Micrornas in Extracellular Vesicles as Novel Biomarkers in Environmental Epidemiology

Despite important achievements of Environmental Epidemiology in identifying major environmental health problems in recent years, little is known about the underlying biological mechanisms that link environmental exposures to certain outcomes. Recent discovery of extracellular vesicles (EVs) as a novel mechanism of cellular communication has opened new avenues for non-invasive access to subclinical molecular signals, which might help exposing such mechanisms. In this work, we evaluate the potential of microRNAs, molecular signals that are contained in EVs circulating in the blood, as biomarkers in two very important environmental health problems: (a) the causal association between air pollution and cardiovascular disease and (b) the association between prenatal lead exposure and impaired fetal growth. For this work, we used cutting-edge and high-throughput methods to isolate EVs from the blood of study participants, and profile their content in microRNAs (evmiRNAs). We further incorporated a broad array of sophisticated statistical methods to (a) determine the association of ambient particulate matter of <2.5μm diameter (PM2.5) and evmiRNAs (Chapter 1), (b) determine the association between prenatal lead exposure and fetal growth (Chapter 2), and (c) evaluate the potential of evmiRNAs as early biomarkers of fetal growth impairment (Chapter 3). The findings from Chapter 1 showed positive associations between long-term exposure to PM2.5 and levels of evmiRNAs in the blood circulation of older individuals, several of which were found to be enriched in biological pathways related to cardiovascular disease. Results from Chapter 2 showed a negative association between prenatal exposure to lead and birthweight-for-gestational age (BWGA), and revealed that the magnitude of the association is much bigger in the lower percentiles of the BWGA distribution. Finally, the findings from Chapter 3 suggested that levels of evmiRNAs provide a very promising opportunity for the development of minimally-invasive biomarkers to detect and monitor impaired fetal growth early in pregnancy. This work demonstrates the tremendous potential of evmiRNAs in the field of Environmental Epidemiology. EVs and their content provide an unprecedented, yet easily accessible source of molecular signals that can help us better understand the biological mechanisms involved in linking environmental exposures to certain outcomes.