Bisphenol-A and Breast Cancer -- It's Beginning to Look a Lot Like DES

An Expert Interview With Hugh S. Taylor, MD

Carol Peckham

Disclosures

July 27, 2010

Editor's Note:

As part of a special feature on the potential risks from exposure to bisphenol-A (BPA) during pregnancy, Medscape talked to Hugh S. Taylor, MD. He is Professor of Obstetrics, Gynecology, and Reproductive Sciences, Professor of Molecular, Cellular, and Developmental Biology and Chief of Reproductive endocrinology and Infertility at the Yale School of Medicine. He is also Director, Yale Center for Endometrium and Endometriosis. He was the lead investigator on a study that identified an important mechanism triggered by BPA exposure during pregnancy that could lead to breast cancer decades later in the offspring.[1]

Medscape: Could you describe your study on the risk of breast cancer in female offspring of mother's exposed to bisphenol-A (BPA),[1] and just give any thoughts on whether this was clinically significant?

Dr. Taylor: In this study we used a mouse model to look at the risk of breast cancer or -- more precisely -- the mechanism by which breast cancer risk may be increased after in utero exposure to either diethylstilbestrol (DES) or BPA. We looked at mothers ingesting either of these estrogen-like compounds during pregnancy and then determined what effect these compounds had on the female offspring after they had been born and as adults. They weren't being exposed to these agents as adults. They were only exposed in utero as fetuses.

In this study, we looked at the breast tissue. Recent evidence demonstrates that women who were exposed to DES as fetuses start to show an increased relative risk of breast cancer when they reach ages greater than 40. This drug was used in the 1950s and 1960s to prevent miscarriage in high-risk women, and now we are seeing an increased risk of breast cancer in their daughters, who are getting to the age where breast cancer risk starts to climb. We wanted to get at the mechanism behind that risk. How could exposure to estrogen as a fetus be influencing your risk of breast cancer half a century later as a 40-, 50-, 60-year-old adult?

We also wanted to determine if BPA had the same effect. While the data on BPA in humans is less clear than with DES, adult animal models are clearly showing that in utero exposure to BPA can increase the risk of pre-neoplastic changes in the breast and the risk of developing breast cancer when other carcinogens are also administered. In these adult animal models, BPA increases their susceptibility or risk rather than directly causing increased breast cancers.

Medscape: Could you compare the differences between DES and BPA in terms of the strength of their effect?

Dr. Taylor: Well, this is what was somewhat surprising. DES is a very powerful estrogen. It has a very high affinity for the estrogen receptor and functions as a very strong estrogen, whereas BPA is a very weak estrogen. It has some estrogen-like effects, but they are very small, and it has an affinity for the estrogen receptor that is several thousand-fold lower than the natural estrogen estradiol. It was surprising then that both of these estrogens had the same effect in our study, which makes us speculate that they may be affecting gene expression through a mechanism other than just their effect on the estrogen receptor.

Medscape: Any idea what that would be?

Dr. Taylor: No, we don't know yet. However, we do speculate. We administered either BPA or DES throughout pregnancy, waited until these mice had become adults, and then we looked at the breast tissue or the mammary gland, as it's called in mice. We showed that one gene that has been very closely linked to breast cancer is permanently elevated in these mice, and that brief exposure to either DES or BPA during pregnancy leads to a permanent lifelong elevation of a molecule called enhancer of zeste homologue (EZH2).[2] Despite the fact that DES and BPA vary dramatically in their potency, they both have a similar effect on the expression of the EZH2 molecule, and women with elevations in EZH2 have a higher risk of developing breast cancer.

EZH2 modifies histones, which are the proteins that wrap DNA and compact it. Modifying histones can open up or uncoil DNA or make it more compact and less accessible and turn a multitude of genes on and off. A whole battery of downstream genes is probably regulated differentially by this change in EZH2. The modification alters accessibility to DNA and is therefore epigenetic. The histone modification continues to influence the way DNA is packaged and therefore whether a gene is turned on or off throughout the life of this individual. We also know that this particular modification increases the risk of breast cancer. Women who had biopsies that turned out to be benign but showed elevated EZH2 had a greater chance of developing breast cancer in the future. Furthermore, women with breast cancer who have EZH2 expressed at high levels have a worse prognosis.

Medscape: To get back to your study, one of the criticisms was that you injected BPA into the pregnant mice. Some other studies using oral ingestion in certain rats didn't find any risk for breast cancer, or it was very low and not significant.[2,3]

Dr. Taylor: It is somewhat controversial, I'll admit that. The injection is obviously not the route of human exposure, but I think there are two things to note. One, we tried to mimic on average the levels that humans are exposed to, and we did this. We showed serum levels that on average are similar to human levels after oral exposure, although over a different time course. The mice get a bolus and then it tapers off very quickly. BPA is metabolized and excreted in the urine fairly quickly, so the injection does not provide the same steady even exposure as oral ingestion. That certainly could be a criticism of our paper.

However, we are not trying to exactly mimic human exposure. Our point is to figure out the mechanism of action. We want to know how exposure during pregnancy can lead to lifelong changes. It seems unusual that these changes don't occur with exposure during adulthood, but exposure during pregnancy results in lifelong changes in the offspring that increase the risk of breast cancer. What is the mechanism behind that? How can we explain such a strange phenomenon in which the risk is only there years after the exposure? In this case, the breast is programmed during development to respond later in life. We clearly show that the mechanism at play here is programming in utero. Early life exposure permanently changes expression of a molecule that increases the risk of breast cancer.

Medscape: In terms of clinical significance, how concerned are you about this?

Dr. Taylor: As I mentioned, our goal was to understand the mechanism -- not to decide what dose is safe and what isn't. We will subsequently look at those things, but that wasn't really our purpose here. However, I think the link to DES makes our findings very relevant. In humans it is clear that women exposed to DES have terrible reproductive outcomes, including abnormal uteri, and it is becoming apparent that they have an increased risk of breast cancer as well, especially as they get older. Our study tells us that BPA is doing the very same thing in the breast that DES does. That is what concerns me. Now, what level of exposure we need to worry about is still an unanswered question. Exactly what women should do when they are pregnant is still really not clearly defined, but I would say it makes sense to be cautious. Most of the available evidence shows that there is some risk.

Medscape: Is it possible to study the effects of BPA in women?

Dr. Taylor: We are not ever going to have the perfect study in women. For one, in developed countries all women are exposed to BPA, so you are never going to have a group in whom you don't find BPA. And, if you go to an area in the world where there is no BPA, [you still can't compare women there with those in developed nations.] There are too many other differences, so you can't attribute anything you see just to the effect of BPA. You are also never going to give a group of pregnant women high doses of BPA when we think it is dangerous. It would be unethical, so we will never have the human study to prove this. We do see correlation between the serum or urine BPA levels and disease in humans. With plenty of concerning animal studies and similar correlations in humans I think it makes sense to be cautious and not take the risk of BPA exposure -- especially during pregnancy. We are showing that pregnancy is the most vulnerable time. Therefore, I am advising my pregnant patients to avoid BPA as much as possible.

Medscape: So what are some specific tips on avoiding BPA?

Dr. Taylor: It may be almost impossible to avoid BPA entirely. It is so pervasive and in so many products. I am still learning about things that contain BPA. I think some of the common exposures are hard plastic water bottles. Many manufacturers are removing BPA from them.

Medscape: Does that include hard food containers?

Dr. Taylor: The recycling number in the little triangle on the bottom of the object is often a clue. If it has the number 7 then it may contain BPA.

Medscape: Cans of course are a major source of BPA, It's hard to avoid those.

Dr. Taylor: Yes, almost every can is lined with an epoxy coating that contains BPA. The resin sealant keeps the can from leaking and bacteria from getting in, which is a good thing, but the BPA does leech out into the food. It probably behooves any pregnant woman to try and avoid canned goods, especially during the early months. That includes eating out, because in most restaurants you will get food that comes out of a can. Eating fresh vegetables and fruits is a good idea and has many other benefits. There is really not much of a downside except perhaps expense.

Medscape: Of course, there is a concern that since canned food is the least costly way for people to get vegetables, women with lower incomes might skip vegetables out of fear of passing on the risk of breast cancer to their child.

Dr. Taylor. Yes, it may be a little more expensive to avoid canned foods, but certainly the net savings to society will be much greater if we can reduce breast cancer and reproductive risks in the future. There are also so many other health benefits from eating fresh fruits and vegetables, especially during pregnancy, that I would certainly advocate for that little extra expense. I think if you eat the right fruits and vegetables in season you can probably get them relatively inexpensively rather than eating the canned goods.

Medscape: But BPA in cans has been around for decades. Doesn't that argue for their safety?

Dr. Taylor: But we are also seeing increasing rates of cancers, including breast cancer, over the last few decades. How much of that is tied to BPA? I don't know.

Medscape: You have a number of other estrogenic compounds that people are also worried about, so there is of course the issue of the synergistic effect of all these chemicals.

Dr. Taylor: Absolutely, we just don't know. Obviously, we are exposed to a whole plethora of different chemicals, some of which are hormones and many undoubtedly have interactions; but until we know more I think it makes sense to at least eliminate or try to avoid the ones that we know are harmful. However, BPA exposure has certainly been shown to lead to problems in the uterus and the breasts.

Medscape: Why do you think your particular study has generated so much interest in the media?

Dr. Taylor: Well, I think it is the first time we have a mechanism that tells us why we might be seeing the increased risk of breast cancer with BPA and helps resolve the mystery of how brief exposure can program someone for life. It has not been known before.

Medscape: Are there any public efforts going on to eliminate BPA from products?

Dr. Taylor: Well, a few things. For example, California and Connecticut just enacted a law removing BPA from children's toys. Nalgene has taken the BPA out of their water bottles. The National Institute of Environmental Health Sciences (NIEHS) has invested quite heavily in studies to look at the consequences of BPA. NIEHS is trying in an unprecedented way to coordinate them so that we will have sound data that we can use to understand this better. Jerry Heindel at the NIEHS has really been driving that.

Actually, the media and the general public are doing more than anyone else to impact this issue. The market is causing most of these changes. Nalgene taking the BPA out of the water bottles was not because it was legislated but because people started noticing and switching to stainless steel bottles. Walmart is taking BPA-containing materials off the shelf as well, and, again, that is due to consumer information being out there and an educated public demanding these changes. It is market forces empowered by news and by good government-sponsored research rather than legislation that are driving these actions.

Medscape: Well, thank you so much. I really enjoyed hearing about this. You clarified the issue for me and I think for our readers as well, so thanks a lot.

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