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Occupational Exposure to Pesticides Is Associated with Differential DNA OEM Online First, published on February 19, 2018 as 10.1136/oemed-2017-104787 Occup Environ Med: first published as 10.1136/oemed-2017-104787 on 19 February 2018. Downloaded from Exposure assessment ORIGINAL ARTICLE Occupational exposure to pesticides is associated with differential DNA methylation Diana A van der Plaat,1,2 Kim de Jong,2 Maaike de Vries,1,2 Cleo C van Diemen,3 Ivana Nedeljković,4 Najaf Amin,4 Hans Kromhout,5 Biobank-based Integrative Omics Study Consortium, Roel Vermeulen,5 Dirkje S Postma,2,6 Cornelia M van Duijn,3 H Marike Boezen,1,2 Judith M Vonk1,2 ► Additional material is ABSTRact Key messages published online only. To view Objectives Occupational pesticide exposure is please visit the journal online associated with a wide range of diseases, including (http:// dx. doi. org/ 10. 1136/ What is already known about this subject? oemed- 2017- 104787). lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis.A potential ► Millions of workers worldwide are exposed 1 Department of Epidemiology, mechanism might be through epigenetic mechanisms, daily to occupational pesticide exposure, but University of Groningen, like DNA methylation. Therefore, we assessed it is largely unknown how pesticides influence University Medical Center airway disease pathogenesis. Groningen, Groningen, The associations between occupational exposure to ► To date, no large-scale epigenome-wide Netherlands pesticides and genome-wide DNA methylation sites. 2Groningen Research Institute Methods 1561 subjects of LifeLines were included association study assessing the association for Asthma and COPD (GRIAC), with either no (n=1392), low (n=108) or high (n=61) between DNA methylation and occupational University of Groningen, pesticide exposures has been performed. University Medical Center exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels Groningen, Groningen, The What are the new findings? Netherlands were measured using Illumina 450K arrays. Associations 3 Occupational pesticide exposure is associated Department of Genetics, between pesticide exposure and 420 938 methylation ► with differential DNA methylation, and this may University of Groningen, sites (CpGs) were assessed using robust linear regression University Medical Center be an important mechanism how pesticides adjusted for appropriate confounders. In addition, we Groningen, Groningen, The induce airway diseases. Netherlands performed genome-wide stratified and interaction 4 We identified multiple differentially methylated Department of Epidemiology, analyses by gender, smoking and airway obstruction ► sites associated with pesticide exposure, and Erasmus Medical Center, status, and assessed associations between gene Rotterdam, The Netherlands some of these were associated with gene 5 expression and methylation for genome-wide significant Division of Environmental expression levels as well. Epidemiology, Institute for Risk CpGs (n=2802). Assessment Sciences, Utrecht Results In total for all analyses, high pesticide exposure University, Groningen, The How might this impact on policy or clinical was genome-wide significantly (false discovery rate http://oem.bmj.com/ Netherlands practice in the foreseeable future? 6Department of Pulmonary P<0.05) associated with differential DNA methylation ► Further research should reveal whether this Diseases, University of of 31 CpGs annotated to 29 genes. Twenty of these differential methylation plays a role in the Groningen, University Medical CpGs were found in subjects with airway obstruction. disease pathogenesis induced by pesticides and Center Groningen, Groningen, Several of the identified genes, for example, RYR1, ALLC, potential preventive interventions. The Netherlands PTPRN2, LRRC3B, PAX2 and VTRNA2-1, are genes previously linked to either pesticide exposure or lung- Correspondence to Professor H Marike Boezen, related diseases. Seven out of 31 CpGs were associated on September 28, 2021 by guest. Protected copyright. Department of Epidemiology, with gene expression levels. that about 25 million workers experience uninten- University of Groningen, Conclusions We show for the first time that tional pesticide poisoning each year, due to inha- University Medical Center occupational exposure to pesticides is genome-wide lation or skin absorption.2 Long-term exposure to Groningen, Groningen RB 9700, pesticides, like in occupational settings, has been The Netherlands; associated with differential DNA methylation. Further h. m. boezen@ umcg. nl research should reveal whether this differential associated with an increased risk for birth defects, methylation plays a role in the airway disease several types of cancer and chronic diseases such Received 26 September 2017 pathogenesis induced by pesticides. as Parkinson’s disease, diabetes, chronic obstruc- Revised 1 December 2017 tive pulmonary disease (COPD), atherosclerosis Accepted 31 December 2017 and autoimmune diseases.3–5 Moreover, our own previous studies have shown that occupational INTRODUCTION exposure to pesticides is associated with lower lung Pesticides, including insecticides, herbicides and function levels and airway obstruction cross-sec- fungicides, are widely used in the agricultural tionally and with accelerated lung function decline sector to protect crops against harmful or unwanted longitudinally.6 7 To cite: van der Plaat DA, insects, weeds and fungi. Exposure to pesticides Despite the associations with a wide range of de Jong K, de Vries M, et al. Occup Environ Med Epub can, however, also be toxic to humans and it has diseases and health outcomes, it is still largely ahead of print: [please include been estimated that approximately 250 000 people unknown how pesticides affect disease develop- Day Month Year]. doi:10.1136/ worldwide die of pesticide poisoning each year.1 ment. Several mechanisms have been proposed that oemed-2017-104787 In the occupational setting, it has been estimated may underlie the detrimental effects of pesticide van der Plaat DA, et al. Occup Environ Med 2018;0:1–9. doi:10.1136/oemed-2017-104787 1 Copyright Article author (or their employer) 2018. Produced by BMJ Publishing Group Ltd under licence. Occup Environ Med: first published as 10.1136/oemed-2017-104787 on 19 February 2018. Downloaded from Exposure assessment exposures, such as induction of oxidative stress, disruption of To assess whether methylation levels at the identified CpGs the endocrine system, mitochondrial dysfunction and epigenetic are associated with gene expression levels in blood, we used modifications.4 A well-known epigenetic modification is DNA data of the BIOS (Biobank-based Integrative Omics Studies) methylation, which is the binding of a methyl group to a cytosine project, from the Biobanking and Biomolecular Resources base adjacent to a guanine base (a CpG) site.8 DNA methylation Research Infrastructure for The Netherlands (BBMRI-NL).20 In can alter gene expression without changing the DNA sequence total, 2802 subjects were selected from four population-based 21 22 and is increasingly recognised as an important link between cohorts, LifeLines (n=727) Rotterdam Study III-2 (n=589), 23 environmental exposures and disease.9 Altered DNA methyla- Netherlands Twin Registry (n=900) and Leiden Longevity 24 tion levels have been found to play a role in multiple complex Study (n=586). diseases, such as cancer, respiratory and neurodegenerative 10 diseases. An in vitro study by Zhang et al provided evidence Genome-wide methylation assay that gene promoter DNA methylation levels are indeed altered The Illumina Infinium Human Methylation 450K arrays 11 upon exposure to pesticides. Furthermore, studies in Green- (Illumina, San Diego, California, USA) were used to deter- landic Inuit as well as in Koreans have shown that exposure to mine genome-wide DNA methylation levels at approximately persistent organic pollutants is associated with global hypometh- 485 000 CpG sites of blood taken at the baseline visit. We 12–14 ylation, based on the Alu and LINE-1 assay. These studies randomised 1656 LifeLines subjects based on sex, exposure and thus showed that pesticide exposure affects global DNA methyl- airway obstruction across the arrays. Using 500 ng DNA for each ation levels, and therefore it might be possible that differential sample, we first performed a bisulphite conversion using the methylation at specific genomic locations may contribute to the EZ-96 DNA methylation kit (Zymo Research, Irvine, California, deleterious effects of pesticides. USA), which was validated using commercially available bisul- The current study is the first large-scale epigenome-wide asso- phite conversion control samples (Zymo Research). After this ciation study assessing associations between occupational expo- step, the samples were processed according to the Illumina 450K sure to pesticides and DNA methylation levels. Since pesticide protocol. After quality control, the final data set contained data exposure can affect organs in the entire body, we used blood for 1561 subjects and 420 938 CpG probes (see online supple- methylation to assess the effects of occupational exposure to mentary methods for quality control). any type of pesticide on DNA methylation levels.4 In addition, since there might be interindividual differences in the effects of Statistical analysis pesticides on methylation, we decided to stratify our analysis To assess the relationship between occupational exposure to based on susceptibility
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