Description
Introduction: Air pollution has a number of negative effects on human health including an increase in the risk of respiratory and cardiovascular diseases. Recent findings highlighted that air pollution plays a role in the onset of neuropsychiatric conditions including Major Depressive Disorder (MDD) as a result of alterations of different biological systems affecting the correct functioning of the Central Nervous System (CNS).
Objective: Purpose of the present research was, among others, to study the effect of air pollution on methylation of clock genes implicated in the regulation of circadian rhythms.
Methodology: the study population includes 416 adult subjects affected by MDD. Patients with severe medical comorbidities associated with prominent inflammation or behavioural disturbances, subjects with current substance use disorders or pregnant women were excluded because all these factors could potentially affect regulation of clock genes as well as MDD. The methylation of the following clock or clock-related genes was assessed through pyrosequencing: CLOCK, BMAL1, PER1, PER2, OX1R, CRY1, CRY2, OXTR, FOXp3, HERV-W. We evaluated exposure to particulate matter (PM10 and PM2.5) and nitrogen dioxide (NO2), averaging the mean concentration levels of pollutants in the day of recruitment with those of each preceding day: i.e., short- (lag0-1 to lag0-7), middle- (lag0-14, lag0-21, lag0-30) and long-term (lag0-60, lag0-90, lag0-180, lag0-365) exposures. The association between air pollution and DNA methylation was estimated by multivariate regression analyses.
Results: Short-term exposure to PM10 was associated with hypomethylation of CRY2 and hypermethylation of OX1R, CRY1, and BMAL1 at different lags of exposure within the two weeks preceding recruitment. Long-term exposure to PM10 (average of the three- and six-months preceding recruitment) was positively associated with CRY1 (lag0-90: β=2.24, p=0.007; lag0-180: β=3.41, p=0.003) and negatively associated with CRY2 (lag0-90: β=-0.21, p=0.006; lag0-180: β=-0.23, p=0.017). Results were similar for PM2.5. When short-term exposure to NO2 was considered, we observed an increased methylation of CRY1 (lag0-1: β=0.84, p=0.001; lag0-2: β=0.65, p=0.010; lag0-3: β=0.58, p=0.026) and a reduced methylation of CRY2 (lag0-5: β=-0.66, p=0.024; lag0-6: β=-0.63, p=0.035). Long-term exposure to NO2 was positively associated to the methylation of CRY1 (lag0-90: β=1.04, p=0.025; lag0-180: β=1.39, p=0.006) and HERVW (lag0-365: β=0.01, p=0.049).
Discussion: The findings of the present study show as air pollution can alter biological systems that have a role in human behaviour such as neuropeptide pathways. Of note, orexin regulates numerous circadian functions such as appetite and sleep that are prominently altered in psychiatric conditions such as MDD. In addition, both short- and long-term air pollution exposure affects methylation of cryptochrome genes (CRY) that play a crucial role in the regulation of circadian rhythms.
Conclusions: Our findings support the role of air pollution in alteration of biological pathways associated with the correct function of CNS, thus further underlying the importance of continuous pollutants monitoring and control, as well as of mitigation measures useful to preserve the physiological functioning of CNS, such as the expansion of green areas in the urban environment.
Acknowledgment: this research was funded by Cariplo Foundation and dissemination was supported by 4EU+ Alliance that includes University of Milan
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