Dibutyl phthalate induces atopic dermatitis via semaphorin-plexin signaling and IL-5: ECHO-COCOA study.

Abstract

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.