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

Mei-Lan Tsai; Shih-Hsien Hsu; Li-Ting Wang; Wei-Ting Liao; Yi-Ching Lin; Chang-Hung Kuo; Ya-Ling Hsu; Ming-Chu Feng; Fu-Chen Kuo; Chih-Hsing Hung

doi:10.3389/fimmu.2023.1193647

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

Front Immunol. 2023 Jul 21:14:1193647. doi: 10.3389/fimmu.2023.1193647. eCollection 2023.

Authors

Mei-Lan Tsai^{1

2}, Shih-Hsien Hsu^{1

3

4}, Li-Ting Wang⁵, Wei-Ting Liao^{3

6}, Yi-Ching Lin^{3

7

8

9}, Chang-Hung Kuo^{10

11}, Ya-Ling Hsu^{1

12}, Ming-Chu Feng^{13

14}, Fu-Chen Kuo^{15

16}, Chih-Hsing Hung^{1

2

4

17

18}

Affiliations

¹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁵ Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
⁶ Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Doctoral Degree Program of Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁹ Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁰ Ta-Kuo Clinic, Kaohsiung, Taiwan.
¹¹ Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
¹² Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹³ Department of Superintendent, High Commissioner, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan.
¹⁴ Department of Nursing, Fooyin University, Kaohsiung, Taiwan.
¹⁵ Department of Gynecology and Obstetrics, E-Da Hospital, Kaohsiung, Taiwan.
¹⁶ School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
¹⁷ Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁸ Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan.

Abstract

Background: Few 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.

Methods: 66 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.

Results: The 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.

Conclusions: Cord 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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Asthma* / chemically induced
Child, Preschool
Diethylhexyl Phthalate* / toxicity
Female
Humans
Hypersensitivity*
Interleukin-33*
Maternal Exposure
Mice
Pregnancy
Receptors, Aryl Hydrocarbon / genetics

Substances

Diethylhexyl Phthalate
Interleukin-33
phthalic acid
Receptors, Aryl Hydrocarbon

Grants and funding

The study was supported by grants from the Ministry of Science and Technology of the Republic of China (MOST107-2635-B-037-003-; MOST108-2314-B-037-071-), the E-Da Hospital (EDAHP104036, EDAHP107007), the Kaohsiung Medical University Hospital Research Foundation (KMUH107-7R86), Kaohsiung Municipal Siaogang Hospital Research Foundation (S-110-10) and the Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and by Kaohsiung Medical University Research Center Grant (KMU-TC112A01).