Environmental Exposures and Our Dynamic Epigenome

"Air pollution can cause epigenetic changes for example. Hormonally active chemicals like
phthalates and BPA, chemicals like tributyltin, dioxin, PCBs, flame retardants.
A wide range of chemicals can cause epigenetic modification."

Linda S. Birnbaum, PhD, is Director of the National Institute of Environmental Health Sciences (NIEHS), one of the National Institutes of Health branches, and also of the National Toxicology Program (NTP), taking the helm in 2009. The mission of the NIEHS includes fostering research on environmental triggers of disease, including federal funding for biomedical research. Birnbaum is the first toxicologist and the first woman to lead the NIEHS/NTP. She has spent most of her career as a federal scientist.

Dr. Birnbaum has received numerous awards and recognitions, including being elected to the Institute of Medicine of the National Academies, in October 2010, one of the highest honors in the fields of medicine and health. Birnbaum’s own research and many of her publications focus on the pharmacokinetic behavior of environmental chemicals; mechanisms of actions of toxicants, including endocrine disruption; and linking of real-world exposures to health effects. A native of New Jersey, Dr. Birnbaum received her M.S. and Ph.D. in microbiology from the University of Illinois at Urbana-Champaign.

Interviewed by Jill Escher, April 2014

---

Thank you so much for taking the time out of your busy schedule to speak with us and contribute to our new website.  Our mission is to provide information about the vulnerability of our genome and epigenome to exposures—can you speak to the NIEHS’s perspective on gene-environment interaction?

We’re all begining to realize that very few things are either one or the other, genes or environment. Genes set up our basic susceptibility and then our environment acts upon that, so I think there are very few health conditions which are exclusively one or the other. Now if you’re living in Beijing and you can’t see your hand in front of your face, lots of people will feel impacted by the environment. But the people who will be most severely impacted are those who are at enhanced susceptibility, because of genetics, or age, or past exposures, for example. We are increasingly interested in this whole interplay.

In addition to acting upon our bodies, it appears that environmental exposures can also directly impact our genome.

With respect to the genome itself and the germline, we certainly have the animal data demonstrating exposure-induced epigenetic changes and we are finding transgenerational effects. Many of those effects would have to go through the germline for that to happen. With many different environmental exposures, we have a number of grantees who are finding effects induced in the original generation can extend to the great grand-children and beyond.

What mechanisms do you think may be at play?

We are doing a lot of work in the area of epigenetics. There are many analogies people use-- the genome is the score and the epigenome is the conductor interpreting the score; or the genes are the hardware and the epigenetic control is the software. The point is that we are beginning to understand more and more, that for a long time that a skin cell is different than a bone cell which is different than a muscle cell. And we understand they all have the same DNA but different genes are turned on and off. Epigenetics teaches us how and why genes are turned on or off.
 
There are multiple modifications that can occur to the DNA, to the proteins that bind the DNA, and to the little nuclear RNAs that also play a role in gene expression. And we are also beginning to learn that lots of regions of the genome, which we used to call deserts, are very important to regulation, and the same thing is true with RNA. We used to only talk about three types of RNA, ribosomal RNA, transfer RNA and messenger RNA, and everything else was kind of garbage. Now we are understanding that the “garbage” has an important regulatory role.

The modifications of DNA involve things like methylation of cytosine residues adjacent to guanine residues. People talk about islands and shores, if you have a whole run of CpGs [Editor’s note: CpGs are cytosine nucleotides next to guanine nucleotides along the DNA], you get lots of methylation in a cluster but then sometimes you can have isolated CpGs where the methylation is extremely important. Methylation of DNA in general shuts down gene expression but there are loads of exceptions where it actually turns on gene expression.

And there’s also new evidence that the methyl groups can be further modified, for example to be hydroxylated, which changes what they do. And there’s beginning to be some evidence that you may be able to methylate adenosine residues as well as cytosine residues, which may be very important right around the time of fertilization and in very early development.

Then you have the histone proteins, the DNA curls up around these histones, providing the chromatin structure that is folded up. Well the DNA must be accessible in order for enzymes to get in and begin to transcribe the DNA to RNA, and we’re understanding that the histones can be modified not only with methylation but also other kinds of small, functional groups can also attach, as with acetylation, propionylation, etc. And you might not have methylation, you might have two or three methyl groups, or two or three acetyl groups, and so on.  And the positions of these modifications on these specific amino acids is going to determine whether those modifications make the histones glom on tighter to the DNA or maybe it causes them to fall off the DNA.

So while in general DNA methylation shuts down gene expression, in general, methylation of histones turns on expression. And there are loads and loads of exceptions which are turning out to be extremely important. And then you have the microRNAs, which are short RNAs, maybe 20 to 23 nucleotides long which we’re finding circulating in the cells but also in the body, appearing to play key regulatory roles, especially at blocking the expression of genes.

So, we are beginning to understand that there are multiple levels of control and multiple mechanisms of control. But I personally think epigenetics is the site of action for much of the environmental exposures. In other words, yes, exposures may cause actual mutations in the primary gene sequence but I think they can also change what happens to the expression of genes. And if you alter the expression and functioning of genes, that may in itself lead to mutations in the primary sequence of genes. 

Thank you for that excellent overview. What about epigenetic changes during development?

We know that epigenetic changes are absolutely critical during development. If you block them or interfere with them, you can mess up development. We know that epigenetic changes are critical in numerous different diseases and conditions. We know they are important during aging, and in cancer. 

What are some of the agents and exposures that may impact epigenetic programming?

We’re finding lots and lots of different exposures. Air pollution can cause epigenetic changes for example. Hormonally active chemicals like phthalates and BPA, chemicals like tributyltin, dioxin, PCBs, flame retardants. A wide range of chemicals can cause epigenetic modification. 

What about pharmaceuticals?

Obviously. People forget the pharmaceuticals or personal care products are chemicals.  So why would we think that drugs, which are made to cause a biological response, wouldn’t have the capability to do some of the same things environmental chemicals have? And in fact, I think they probably do a lot more, because you generally take a drug at a dose that you want to have an effect. The issue with environmental chemicals is you are being exposed to something where you don’t want to have an effect. 

And the pharmaceuticals are administered more regularly.

Not necessarily.  If you’re talking about air pollution or personal care products, or microcontamination of food, for example, we are all exposed, all the time.

What more can be done in the short term to address germline vulnerabilities from a toxicology point of view?

The National Toxicology Program was set up to coordinate toxicity testing, to develop new tests, to conduct the testing, and then to do evaluations of results. I think the whole issue of germline effects would be a great subject for an authoritative review. Our program takes nominations in the NTP and maybe you should nominate that. OHAT, the Office of Hazard Assessment and Translation, does authoritative reviews. The predecessor organization to OHAT did a review that drew attention to the hazards of BPA. They were also the group that released a report on low-level lead, stressing no safe level, and the fact that effects are occurring below 5 mcgs/dcl of exposure. The action level at the CDC used to be 10. So it’s a group whose evaluations have impact. 

That’s a great suggestion. I wanted touch on neurodevelopmental disorders like autism and ADHD.

Absolutely, and when you look at the trends, they are absolutely overwhelming and frightening. There’s a tendency to blame the parents or the kids, which is of course not helpful. 

We need to think about the fetal exposures, which are no doubt extremely important, but I think we also need to think about what may have happened to our germline, decades ago. Including maternal smoking, which was rampant.

The numbers were huge. And I think 19-20% of our young women are still smoking. There is good epidemiological evidence for an association between autism and air pollution as a very early life exposure.  Almost everything you see with smoking you see with air pollution. And this new craze with e-cigarettes is scary.

Yes, I saw data on epigenetic changes in sperm caused by e-cigarettes.  Nobody thinks about that! I know you need to run to your next meeting, but thank you so much for your time today, and for all the work the NIEHS is doing in the field of toxicology and epigenetics.

And thank you.