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Dibutyl phthalate induces atopic dermatitis via semaphorin-plexin signaling and IL-5: ECHO-COCOA study
Mi-Jin Kang1, Jeonghun Yeom2, Yong Joo Park3
1Humidifier Disinfectant Health Center, Asan Medical Center, Seoul, Korea.
Insights
Dibutyl phthalate (DBP) exposure in children is linked to atopic dermatitis (AD) through semaphorin-plexin signaling and increased interleukin-5 (IL-5). This study clarifies the molecular pathways connecting phthalate exposure to childhood AD development.
Area of Science:
- Environmental Health
- Immunology
- Molecular Biology
Background:
- Phthalate exposure is associated with increased atopic dermatitis (AD) risk.
- The precise molecular mechanisms linking phthalate exposure to childhood AD remain unclear.
Purpose of the Study:
- To investigate the impact of dibutyl phthalate (DBP) on AD development in a birth cohort.
- To explore the underlying molecular mechanisms using multi-omics approaches.
Main Methods:
- Measured urinary phthalate metabolites (MnBP, MiBP) in 222 children.
- Assessed physician-diagnosed AD, blood proteome, and transcriptome.
- Analyzed interleukin (IL)-5 and IL-10 production in vitro after MnBP exposure.
Main Results:
- Higher MnBP and MiBP levels correlated with increased AD risk, eosinophils, and IL-5.
- Differentially expressed proteins (DEPs) linked to MnBP and AD were enriched in semaphorin-plexin signaling.
- IL-5 mediated the association between MnBP and eosinophils; IL-5 increased and IL-10 decreased dose-dependently with MnBP exposure.
Conclusions:
- DBP exposure influences childhood AD development.
- Semaphorin-plexin signaling and IL-5 are key molecular pathways involved.
Background:
Several studies have reported an association between phthalate exposure and an increased risk of atopic dermatitis (AD). However, the molecular mechanism underlying this phenomenon in children remains unknown.
Objectives:
In this study, we investigated the effect of dibutyl phthalate (DBP) on AD development from a birth cohort and explored the potential mechanisms using multi-omics.
Methods:
Urinary concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) metabolites were measured in 222 children aged 7 years from the Exposome and Child Health with Omics-Cohort for Childhood of Asthma and Allergic Diseases (ECHO-COCOA) study. Physician diagnosed AD in these participants. Luminex multiplex assay, proteome, and transcriptome were performed on blood samples. The production of interleukin (IL)-5 and IL-10 was analyzed after MnBP exposure in human keratinocytes and macrophage.
Results:
Higher MnBP and MiBP levels increased the risk of AD development. These phthalates were positively correlated with eosinophils and IL-5. In total, 24 differentially expressed proteins (DEPs) and IL-5 were associated with MnBP and the development of AD. DEPs were predominantly enriched in the semaphorin-plexin signaling pathway. Plexin B1 was negatively correlated with IL-10 and interferon gamma and positively correlated with egg white specific immunoglobulin E. Moreover, mediation analysis indicated that IL-5 had a significantly positive mediation effect on the association between MnBP and eosinophils. The IL-5-mediated signaling pathway was enriched in the blood transcriptome. IL-10 was decreased and IL-5 was increased in a dose-dependent manner after MnBP exposure from THP-1 and HaCaT cells.
Conclusion:
Exposure to DBP affects childhood AD via semaphorin-plexin signaling and IL-5.
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