Do epigenetic changes play a role in the development of chronic toxic encephalopathy?

Introduction
Workers chronically exposed to solvents are at risk for developing chronic toxic encephalopathy (CTE). Epigenetic mechanisms, such as DNA methylation, might play a role in the development and progression of CTE, since they have an impact in other neurodegenerative and neuropsychiatric diseases and in neurotoxicity induced by ethanol and drugs.

Methods
We investigated the association between solvent exposure, DNA methylation alterations and neurobehavioral changes in active solvent-workers (n = 144) and CTE-patients of the Belgian Neuropsychotoxicological Centre of Expertise (n = 33). A cumulative exposure index was calculated from data obtained by interview (total exposure time) and measurements (level of exposure). Total DNA deoxycytidine methylation percentage was determined by liquid chromatography-mass spectrometry. Each participant underwent a series of tests based on the Neurobehavioral Evaluation System and validated for the Flemish population including f.e. Neurotoxicity Symptom Checklist-60; neurobehavioral tests [simple reaction time, symbol digit substitution, hand-eye coordination, and digit span backwards]. We performed correlation and multivariate regression analyses correcting for confounders.

Results
CTE-patients were older and had been longer exposed (23.8; interquartile range (IQR): 16.3-28.5) years) than solvent-workers (4.9; IQR: 2.4-10.7). DNA methylation percentage was significantly different between solvent-workers (6.3; IQR: 5.9-6.8) and CTE-patients (4.3; IQR: 3.7-4.6). After correction for age, both total exposure time and cumulative exposure index were significantly correlated with DNA methylation (solvent-workers: r=-0.198, r=-0.244; CTE patients: r=-0.441, r=-0.367). DNA methylation and exposure parameters were the most important predictors for neurobehavioral outcomes in the multivariate regression models (all p<0.012).

Discussion
This study indicates that solvent exposure can induce DNA hypomethylation in lymphocytes. Hypomethylation leads to altered gene expression, which could have an impact on neurotoxicity and on the development of CTE. Lymphocytes are not the target tissue, but might be a good surrogate because of their accessibility and since CpG island methylation profiles are highly correlated with somatic tissues.