model, ear‐swelling response and scratching behavior were promoted by BaP exposure, which supported the observed significant increases in local cytokine secretion. The infiltration of helper T cells, B cells and dendritic cells into the auricular lymph node was significantly enhanced by BaP administration, although Th1‐type immune responses were not influenced by AhR activation. Our findings demonstrate that AhR activation directly activates keratinocytes and T cells, which leads to the exacerbation of Th2‐type cutaneous allergy.

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We recently demonstrated that benzo[a]pyrene (BaP), the aryl hydrocarbon receptor (AhR) ligand, directly contributes to aggravation of cutaneous allergy in a mouse model of allergic dermatitis. The present study aimed to determine whether BaP-induced AhR activation results in development of airway inflammation. Initially, the potential for a direct relationship between BaP-induced AhR activation and airway inflammation was investigated in vivo, using a mouse model of type 2 helper T cell (Th2) hapten toluene-2,4-diisocyanate (TDI)-induced airway inflammation. Mice were orally administered BaP at 48, 24, and 4 h before the final allergen challenge. Oral administration of BaP showed a significant increase in lung inflammation and eosinophil infiltration. While expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to BaP, AhR activation significantly increased IL-33 expression. To confirm the in vivo results, in vitro experiments were performed using the human eosinophilic leukemia cell line (EOL-1), human bronchial epithelial cell line (BEAS-2B), and human lung adenocarcinoma epithelial cell line (A549). Results indicated that pre-treatment with BaP increased expression of IL-8 in house dust mite-activated EOL-1, BEAS-2B, and A549 cells. In addition, IL-33 levels in BEAS-2B cells were significantly increased after BaP exposure. Our findings indicated that BaP-induced AhR activation is involved in the pro-inflammatory response in respiratory allergy, and that this effect may be mediated by increased IL-33 expression and eosinophil infiltration.

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