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Published on: June 2, 2023
Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation
I-Jen Wang1, Wilfried Jj Karmaus2, Su-Lien Chen3
1Department of Pediatrics, Taipei Hospital, Ministry of Health and Welfare, #127, Su-Yuan Road, Hsin-Chuang Dist 242 New Taipei City, Taiwan ; Institute of Environmental and Occupational Health Sciences, College of Medicine, National Yang-Ming University, Taipei, 112 Taiwan ; Department of Health Risk Management, China Medical University, Taichung, 404 Taiwan.
Insights
Phthalate exposure in children may lead to asthma through changes in DNA methylation. Lower methylation of the TNFα gene promoter was linked to higher phthalate levels and increased asthma risk.
Area of Science:
- Environmental Epigenetics
- Toxicology
- Pediatric Asthma Research
Background:
- Phthalate exposure is a potential risk factor for childhood asthma.
- The underlying mechanisms, particularly epigenetic modifications, require further investigation.
- This study explores the link between phthalate exposure, DNA methylation, and asthma development in children.
Purpose of the Study:
- To assess the impact of phthalate exposure on DNA methylation patterns in children.
- To determine if epigenetic changes mediate the association between phthalates and asthma.
- To validate findings across different cohorts and biological samples.
Main Methods:
- Quantified urinary phthalate metabolite (5OH-MEHP) levels as a marker of exposure.
- Measured DNA methylation (DNA-M) in blood samples using quantitative PCR.
- Analyzed candidate genes and validated findings in independent cohorts (CEAS and IOW).
Main Results:
- Identified differential methylation in AR, TNFα, and IL-4 genes.
- Found lower TNFα promoter methylation with higher phthalate exposure (5OH-MEHP).
- Lower TNFα methylation was associated with increased asthma risk in two independent cohorts.
Conclusions:
- Phthalate exposure may increase asthma risk in children via epigenetic alterations.
- DNA methylation changes, specifically in the TNFα gene, are implicated in this pathway.
- Findings highlight a potential mechanism linking environmental exposures to childhood asthma.
Background:
Phthalates may increase the asthma risk in children. Mechanisms underlying this association remain to be addressed. This study assesses the effect of phthalate exposures on epigenetic changes and the role of epigenetic changes for asthma. In the first step, urine and blood samples from 256 children of the Childhood Environment and Allergic diseases Study (CEAS) were analyzed. Urine 5OH-MEHP levels were quantified as an indicator of exposure, and asthma information was collected. DNA methylation (DNA-M) was measured by quantitative PCR. In the screening part of step 1, DNA-M of 21 potential human candidate genes suggested by a toxicogenomic data were investigated in 22 blood samples. Then, in the testing part of step 1, positively screened genes were tested in a larger sample of 256 children and then validated by protein measurements. In step 2, we replicated the association between phthalate exposure and gene-specific DNA-M in 54 children in the phthalate contaminated food event. In step 3, the risk of DNA-M for asthma was tested in 256 children from CEAS and corroborated in 270 children from the Isle of Wight (IOW) birth cohort.
Results:
Differential methylation in three genes (AR, TNFα, and IL-4) was identified through screening. Testing in 256 children showed that methylation of the TNFα gene promoter was lower when children had higher urine 5OH-MEHP values (β = -0.138, P = 0.040). Functional validation revealed that TNFα methylation was inversely correlated with TNFα protein levels (β = -0.18, P = 0.041). In an additional sample of 54 children, we corroborated that methylation of the TNFα gene promoter was lower when urine 5OH-MEHP concentrations were higher. Finally, we found that a lower methylation of 5'CGI region of TNFα was associated with asthma in 256 CEAS children (OR = 2.15, 95% CI = 1.01 to 4.62). We replicated this in 270 children from the IOW birth cohort study. Methylation of the CpG site cg10717214 was negatively associated with asthma, when children had 'AA' or 'AG' genotype of the TNFα single nucleotide rs1800610.
Conclusions:
Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation.
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