PhD course on epigenetic mechanisms and their relevance for human pathology

Epstein-Barr virus (EBV) is a ubiquitous herpes virus implicated in many types of cancers and autoimmune disorders. After primary infection, EBV persists in most individuals as a lifelong asymptomatic infection of B-lymphocytes. Latent viral oncogenes expression is under the control of epigenetic mechanisms, such as DNA methylation. EBV hypermethylation helps to inhibit the expression of viral latency proteins that could be recognized by cytotoxic T-cells. Several studies showed as Human endogenous retrovirus (HERV), that represents approximately 8% of human genome is associated with EBV expression. We examined the effects of PM exposure on both EBV and HERV DNA methylation in 48 healthy workers at an electric-furnace steel plant with well-characterized exposure to metal-rich particulate matter. We measured DNA methylation (in Wp promoter) through bisulfite PCR Pyrosequencing in the first day of a work week (baseline, after 2 days-off work), and after 3 days of work (postexposure) as well. We determined individual exposure to inhalable particles and metals for all subjects. Paired t-test was used to compare baseline and post-exposure samples while linear mixed models were fitted to evaluate the association between metal-rich particle exposure and DNA methylation. The results revealed a change in EBV methylation measured at the baseline and at the post-exposure (difference post exposure-baseline= -9.5%, p-value= 0.009). In multivariable mixed models adjusted for age, body mass index and smoking, Nickel, Arsenic and Lead showed a positive correlation with EBV methylation (Nickel: β=16.16, p-value <0.001; Arsenic: β=13.0, pvalue=0.02; Lead: β=16.53, p-value <0.001). No significant correlation was found in HERV methylation. These results could suggest a correlation between EBV methylation and metals exposure such as adaptive mechanism.