Objectives Occupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. A potential mechanism might be through epigenetic mechanisms, like DNA methylation. Therefore, we assessed associations between occupational exposure to pesticides and genome-wide DNA methylation sites.
Methods 1561 subjects of LifeLines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels were measured using Illumina 450K arrays. Associations between pesticide exposure and 420 938 methylation sites (CpGs) were assessed using robust linear regression adjusted for appropriate confounders. In addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant CpGs (n=2802).
Results In total for all analyses, high pesticide exposure was genome-wide significantly (false discovery rate P<0.05) associated with differential DNA methylation of 31 CpGs annotated to 29 genes. Twenty of these CpGs were found in subjects with airway obstruction. Several of the identified genes, for example, RYR1, ALLC, PTPRN2, LRRC3B, PAX2 and VTRNA2-1, are genes previously linked to either pesticide exposure or lung-related diseases. Seven out of 31 CpGs were associated with gene expression levels.
Conclusions We show for the first time that occupational exposure to pesticides is genome-wide associated with differential DNA methylation. Further research should reveal whether this differential methylation plays a role in the airway disease pathogenesis induced by pesticides.
- occupational exposure
- Dna methylation
- epigenetic epidemiology
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Contributors DAvdP participated in the study design, analysis and interpretation of the data, and drafting of the manuscript, tables and figures. HMB, DSP, CCvD and CMVD obtained funding. JMV, KdJ, HMB, DSP, CCvD, CMVD, MdV, IN and NA determined the study design, participated in the analysis and interpretation of data, and critically supervised writing of the manuscript. HK and RV designed and provided the ALOHA+ JEM. All researchers part of the group author BBMRI BIOS participated in collecting the BIOS data. All authors approved the final version of the manuscript.
Funding This study is sponsored by grant number 4.1.13.007 of Lung Foundation Netherlands (Longfonds). The LifeLines Biobank initiative has been made possible by funds from FES (Fonds Economische Structuurversterking), SNN (Samenwerkingsverband Noord Nederland) and REP (Ruimtelijke Economisch Programma). The Biobank-Based Integrative Omics Studies (BIOS) Consortium is funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007). The sponsors of this study played no role in the design of the study, data collection, analysis, interpretation or in the writing and submission of the manuscript.
Competing interests DSP reports: The University of Groningen has received money for Professor Postma regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. All other authors declare they have no actual or potential competing financial interest.
Patient consent Obtained.
Ethics approval The study was approved by the Medical Ethics Committee of the University Medical Center Groningen, Groningen, the Netherlands.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement LifeLines data are available (at costs) to all scientists. Scientists can apply for access to Lifelines data and samples by submitting a research proposal to the LifeLines biobank (www.lifelines.nl). Data on occupational exposures in LifeLines can be obtained from Professor H M Boezen. Access to the Biobank-based Integrative Omics Study (BIOS) data is available by application to the BIOS Data Access Committee (www.bbmri.nl/acquisition-use-analyze/bios/).