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Air particulate matter (PM) is associated with increased cardiovascular morbidity and mortality. Altered autonomic functions play a key role in PM-induced cardiovascular disease. However, previous studies have not address the impact of PM on sympathetic and parasympathetic control of heart function, independently, and using controlled conditions, i.e., increasing titration of PM of known composition, in absence of other potential confounding factors. To fill this gap, here we used symbolic analysis that is capable of detecting non-mutual changes of the two autonomic branches, thus considering them as independent, and concentrations of PM as they could be measured at peak levels in Milan during a polluted winter day.In this randomized, cross-over study, we enrolled 12 healthy subjects who underwent two random sessions: inhalation of filtered air mixture or inhalation of filtered air containing particulate mixture (PM 10, PM 2.5, PM 1.0 and PM 0.5 μm). ECG and respiration for autonomic analysis and blood sample for DNA Methylation were collected at baseline (T1), after air exposure (T2) and after 2 h (T3). Spectral and symbolic analysis of heart rate variability (HRV) were performed for autonomic control of cardiac function, while alterations in DNA methylation of candidate genes were used to index pro-inflammatory modifications. In the PM expose group, autonomic analysis revealed a significant decrease of 2UV%, index of parasympathetic modulation (14% vs 9%, p = 0.0309), while DNA analysis showed a significant increase of interferon γ (IFN- γ) methylation, from T1 to T3. In a mixed model using T1, T2 and T3, fine and ultrafine PM fractions showed significant associations with IFN- γ methylation and parasympathetic modulation.Our study shows, for the first time, that in healthy subjects, acute exposure to PM affects parasympathetic control of heart function and it increases methylation of a pro-inflammatory gene (i.e. methylation of interferon γ). Thus, our study suggests that, even in absence of other co-factors and in otherwise healthy individuals, PM per se is sufficient to trigger parasympathetic dysautonomia, independently from changes in sympathetic control, and inflammation, in a dose-dependent manner.In healthy subjects, acute exposure to PM affects vagal autonomic control of the heart.PM exposure increases methylation of a pro-inflammatory gene, i.e. methylation of interferon γ (IFN- γ).PM per se is able to trigger autonomic deregulation and inflammation in a dose-dependent manner.