Gene-environment interactions in the induction of epigenetic alterations in solvent-workers

Introduction
There exists epidemiologic evidence on the relationship between organic solvents and cancer. Carcinogenicity of various substances and metabolites has been investigated and information about genotoxic and mutagenic effects is available. In contrast, studies on epigenetic alterations are scarce but evidence is growing that they play an important role in the development of occupational cancers. Cancer cells are mostly characterized by global unmethylated DNA, which leads to transcriptional dysregulation and uncontrolled cell division.

Methods
We investigated global DNA methylation in lymphocytes of 128 workers exposed to a mixture of solvents. A cumulative exposure index was calculated from data obtained by interview and measurements. Methylated and non-methylated deoxycytidine was analyzed by liquid chromatography-mass spectrometry. In addition, we examined whether polymorphisms of metabolizing genes GSTM1, GSTT1 and GSTP1 mediate changes in the epigenome. Gene-environment interactions were studied with correlation and multivariate linear regression analyses correcting for confounders.

Results
Participants were exposed to solvents for 4.9 (interquartile range (IQR): 2.4-10.7) years. The median DNA methylation was 6.3% (IQR: 5.9%-6.8%). Age and smoking were associated with a global DNA hypomethylation, while use of alcohol was associated with hypermethylation. Total exposure time (partial r=-0.198, p=0.025) and cumulative exposure index (partial r=-0.244, p=0.006) were negatively correlated with global DNA methylation after correction for age. Type 2 gene-environment interactions could be described for GSTP1, GSTM1 and GSTT1 polymorphisms.

Discussion
Solvents induce global DNA hypomethylation in lymphocytes of workers in a dose-dependent manner. The effect of exposure on DNA methylation is bigger in genetically susceptible workers. These results demonstrate that solvents could potentially cause cancer not only through genetic effects, but also via non-genotoxic mechanisms. Other epigenetic processes (e.g. histone modifications) and pathways will be studied in the near future.