Pete Myers, MD: Epigenetics and Endocrine Disruption

John Peterson “Pete” Myers, PhD is founder and chief scientist of Environmental Health Sciences, a not-for-profit organization that promotes public understanding of advances in scientific research on links between the environment and health (http://www.EnvironmentalHealthNews.org). Dr Myers holds a doctorate in the biological sciences from the University of California, Berkeley. For a dozen years beginning in 1990, Dr Myers served as director of the W. Alton Jones Foundation. Along with coauthors Theo Colborn, PhD, and Dianne Dumanoski, Myers wrote Our Stolen Future, a best-seller that explores the scientific basis of concern for how contamination threatens fetal development. He is on the boards of the Food Packaging Forum, the Science Communication Network, and the Jenifer Altman Foundation. He is an adjunct professor of chemistry at Carnegie Mellon University in Pittsburg, Pennsylvania. From 2012 to 2014, he served as board chair of the H. John Heinz Center for Science, Economics, and the Environment. Myers has received multiple major national and international awards, including the Laureate Award for Outstanding Public Service from the Endocrine Society (2016), the first Champion of Environmental Health Research award from the US National Institutes of Health (2016), and the Distinguished Service Award from the Sierra Club (2017). In 2017, he also received the International Cooperation Award from the US Forest Service for an effort he founded in 1985 that now protects 39 million acres of migratory shorebird habitat in 100 critical migration sites from Tierra del Fuego to the United States and Canadian Arctic, the Western Hemisphere Shorebird Reserve Network (http://www.WHSRN.org).

Integrative Medicine: A Clinician’s Journal (IMCJ): At the Environmental Health Symposium, or EHS, what do you intend to address with your presentation?

Dr Myers: We live in an era in which people all over the country, in fact, all over the world, are beset by failures in the endocrine system. We have epidemics of type 2 diabetes, obesity, various hormonally related cancers, and malfunctions during brain development that are guided normally by hormone systems working properly. It’s actually very serious because if you read public health, you’ll know that leaders in the field say this current generation of kids is not going to be as healthy as their parents, and that hasn’t happened very often in the entire history of the human species. So, what’s happening? I want to talk about what’s happening and what opportunities there are to fix it.

IMCJ: So, you want to focus on how exposures, via environment, and lifestyle, affect the endocrine system for people from their developmental stages right into adulthood.

Dr Myers: Right into adulthood, because sometimes things that start in the womb don’t show up until middle age or when you’re a senior. It’s truly astounding. And this is mostly a result of epigenetic changes made early in life that play out over the lifetime of the individual.

IMCJ: What are some examples of issues that would show up in midlife as a result of exposures in the womb?

Dr Myers: Quite a few things, actually. Some famous work was published by a research scientist at the Public Health Institute in Berkeley, California, named Barbara Cohn, PhD, MPH, who was fortunate enough to gain access to cord blood that had been deposited 50 to 60 years prior to her research. All this unfolded at Kaiser Permanente. So many of the babies whose cord blood was obtained are still in the Kaiser system. They can look at contaminants in the womb and relate them epidemiologically to problems in adulthood. And it turns out, if you were exposed to [dichlorodiphenyl-trichloroethane, or] DDT in the womb, you are almost 4 times more likely to develop breast cancer by the age of 50 than someone who was in the lowest quartile of exposure.

There’s no way that you could anticipate that impact. The impacts between DDT—and chemicals like DDT— and breast cancer, heretofore had mostly been carried out by looking at groups: 2 groups of women, matched for age and at the age of 50 to 60, comparing how much DDT—or DDE, a metabolic breakdown of DDT—they had currently had in their body. In that scenario, you don’t find anything. I am not surprised by that. The crucial things that lead to breast cancer as a result of exposure to DDT involve epigenetic changes that alter mammary gland development in the womb and alter how mammary tissues respond to changing levels of hormones in the blood of the women as they grow older.

IMCJ: That association didn’t show up nearly as well in matched cohorts versus measurements of cord blood obtained when they were born in relation to breast cancer development 5 decades later?

Dr Myers: Having a measurement of DDT exposure at the end of fetal life, it turns out—because DDT is persistent— is a pretty good measure of total DDT exposure during pregnancy. That is the predictor of whether or not at the age of 50 you are going to get breast cancer, not current DDT levels when you are 50. In fact, the DDT has by and large either completely disappeared or been metabolized into DDE over the 5-decade time period. And so, when that question started to be asked in the 1990s, a series of cohort studies compared women with breast cancer and women without. Their DDT, or polychlorinated biphenyl levels, were compared, and researchers didn’t find anything. But anyone who does experiments with animals would have told you that they wouldn’t find anything because the animal studies involve fetal exposure and adult mammary gland problems.

IMCJ: Which is a completely different study structure.

Dr Myers: Completely different. And, frankly, we were really fortunate that Dr Cohn gained access to these samples. And we were even more fortunate that Jacob Yerushalmy, PhD, a biostatistician at the University of California, Berkeley, who created the repository, had the foresight to know that they could yield medical information 5 decades later—important medical information.

IMCJ: Is that team finding any other interesting results looking at these cord-blood samples?

Dr Myers: Yes. There are some neurobehavioral effects. I’m not as familiar with those as I am with the breast cancer results. The problem is that they are a nonprofit, public health Institute. They raise as much money as they can, but these are expensive things to do, so they never have enough money to carry out all the research that could be done with the samples they have.

IMCJ: It sounds like a treasure trove of information.

Dr Myers: It really is. It’s almost unique. I don’t use that word lightly. We owe a huge debt to Dr Yerushalmy.

IMCJ: Are there any other pearls out there in the research like this example?

Dr Myers: There are. Probably the biggest pearl out there is the story of diethylstilbestrol, or DES.

In the late 1940s, people were looking for synthetic estrogens in the belief that they could help manage difficult pregnancies. And the strongest synthetic estrogen located was a compound called DES. Everything seemed to be going okay. It was expensive, so using it was common only in relatively well-off centers where there were big medical facilities, places like Boston, Massachusetts, or San Francisco, California.

Eighteen years later, a Chicago doctor named Arthur Herbst, MD, had a patient come into his office—a young woman, 18 years old—who presented with a very rare cancer—clear cell adenocarcinoma of the vagina and/or cervix—which heretofore had been seen only in relatively old women. He was surprised by that case. Her mother, in the medical appointment, asked him, “Could this have anything to do with a drug I took while I was pregnant with my daughter, a drug called DES?” And Herbst said, “No. No way.”

Well, in the span of I think a few days, a second young woman with this cancer came in—really unusual. And Herbst had the presence of mind to ask the mom, “Did you take DES?” And she said, “Yes.” And that then unleashed the power of public health and epidemiology. That was in 1971 and, within 2 years, DES was banned.

Now, this has created a whole class of people called DES daughters and DES sons, and people have been following them closely as they have aged and had kids. Not only do they have other problems beyond the clear cell adenocarcinoma cancer, buy also the women have deformed reproductive tracts. They have a whole series of deformities that relate largely to reproduction. Their daughters also have deformities, so it persists. There are also effects in DES sons. And actually, this research is reaching a crucial junction right now. Because, if you remember your mammalian biology, when a female fetus is in the womb, it’s actually forming the eggs of her own daughter, so those daughters of the daughter were likely exposed to DES also. Does that make sense?

So now the granddaughters of the girls exposed in the womb, the great-granddaughters of the exposed mothers who took DES, are now being studied, and at least some of the initial reports indicate that they’re having problems also.

Quite a lot is known from animal models about this persistence because beginning in 2005, a guy named Michael Skinner, PhD, who is at Washington State University and a reproductive biologist, was running experiments on several different endocrine disrupting compounds. They had finished one round of experiments, but there was some miscommunication, so they continued raising the daughters of the daughter that was exposed, and they started to see the same things. And then they carried it out to the great-granddaughters and great-grandsons and saw the same things. And those great-granddaughters and great-grandsons could not have been exposed in the womb. The research that has unfolded since 2005 on that subject is called transgenerational inheritance of epigenetic change.

There are now multiple endocrine-disrupting compounds that are known to cause effects down to the F4 generation. F0 is the mom who was exposed while pregnant. F1 is the daughter. F2 is the granddaughter. So, once you get to F4, there is no direct exposure to the chemical.

Now there is a huge industry, I mean that in a positive sense, of people trying to understand how it happens. It is pretty clear there’s not a change in DNA sequence, but there is a change in the epigenetic markers that control gene expression. And so, there are multiple endpoints which now are known to transmit epigenetically like that. There’s a researcher at North Carolina State University, Emilie Rissman, PhD, who has studied a mouse model of autism, and low levels of BPA to F0 produce autistic-like symptoms in F4.

Actually, I studied BPA experimentally. But the more interesting part of this story is not about what I do; it’s what I can tell you about what’s happened. I know that’s not how most scientists think, but I like to look at the big picture because I’ve been working on endocrine disruption since 1988. In 1991, I coined the term endocrine disruption in a scientific workshop, so I’ve been doing this for a long time.

The changes that have unfolded in this science are quite remarkable. In 1988, 1989, and 1990, we were in the medical wilderness. No one wanted to pay attention. It was hard to get funding to work on it. Physicians had no interest, whatsoever. Fast forward almost 30 years now, and I got an award from Francis Collins last year. He was mentioned in the press release. I also got an award from the Endocrine Society, a Laureate award for Outstanding Public Service. Just 3 weeks ago, the American Academy of Pediatrics issued a big report on endocrine disruption and the risks that it creates for the patients of the pediatricians who are in that society. So, we’ve gone from what was way out in the wilderness to now being poised at the edge of mainstream science—actually, within mainstream science—and finding things that, if we act on them from a policy perspective, we can use to make people healthier.

IMCJ: Has the reverse research started to find out what kinds of things may change the methylation of those epigenetic changes and flip those switches back?

Dr Myers: There has been some research on that, the most famous of it by a lab from Duke headed by Randy Jirtle, PhD. He studied a strain of mice that had an odd fur color, which responded to bisphenol A. And then when he fed them some chow rich in methyl groups, it eliminated the effect. This sort of approach is rare because when you methylate, you may methylate more than just what you wanted to, including some bad stuff.

And so I think that I think the healthier, wiser approach is to try and figure out what caused the methylation in the first place, and take it out of circulation.

I wrote a book along with Theo Colborn, PhD, and Dianne Dumanoski in 1996 called Our Stolen Future.¹ It became the introduction to the public on these issues. I can’t tell you how many physicians I’ve spoken who said, “You changed my career with that book.” It is a very humbling experience. When we wrote that, the book was about a lot of research questions for which we didn’t have answers, but for which we knew we needed answers. And 25 years later, it holds up. In fact, the book is still for sale.

We didn’t make errors of inclusion. We didn’t make mistakes about the questions we thought were important. We did miss a couple of things, which have now become really important. One of those: We did not even remotely see transgenerational inheritance coming. In fact, we said, “The good news about endocrine disruption is that if you can remove the exposure, because you haven’t changed the DNA code, the next generation will get better.” Well, that’s not always the case. We don’t know how many endocrine-disrupting compounds do cause transgenerational epigenetic inheritance, but it’s more than a dozen. And it’s really hard work to do. It’s very expensive because of the numbers of mice you have to raise.

The more complicated an experiment gets, the more likely it is you’re going to have some problem in it. And those problems don’t cause artificial effects; they hide real effects. That’s the way experimental biology usually works.

So, we missed that. We also missed what are called obesogens, which are a subset of endocrine-disrupting compounds that act to cause exposed individuals to become obese, sometimes morbidly obese. It turns out, it’s not just what you eat and how much you exercise. Obesogens act through a couple of different pathways. One of which is by changing differentiation of stem cells. Mesenchymal stem cells, which were destined to become bone cells, become fat cells because the genes that are turned on by these endocrine-disrupting obesogens control the fate of the stem cell. Not only do you end up with more fat cells, but often the new cells also are better at assimilating fat, lipids.

IMCJ: Do people with those exposures also end up with bone density issues?

Dr Myers: That’s being looked at currently, and it’s highly likely. And there are other results with related chemicals, which weren’t looking at the fat issues, but were already reporting loss of bone density, so this could be a contributor to osteoporosis.

The other way that obesogens work by a completely different set of mechanisms is by affecting appetite. They can make you want to eat a whole lot more. They also can change the efficiency with which you absorb lipids. So, we now know of several different pathways. It’s something I became concerned about a long time ago. Shortly after we wrote the book, I wasn’t in a position to move the research forward. But Bruce Blumberg, PhD, beginning in the early 2000s, really started to move that ahead. He has just written a book called The Obesogen Effect,² which is intended for the general public. It gets a little sticky in some places, but it’s really good. And Bruce, who is at the University of California, Irvine, is a superb geneticist.

A lot of the people who work on this field got into it by accident. You didn’t come to it through toxicology. Toxicology is pretty much an applied science. And it uses tools and approaches that stem from the 16th century.

IMCJ: You mean the LD50: What loading level does it take to poison you? They’re not looking at the subtleties that are at play. They’re looking at killing a fruit fly with a sledgehammer.

Dr Myers: That’s right. And the subtleties can kill you too, over time. You get type 2 diabetes because of early life exposure, or like I was saying earlier about breast cancer. That is life threatening. It is not a subtle effect once it is in full-blown mode, but it is subtle at first, and you can’t use traditional toxicological tools to detect it.

So, this perspective has us in an argument right now with the FDA. In the first year of endocrinology you learn that different genes are expressed at different doses of hormones. It is a classic response. It is the default expectation that a very, very low dose, within the physiological range that hormones circulate, causes one set of genes to be expressed. Then you go up the dose—response curve and at another level, a different set of genes will be expressed—sometimes, the result of those genes being turned on is to turn off the ones that are operational at the lowest dosing levels. So, you get a negative-feedback loop, which means that you cannot use high-dose testing to anticipate low-dose results.

One of the key things I stress is that the systems we have used to test what is safe and what is not are blind to really important health endpoints. They don’t use tests that are that relevant to human health conditions, and they use assumptions that are way out of date. Some of the tools used, literally, date to the 1930s. One of the core assumptions dates to the 16th century. Literally. And there is a lot of science that refutes it. Imagine today arguing against plate tectonics or quantum mechanics. That’s analogous to what FDA, EPA, and industry scientists do today on chemicals.

We are also arguing, right now, with the FDA, over a big experiment on BPA that was done with the FDA and some world-class, endocrine-disruption scientists. Looking at everyone’s results together reveals low-dose effects, quite a few. More than half of the endpoints tested had low-dose effects, but the FDA rejects them because they don’t see the same effect at high doses. And every regulatory test that has ever been done in the world, by any regulating authority, makes that same assumption. We did some calculations, and it shows that if the FDA were to acknowledge low-dose effects, it would have to lower what it considers safe by a factor of 20 000.

IMCJ: And they keep raising the limits for things like glyphosate.

Dr Myers: Yes. And do you know why they increased the tolerable limits for glyphosate? The applicators were having to use more and more of it because so many weeds were becoming glyphosate-resistant. So the EPA knew that there was going to be more glyphosate in the food, so they upped the levels. I published on glyphosate a couple years ago.

IMCJ: What more will somebody take away from this by attending your lecture?

Dr Myers: Two things. One, the field of endocrine disruption is a great example of the Oceans Eleven theory of science. You don’t get anywhere if everyone on the team is Brad Pitt. You have got to have a team composed of lots of different types of people and skills: a little guy, a big guy, a woman. Scientists who work together have come to realize that by working together, they accomplish so much more than they could by themselves.

Endocrine disruption has grown to where it is today because people with very different specialties—almost none of them, toxicology—began using modern medical insights and tools to ask questions that toxicologists were not asking.

The other is that there is a lot of money at stake. Every endocrine-disruption scientist has been harassed in one form or another—some more, some less. You can’t have a thin skin and work in this field.

The Gordon Foundation collaborates with the American Association for the Advancement of Science to hold about 250 conferences every year in places like Asia, Europe, and the United States. It is the elite of the elite on issues from physics, to cosmology, to endocrinology, to endocrine disruption. The endocrine disruption field holds one every 2 years.

I’ve been to different types of Gordon Conferences, and usually the dynamic is a bunch of big-ego dudes who want to throw their weight around—competition at its worst. The endocrine-disruption Gordon Conference is different. It is a collection of people who have each other’s backs because of what they have been through—attacks by industry hacks because their results are inconvenient, despite overwhelming scientific evidence. So, the tone of the meeting is completely different, and it’s really rewarding to have watched that grow. EDC Gordon Conferences don’t devolve into ego competition. They rise to supporting one another and pushing the science forward in a shared way.