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.