Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression.

Diana A Van Der Plaat,Hans Kromhout,Najaf Amin,Natalie Terzikhan,Kim De Jong,Maaike De Vries,Lies Lahousse,Guy Brusselle ,Dirkje S Postma ,Ivana Nedeljković ,Sacha La Bastide‐Van Gemert ,Cornelia M Van Duijn ,Judith M Vonk ,Roel Vermeulen ,Cleo C Van Diemen ,H Marike Boezen

doi:10.1093/hmg/ddz067

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.

Highlights

Millions of workers worldwide are exposed to chemical agents, fumes andorganic dusts [1]
The validation cohort comprised 233 never-smokers of the Rotterdam Study and the characteristics of both cohorts are presented in Table 1, with additional characteristics of LifeLines subjects shown in Supplementary Material, Table S1 [14]
Three genome-wide methylation analyses were performed in never-smokers, one per occupational exposure being gases/fumes, mineral dust and biological dust, and differentially methylated regions (DMRs) were identified

Summary

Introduction

Millions of workers worldwide are exposed to chemical agents, fumes and (in)organic dusts [1]. The leading occupational causes of death in 2000 were unintentional injuries (41%), chronic obstructive pulmonary disease (COPD, 40%) and lung cancer (13%) [1]. This is not remarkable, since the skin and the lungs are most directly exposed to occupational pollutants, which could be prevented by implementing protective measures. Even though occupational exposures are common, it is still largely unknown how these exposures are involved in (lung) disease development Epigenetic mechanisms such as DNA methylation have been suggested to play a role, and researchers have advocated the importance of epigenetic studies into environmental exposures and lung health [7]. Several small studies showed suggestive evidence that specific compounds found in occupational exposures, like cadmium, lead and mercury, affect DNA methylation [8,10,11,12]

Methods

Results

Conclusion