Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression
Authors: van der Plaat Diana A , Vonk Judith M , Terzikhan Natalie , de Jong Kim , de Vries Maaike , La Bastide-van Gemert Sacha , van Diemen Cleo C , Lahousse Lies , Brusselle Guy G , Nedeljkovic Ivana , Amin Najaf ,   BIOS Consortium, Heijmans Bastiaan T , ‘t Hoen Peter A C , van Meurs Joyce , Isaacs Aaron , Jansen Rick , Franke Lude , Boomsma Dorret I , Pool René , van Dongen Jenny , Hottenga Jouke J , van Greevenbroek Marleen MJ , Stehouwer Coen D A , van der Kallen Carla J H , Schalkwijk Casper G , Wijmenga Cisca , Franke Lude , Zhernakova Sasha , Tigchelaar Ettje F , Slagboom P Eline , Beekman Marian , Deelen Joris , van Heemst Diana , Veldink Jan H , van den Berg Leonard H , van Duijn Cornelia M , Hofman Bert A , Isaacs Aaron , Uitterlinden André G , van Meurs Joyce , Jhamai P Mila , Verbiest Michael , Suchiman H Eka D , Verkerk Marijn , der Breggen Ruud van , van Rooij Jeroen , Lakenberg Nico , Mei Hailiang , van Iterson Maarten , van Galen Michiel , Bot Jan , Zhernakova Dasha V , Jansen Rick , van’t Hof Peter , Deelen Patrick , Nooren Irene , ‘t Hoen Peter A C , Heijmans Bastiaan T , Moed Matthijs , Franke Lude , Vermaat Martijn , Zhernakova Dasha V , Luijk René , Bonder Marc Jan , van Iterson Maarten , Deelen Patrick , van Dijk Freerk , van Galen Michiel , Arindrarto Wibowo , Kielbasa Szymon M , Swertz Morris A , van Zwet Erik W , Jansen Rick , Hoen Peter-Bram’t , Heijmans Bastiaan T , Heijmans Bastiaan T , ‘t Hoen Peter A C , van Meurs Joyce , Isaacs Aaron , Jansen Rick , Franke Lude , Boomsma Dorret I , Pool René , van Dongen Jenny , Hottenga Jouke J , van Greevenbroek Marleen MJ , Stehouwer Coen D A , van der Kallen Carla J H , Schalkwijk Casper G , Wijmenga Cisca , Franke Lude , Zhernakova Sasha , Tigchelaar Ettje F , Slagboom P Eline , Beekman Marian , Deelen Joris , van Heemst Diana , Veldink Jan H , van den Berg Leonard H , van Duijn Cornelia M , Hofman Bert A , Isaacs Aaron , Uitterlinden André G , van Meurs Joyce , Jhamai P Mila , Verbiest Michael , Suchiman H Eka D , Verkerk Marijn , van der Breggen Ruud , van Rooij Jeroen , Lakenberg Nico , Mei Hailiang , van Iterson Maarten , van Galen Michiel , Bot Jan , Zhernakova Dasha V , Jansen Rick , van ‘t Hof Peter , Deelen Patrick , Nooren Irene , ‘t Hoen Peter A C , Heijmans Bastiaan T , Moed Matthijs , Franke Lude , Vermaat Martijn , Zhernakova Dasha V , Luijk René , Bonder Marc Jan , van Iterson Maarten , Deelen Patrick , van Dijk Freerk , van Galen Michiel , Arindrarto Wibowo , Kielbasa Szymon M , Swertz Morris A , van Zwet Erik W , Jansen Rick , ‘t Hoen Peter-Bram , Heijmans Bastiaan T , Kromhout Hans , Vermeulen Roel C H , Postma Dirkje S , van Duijn Cornelia M , Boezen H Marike 
Published: March 2019

Abstract
Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.