Andrea Baccarelli, MD, PhD on Epigenetic Susceptibility in Environmental Health

"A philosophical shift needs to happen in the way we consider biology. And it’s happening now.... At this point we know that the epigenome is a very sensitive biosensor of exposure."


Andrea Baccarelli, MD, PhD, is the Mark and Catherine Winkler Associate Professor of Environmental Epigenetics in the Department of Environmental Health, Harvard School of Public Health. Dr. Baccarelli’s research focuses on epigenomics as a unique molecular substrate reflecting the impact of environmental exposures on human health. 

Dr. Baccarelli’s laboratory is dedicated to the investigation of environmental epigenetics at different life stages.

Ongoing projects range from the investigation of the effects of in-utero exposures to toxic metals, second-hand smoking, and psychosocial stress on the methylome of human fetal tissues to the study of the influences of air pollution on non-coding miRNA in adult and elderly individuals. Epigenetic mechanisms are investigated in relation to fetal growth and perinatal outcomes, cardiovascular function, obesity, and neuro-cognition. Active studies include investigations in the U.S., Mexico, China, Italy, Bulgaria, Poland, Thailand, Oman, and Bangladesh.

 Since 2010, Dr. Baccarelli’s laboratory has produced more than 60 publications in epigenetics, environmental health, and epidemiology.



Interviewed by Jill Escher, October 2014



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Andrea Baccarelli, MD PhD

Websites:

Harvard School of Public Health
http://www.hsph.harvard.edu/andrea-baccarelli/

Baccarelli Lab:
http://www.hsph.harvard.edu/baccarelli-lab/

"[E]pigenetics on the other hand was something that seemed to have the potential make a difference in public health."



'[W]e contrasted the three groups and found an incredible dose-response relationship between exposures to benzene and changes in DNA methylation in the blood. Benzene is known to cause leukemia, for example, so this was one of the first studies to raise the question whether aberrations in genome-wide methylation can predict disease.

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"[T]hrough epigenetics there is the evolving concept of responsibility for the germ cells through which we transmit epigenetic information to our children. Whether I smoke or drink or exercise, it does not just influence myself, it could influence my children or grandchildren or great grandchildren.

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"It will be a huge moment when we can factor into risk assessment potential damage to the epigenome and to future generations."

You started off as an endocrinologist in Italy. How did you now come to study epigenetics?



As an endocrinologist, I used to work in diseases such as diabetes and thyroid disorders. At a certain point I realized I wanted to do research, particularly in epidemiology and environmental health. My first bout of studies, during my residency, looked at people exposed to dioxin, as part of the Seveso disaster in Northern Italy in 1976. In this disaster, a chemical plant accidentally released many tons of chemicals over many square miles. It exposed about 12,000 people to dioxin in high doses and about 30,000 were exposed at lower doses. It was a major trauma at the time in Italy. 

My mentor in environmental epidemiology encouraged me at the time to study gene-environment interactions. And then later I did a post-doc at the National Cancer Institute in Bethesda in 2000-04 mostly to work on genotypes and genetics.

But I became annoyed, for two reasons. First, the results we were getting were not robust. Second, once you find someone is more genetically susceptible to a disease or to the effects of a chemical, there is not really much you can do.

At this point while at NCI I was learning about epigenetics, in about 2003. In 2004 I went back to Italy and got a faculty position at the University of Milan, to do environmental genetics, gene by environment interactions, in other words, how your genetic make-up modifies your susceptibility. But I realized this line of research would not change anyone’s life.



But epigenetics on the other hand was something that seemed to have the potential make a difference in public health. In 2005, we worked on a project involving benzene exposure, it’s a well established carcinogen but does not damage DNA, we thought perhaps it damaged the epigenome. It’s found, for example, in the air due to vehicle emissions.

In a very simple study—we had 60 police officers who worked in traffic, 60 gas station attendants, and 80 controls who were office workers—we contrasted the three groups and found an incredible dose-response relationship between exposures to benzene and changes in DNA methylation in the blood. Benzene is known to cause leukemia, for example, so this was one of the first studies to raise the question whether aberrations in genome-wide methylation can predict disease.



And what are you working on now?



I am working on two different life stages now: early development and older age. We’re looking at childhood obesity in relation to early exposure to chemicals that affect the endocrine system. We have a project funded by NIEHS on BPA and phthalates in relation to childhood obesity and metabolic alterations, which is being conducted in Mexico City.  

And with the Women’s Health Initiative, we are plugging epigenetics into an existing cohort, doing DNA methylation on 2,000 women in middle age, who are transitioning to older age. We follow up with them to measure their health outcomes.



What are you finding are some of the prenatal exposure factors for obesity later in life?


In animal models, increased exposure to endocrine disrupting chemicals, such as BPA and phthalates, and psychosocial stress appear to be linked to obesity. These factors have been shown to alter DNA methylation in humans, so we’re now looking into whether those exposures and associated methylation changes may be linked to a higher risk for obesity in humans too. It’s an ongoing project, so the results are still preliminary, but look pretty interesting.



And what about the women’s cohort? What exposures and pathologies are you looking at, and do you have preliminary data you could share?


In this project, we’re focusing on the effects that air pollution has on DNA methylation and trying to see if those methylation changes are linked to any cardiometabolic outcomes. The labwork is still ongoing with this project, so we don’t have any data to share at the moment.

I’m very interested in smoking, and in fact our latest RFP was about germline effects of maternal smoking.

What epigenetic impacts have you seen with respect to smoking, and second-hand smoke?


We don’t have anything specific to report on here, but I would like to direct your attention to a paper from Environmental Health Perspectives, “450K Epigenome-Wide Scan Identifies Differential DNA Methylation in Newborns Related to Maternal Smoking during Pregnancy”, which was published in October 2012. Two authors discussed the paper in a podcast that can be found here: http://ehp.niehs.nih.gov/september-podcast/. They had some really amazing findings regarding maternal smoking and its effect on children’s epigenomes.


In terms of molecular stressors, are your mainly focused on chemicals?



We do focus mostly on chemicals, such as endocrine disruptors like BPA and phthalates, metals, and air pollution, but we are also starting to work on psychosocial stress, allergens, and dietary factors.


Your work focuses on somatic exposures, but are you looking at any multigenerational impacts of early life exposures? 



This work is hard to do in humans, and I’m not an animal scientist. But animal data are really impressive. Epigenetic programs are ingrained during development, but it’s not just embryogenesis and in utero developmental periods that are important. The genetic marking, as in the case of your prenatal exposures, includes the exposure of germ cells. And there’s now accumulating evidence of it. 

For example, in animal studies you can look at the paternal lineage—with fathers you can do a two-generation study to demonstrate environmentally acquired epigenetic marks or traits, based on alterations of sperm. With women, you need three generations to get to the germ cell exposure, the exposure would be to the fetal germ cells, and the outcome in the grandchild.



Shouldn’t that sort of multigenerational thinking be part of toxicology, and how we assess chemical risks?



A philosophical shift needs to happen in the way we consider biology. And it’s happening now. As scientists, we know these generational risks are possible. In terms of reaching down to toxicology testing, we really need more data to understand how heavy is this contribution. It can be difficult to quantify the impact, we are at the beginning of this era.



We need to think about social responsibility. When we think of social responsibility we tend to think of sustainability, preserving the environment for future generations. We don’t want to exhaust the environment, we want to give it to the next generation. But through epigenetics there is the evolving concept of responsibility for the germ cells through which we transmit epigenetic information to our children. Whether I smoke or drink or exercise, it does not just influence myself, it could influence my children or grandchildren or great grandchildren.



At this point we know that the epigenome is a very sensitive biosensor of exposure. My research is mostly on environmental pollutants, and we have evidence that the epigenome of children and adults is modified by environmental exposure. A lot of the research we do is actually targeting policymakers. But this takes years to happen. For example, early data on cognitive effects of lead, they had data in the 1960s and published seminar papers in the 1970s. But it took years for the EPA, in this case, to regulate lead. The same with air pollution. We learned that the investment in decreasing air pollution was necessary to protect our health. 



The process strikes me as excruciatingly slow. 



It will be a huge moment when we can factor into risk assessment potential damage to the epigenome and to future generations. We are still working on the biology of how environmental chemicals exert multigenerational effects. In humans, studying third-generation effects are difficult.  We transmit a lot to our kids, not just biology. We transmit culture, education, the effects can be subtle. In humans it can be difficult to separate the environmental epigenetic and molecular component from the cultural and social component. 



I’m going to disagree with you in part. It depends what outcome you’re looking for. My primary interest is in etiology of autism, a catastrophic abnormality of early brain development. There is no evidence that stress, or education, or cultural differences cause something as profoundly abnormal and disabling as autism.



Absolutely. I’m thinking more about obesity, where there are many influences.



You mentioned you turned to epigenetics because you thought this field could have an important impact on public health. Do you still feel this way? What do you see as the next big steps for safeguarding public health via our understanding of epigenetics?



Of course I do. Epigenetic contributions to public health are still to come. The body of work that is ongoing in molecular biology and basic science is still much larger than the epigenetics that is being applied to public health. Translating all the findings from basic science to public health is still the challenge of this decade.

Thank you for your time and the important work you are doing, Dr. Baccarelli.