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Mono(2-ethylhexyl) phthalate modulates bone marrow-derived APCs and exacerbates allergic lung inflammation via PPARγ-dependent pro-inflammatory signaling
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DOI：10.1080/08923973.2026.2671722.png)
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Abstract
En 中文
Mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of the plasticizer di-(2-ethylhexyl) phthalate (DEHP), has been implicated in the rising prevalence of allergic diseases. However, its immunotoxic mechanisms remain incompletely understood. In this study, we investigated the immunomodulatory effects of MEHP under tolerable daily intake (TDI)-equivalent exposure conditions using both in vivo and in vitro approaches.
An ovalbumin (OVA)-induced allergic lung inflammation model was used in C57BL/6 mice chronically exposed to DEHP or MEHP. Cytokine profiles in bronchoalveolar lavage fluid (BALF) and anti-OVA IgE levels in serum were assessed using ELISA. In vitro, granulocyte-macrophage colony-stimulating factor (GM-CSF)–differentiated bone marrow–derived antigen-presenting cells (BM-APCs) were treated with MEHP, with or without PPARγ antagonist or agonist. Surface marker expression and cytokine production were evaluated by flow cytometry and ELISA, and IκBα phosphorylation was assessed by immunoblotting.
TDI-equivalent DEHP or MEHP exposure exacerbated allergic lung inflammation, with elevated Th2/Th1 cytokines in bronchoalveolar lavage fluid and serum anti-OVA IgE levels. In vitro, MEHP-treated BM-APCs showed increased IL-6 and IL-12 production, along with reduced IL-10, MHC class II, and CD86 expression. These effects were partially reversed by a modulator of peroxisome proliferator-activated receptor gamma (PPARγ) antagonist and recapitulated by a PPARγ agonist. MEHP also induced IκBα phosphorylation, suggesting activation of NF-κB independently of PPARγ.
Mechanistically, our findings indicate that MEHP modulates APC cytokine profiles and surface phenotype through both PPARγ-dependent and -independent pathways. MEHP exposure aggravated lung inflammation and increased IgE levels at TDI-equivalent doses, supporting its pathogenic potential under physiologically relevant conditions.
Keywords:
Allergic lung inflammation
dendritic cell
MEHP
NF-κB
PPARγ
TDI-equivalent exposure
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