Di(2-ethylhexyl) phthalate mediates IL-33 production via aryl hydrocarbon receptor and is associated with childhood allergy development

Frontiers in Immunology

Immunology

Fu-Chen Kuo¹  Li-Ting Wang²  Wei-Ting Liao³  Yi-Ching Lin⁴  Ming-Chu Feng⁵  Shih-Hsien Hsu⁶  Mei-Lan Tsai⁷  Chih-Hsing Hung⁸  Ya-Ling Hsu⁹  Chang-Hung Kuo^1,10 

[1] Department of Gynecology and Obstetrics, E-Da Hospital, Kaohsiung, Taiwan;School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan;Department of Life Science, National Taiwan Normal University, Taipei, Taiwan;Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Doctoral Degree Program of Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Superintendent, High Commissioner, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan;Department of Nursing, Fooyin University, Kaohsiung, Taiwan;Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan;Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan;Ta-Kuo Clinic, Kaohsiung, Taiwan;Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan;

关键词: childhood allergy;    aryl hydrocarbon receptor;    Di(2-ethylhexyl) phthalate;    flavonoids;    IL-33;   

DOI  :  10.3389/fimmu.2023.1193647

 received in 2023-03-25, accepted in 2023-06-26,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundFew studies assess cord blood biomarkers to predict prenatal exposure to di(2-ethylhexyl) phthalate (DEHP) on the development of allergic diseases later in childhood. IL-33 has been indicated to play an important role in allergic diseases. We evaluated the association of prenatal DEHP exposure and IL-33 in cord blood on the development of allergic diseases. We also investigated the mechanism of DEHP in human lung epithelial cells and asthma animal models.Methods66 pregnant women were recruited, and their children followed when they were aged 3 years. Maternal urinary DEHP metabolites were determined using liquid chromatography-electrospray-ionization-tandem mass spectrometry. The effect of DEHP on IL-33 production was investigated in human lung epithelial cells and club cell-specific aryl hydrocarbon receptor (AhR) deficiency mice. ELISA and RT-PCR, respectively, measured the IL-33 cytokine concentration and mRNA expression.ResultsThe concentrations of maternal urinary DEHP metabolites and serum IL-33 in cord blood with childhood allergy were significantly higher than those in the non-childhood allergy group. DEHP and MEHP could induce IL-33 production and reverse by AhR antagonist and flavonoids in vitro. Enhanced ovalbumin-induced IL-4 and IL-33 production in bronchoalveolar lavage fluid (BALF) by DEHP exposure and suppressed in club cell-specific AhR null mice. Kaempferol has significantly reversed the DEHP effect in the asthma animal model.ConclusionsCord blood IL-33 level was correlated to childhood allergy and associated with maternal DEHP exposure. IL-33 might be a potential target to assess the development of DEHP-related childhood allergic disease. Flavonoids might be the natural antidotes for DEHP.

【 授权许可】

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Copyright © 2023 Tsai, Hsu, Wang, Liao, Lin, Kuo, Hsu, Feng, Kuo and Hung