Yonsei Med J.  2020 Feb;61(2):186-191. 10.3349/ymj.2020.61.2.186.

NOTCH1 Pathway is Involved in Polyhexamethylene Guanidine-Induced Humidifier Disinfectant Lung Injuries

• Lee E
• Kang MJ
• Kim JH
• Lee SH
• Lee SY
• Cho HJ
• Yoon J
• Jung S
• Park Y
• Oh DK
• Hong SB
• Hong SJ

• KMID: 2468494
• DOI: http://doi.org/10.3349/ymj.2020.61.2.186

Abstract

An outbreak of fatal humidifier disinfectant lung injuries (HDLI) occurred in Korea. Human studies on mechanisms underlying HDLI have yet to be conducted. This study aimed to investigate methylation changes and their potential role in HDLI after exposure to HDs containing polyhexamethylene guanidine-phosphate. DNA methylation analysis was performed in blood samples from 10 children with HDLI and 10 healthy children using Infinium Human MethylationEPIC BeadChip. Transcriptome analysis was performed using lung tissues from 5 children with HDLI and 5 controls. Compared to healthy controls, 92 hypo-methylated and 79 hyper-methylated CpG sites were identified in children with HDLI at the statistical significance level of |Δβ|>0.2 and p<0.05. NOTCH1 was identified as a candidate network hub gene in cases. NOTCH1 transcripts significantly increased in lung tissues from HDLI cases compared to unexposed controls (p=0.05). NOTCH1 may play an important role in pulmonary fibrosis of HDLI.

Keyword

Humidifier disinfectant; pulmonary fibrosis; NOTCH1; methylation; polyhexamethylene guanidine

MeSH Terms

Child
DNA Methylation
Gene Expression Profiling
Humans
Humidifiers*
Korea
Lung Injury*
Lung*
Methylation
Pulmonary Fibrosis

Figure

• 

  Fig. 1 Results of methylation, network, and NOTCH1 expression analysis in pediatric HDLI cases. (A) Volcano plot of differentially methylated CpG sites. (B) Heatmap of differentially methylated CpG sites between children with humidifier disinfectant associated lung injuries and unexposed healthy controls. Differentially methylated CpG loci indicated by asterisk. (C) The top network of differentially methylated CpG sites was found to be “cancer, organismal injury and abnormalities, reproductive system disease” and was derived from genes containing hyper-/hypo-methylated CpG sites associated with HDLI. (D) The transcriptional expression of NOTCH1 between HDLI cases and the control group (p=0.05, t-test, nonparametric methods were applied, and no correction for multiple testing was done due to the small sample size of each group, n=5 for each group). HDLI, humidifier disinfectant lung injuries.

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