DERT Story of Success
Andrea Baccarelli, M.D., Ph.D.
NIEHS grantee Andrea Baccarelli, M.D., Ph.D., studies epigenetic changes, which affect the way genes are expressed without directly changing the genetic code in DNA.
Baccarelli's career experiences have led him to become a pioneer in environmental health and epigenetics research. Furthermore, his research continues to provide a greater understanding on how epigenetic changes may be leveraged to prevent certain diseases following exposure to pollutants.
Establishing a career in environmental health and epigenetics research
Although clinically trained as an endocrinologist, Baccarelli's path shifted when he met epidemiologist and mentor Pier Alberto Bertazzi, M.D., from the University of Milan, who encouraged Baccarelli to pursue a career in environmental health research. During residency at the University of Milan, Baccarelli worked with Bertazzi to study the long-term health effects associated with dioxins released by the 1976 Seveso disaster, an industrial accident that impacted thousands of people in northern Italy. Continuing to follow the Seveso cohort, their research team noticed that certain diseases took 20-30 years to develop.
"It became clear to me through this and many other studies, that something happens within the body's cells that is responsible for the delayed time between when an exposure takes place to when disease symptoms first appear," Baccarelli said. He would later discover that epigenetics was one of the answers.
Shortly after completing a postdoctoral fellowship at the National Cancer Institute in Bethesda, Maryland, Baccarelli returned to the University of Milan as an assistant professor in the Department of Occupational and Environmental Health. Baccarelli began to brainstorm different projects that he and his team could study on how exposures modify the genome, or the epigenome. Some of their first projects focused on DNA methylation, a common epigenetic change that alters the way DNA is expressed.
Baccarelli and his team have made significant progress in better understanding the role of epigenetics in environmental health. For example, they published the first human study that showed an association between altered DNA methylation in blood samples from healthy subjects and low doses of benzene, a widespread pollutant shown to be associated with a specific type of leukemia. In another study, results showed that exposure to air pollutants was associated with gene-specific DNA methylation changes among a cohort of elderly men in the Normative Aging Study.
In recent years, Baccarelli and his team have identified a cadre of environmental stressors that affect the human epigenome, including metals and common household chemicals, as well as childhood psychosocial factors. Examples of these psychosocial factors include physical and emotional abuse that occur during childhood.
Examining epigenetics as a method of intervention for health risks
Other findings from Baccarelli and colleagues show promise for making changes to a person’s epigenetic profile, or epigenome, to prevent adverse health outcomes following environmental exposures.
In a recent pilot intervention trial, Baccarelli and colleagues demonstrated the potential for B-vitamins to counteract the negative epigenetic effects of exposure to fine air particulate matter (PM), which has been linked to increased inflammation and oxidative stress.
"B-vitamins are natural methyl donors," Baccarelli said. "Previous experiments in our lab showed that exposure to fine air particulates induce hypomethylation, or low DNA methylation marks, especially in inflammatory genes. Our hypothesis was that by providing B-vitamin supplements to exposed individuals, we could help bring their methylation levels back up again."
Using a cross-over trial method, ten healthy adult volunteers received a controlled exposure experiment to one of three conditions in an exposure facility: a placebo, PM levels common to a busy roadway, or PM exposure along with B-vitamin supplementation. Epigenome-wide DNA methylation analysis was performed before and after each experiment.
In PM-exposed individuals that exhibited either high or low DNA methylation, B-vitamin supplementation led methylation levels to go back to almost a normal, baseline level. “These results were quite surprising, and somewhat countered our original hypothesis,” Baccarelli said. "More follow-up studies are needed to confirm other molecular mechanisms that may play a role in mitigating the epigenetic effects of PM exposure with B-vitamins."
Exploring mitochondria and extracellular vesicles as potential biomarkers
Baccarelli and his team in the Columbia University Department of Environmental Health Sciences are now leveraging the unique aspects of mitochondria to better understand how different environmental exposures impact disease risk.
Mitochondria are a key source and target of oxidative stress, which involves the body's efforts to neutralize harmful free radicals in the body. As more oxidative stress is produced in the mitochondria, an amplification effect can occur, potentially resulting in more stress and greater mitochondrial DNA damage. Compared to DNA that is maintained in the cell nuclei, mitochondrial DNA is more prone to damage because repair mechanisms are not as efficient. "Given their ineffective DNA repair mechanisms, I believe the mitochondria can work like a biological memory box, recording exposures that happen throughout life," Baccarelli said. "Essentially, we can use the mitochondria as new biomarkers for environmental health studies."
Baccarelli and his team are using assays to measure mitochondrial abundance, or the number of mitochondria in cells, because cells that have a greater amount of mitochondrial dysfunction typically exhibit more copy numbers of mitochondrial DNA. In one study funded by NIEHS, they showed that short- to moderate-term exposure to black carbon, a tracer of traffic-related air pollution, was associated with increased blood pressure and blood mitochondrial abundance in elderly men from the Normative Aging Study.
Similar to nuclear DNA, mitochondrial DNA is also susceptible to epigenetic regulation. In a more recent study funded by NIEHS, Baccarelli and colleagues showed that DNA methylation at specific loci in the mitochondrial genome could intervene with thyroid-dependent regulation of mitochondrial DNA during fetal development.
Baccarelli and his team are also investigating the unique properties of extracellular vesicles, or small structures released by cells into the bloodstream, and exploring how the non-coding RNAs they carry can be used as biomarkers of exposure to PM. Extracellular vesicles act as molecular cargoes for non-coding RNAs, such as microRNAs, which are also involved in epigenetic regulation of gene expression. "In theory, exposure to air particulates causes a release of microRNAs that are stored within extracellular vesicles," Baccarelli said. "By extracting these microRNAs from blood samples, we could potentially better predict the effects of PM on inflammatory mechanisms and lung function in different aging populations. This is a new and exciting area of research for us."