395 Solvent-induced DNA methylation changes: A translational study

Objectives Workers exposed to solvents are at risk for developing cancer and neurobehavioral diseases. Evidence is growing on the role of epigenetic alterations involved in the development of both diseases. In this project, we set up a translational study to investigate the impact of solvents on DNA methylation alterations and neurobehavioral changes. Methods First, we assessed global DNA methylation changes in human lymphoblastoid (TK6) cells in vitro in response to 10 solvents. Next, a cross sectional study was set-up to validate these results in 128 solvent workers. Liquid chromatography-mass spectrometry was used to quantify global DNA methylation profile in TK6 cells and in lymphocytes of the workers. Each participant underwent a series of tests based on the Neurobehavioral Evaluation System. Results Benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene induced global DNA hypomethylation in TK6 cells. DNA methylation in solvent-workers was, after correction for age, negatively associated with total exposure time (r = -0.198, p = 0,025) and the cumulative exposure index (r = -0.244, p = 0,006). Age and smoking were associated with a global DNA hypomethylation, while use of alcohol was associated with hypermethylation. Interestingly, both DNA methylation and exposure were significant predictors for neurobehavioral effects in the multivariate regression models. Conclusions We report changes in global DNA methylation as an early event in response to solvents. Global unmethylated DNA is known to dysregulate transcription, which has an impact on the gene expression and the function of cells, e.g. loss of control of cell division. These results are suggestive for the possible involvement of epigenetic mechanisms in neurodegenerative diseases and cancer. Lymphocytes are not necessarily the target tissue, but might be a good surrogate because of their accessibility and the high correlation with methylation profiles in somatic tissues.