CYP2E1 epigenetic regulation in chronic, low-level toluene exposure: Relationship with oxidative stress and smoking habit

•We investigated gene-specific methylation in persons chronically exposed to toluene.•In a previous study, a reduced CYP2E1 activity was observed in these participants.•CYP2E1 promoter methylation correlated with oxidative-stress related gene methylation.•CYP2E1 promoter methylation was higher in exposed smokers compared to nonsmokers.•Epigenetic modifications are critical to detect early toluene-exposure effects.

BackgroundCYP2E1 is a versatile phase I drug-metabolizing enzyme responsible for the biotransformation of most volatile organic compounds, including toluene. Human toluene exposure increases CYP2E1 mRNA and modifies its activity in leucocytes; however, epigenetic implications of this interaction have not been investigated.GoalTo determine promoter methylation of CYP2E1 and other genes known to be affected by toluene exposure.MethodsWe obtained venous blood from 24 tannery workers exposed to toluene (mean levels: 10.86 +/− 7 mg/m3) and 24 administrative workers (reference group, mean levels 0.21 +/− 0.02 mg/m3) all of them from the city of León, Guanajuato, México. After DNA extraction and bisulfite treatment, we performed PCR-pyrosequencing in order to measure methylation levels at promoter region of 13 genes.ResultsIn exposed group we found significant correlations between toluene airborne levels and CYP2E1 promoter methylation (r = − .36, p < 0.05), as well as for IL6 promoter methylation levels (r = .44, p < 0.05). Moreover, CYP2E1 promoter methylation levels where higher in toluene-exposed smokers compared to nonsmokers (p = 0.009). We also observed significant correlations for CYP2E1 promoter methylation with GSTP1 and SOD1 promoter methylation levels (r = − .37, p < 0.05 and r = − .34, p < 0.05 respectively).ConclusionThese results highlight the importance of considering CYP2E1 epigenetic modifications, as well as its interactions with other genes, as key factors for unraveling the sub cellular mechanisms of toxicity exerted by oxidative stress, which can initiate disease process in chronic, low-level toluene exposure. People co-exposed to toluene and tobacco smoke are in higher risk due to a possible CYP2E1 repression.