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Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation

Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation
Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation
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, TNF?, and IL-4) was identified through screening. Testing in 256 children showed that methylation of the TNF? gene promoter was lower when children had higher urine 5OH-MEHP values (??=??0.138, P?=?0.040). Functional validation revealed that TNF? methylation was inversely correlated with TNF? protein levels (??=??0.18, P?=?0.041). In an additional sample of 54 children, we corroborated that methylation of the TNF? gene promoter was lower when urine 5OH-MEHP concentrations were higher. Finally, we found that a lower methylation of 5?CGI region of TNF? 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 TNF? single nucleotide rs1800610.

Conclusions: effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation
1868-7075
1-20
Wang, I-Jen
9f337b62-b820-42d4-9c1c-2bf9d883e44c
Karmaus, Wilfried JJ
af0a33bd-1556-477c-8d72-aa3c40c92f27
Chen, Su-Lien
eb356f70-8c0d-4bcc-984c-52dcc683e465
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Wang, I-Jen
9f337b62-b820-42d4-9c1c-2bf9d883e44c
Karmaus, Wilfried JJ
af0a33bd-1556-477c-8d72-aa3c40c92f27
Chen, Su-Lien
eb356f70-8c0d-4bcc-984c-52dcc683e465
Holloway, John W
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7

Wang, I-Jen, Karmaus, Wilfried JJ, Chen, Su-Lien, Holloway, John W and Ewart, Susan (2015) Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation. Clinical Epigenetics, 7 (1), 1-20. (doi:10.1186/s13148-015-0060-x).

Record type: Article

Abstract

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, TNF?, and IL-4) was identified through screening. Testing in 256 children showed that methylation of the TNF? gene promoter was lower when children had higher urine 5OH-MEHP values (??=??0.138, P?=?0.040). Functional validation revealed that TNF? methylation was inversely correlated with TNF? protein levels (??=??0.18, P?=?0.041). In an additional sample of 54 children, we corroborated that methylation of the TNF? gene promoter was lower when urine 5OH-MEHP concentrations were higher. Finally, we found that a lower methylation of 5?CGI region of TNF? 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 TNF? single nucleotide rs1800610.

Conclusions: effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation

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More information

Accepted/In Press date: 17 February 2015
Published date: 15 March 2015
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 375822
URI: https://eprints.soton.ac.uk/id/eprint/375822
ISSN: 1868-7075
PURE UUID: 6769b35f-92c0-4004-bd81-7f84891477e4
ORCID for John W Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 20 Apr 2015 09:26
Last modified: 06 Jun 2018 12:59

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