Xenoestrogens and Womens’ Health
by Sandra Steinbraber and Kathryn Patton

Manufactured from cholesterol by a woman’s ovaries each month, the hormone called estrogen circulates in the blood, passes easily in and out of all organs and tissues and is eventually metabolized by enzymes in the liver.

Certain tissues in a woman’s body, however, contain receptors that latch onto estrogen molecules as they float through her body. During the few hours when estrogen molecules are bound to the receptors, the cells of these “target tissues” are stimulated to proliferate. The cells of the vagina, the uterus and the breast all contain large numbers of estrogen receptors. In the presence of estrogen, they grow.

A few years ago, cell biologist Dr. Ana Soto was working out the biochemical details of estrogen sensitivity and its relationship to breast cancer when something puzzling happened in her Tufts University laboratory.

Tissues growing in plastic dishes containing no estrogens started proliferating. “This indicated that some type of contamination had occurred,”Soto remembered. “We made an accidental discovery.” Soto traced the contamination to the plastic tubes she was using to store blood serum.

Working with her colleague Carlos Sonnenschein, Soto purified the contaminant and identified it as nonylphenol, a chemical added during the manufacture of plastic to prevent it from cracking. They discovered molecules of nonylphenol were being shed from the tubes into the serum. Soto and Sonnenschein went on to prove that nonylphenol is estrogenic – that is, it mimics the effect of estrogen when added to tissues containing estrogen receptors. In a series of experiments published in 1991, Soto demonstrated

that human breast tissue proliferates in the presence of nonylphenol, possibly placing it on the path to tumour formation. Soto and Sonnenschein’s research is now focused on quantifying the estrigenicity of nonylphenol and other substances. These chemicals are being termed xenoestrogens: substances foreign to the human body that, directly or indirectly, act like estrogens.  Xenoestrogens are a hot area of research right now among biochemists, epidemiologists, cancer researchers and endocrinologists. Because of their ability to interfere with the normal process of hormonal regulation in womens’ bodies, xenoestrogens are being implicated in many reproductive disorders, ranging from infertility and endometriosis to breast and ovarian cancer.And, as increasing numbers of chemicals are demonstrated to function as xenoestrogens, scientists are beginning to learn just how amazingly estrogenic the industrialized world is. Nonylphenol, for example, is not only found in plastic but is also an additive in detergents and pesticides. Accordingto Soto, over 450 million pound on nonylphenols are produced each year. Nonylphenol is also an ingredient in spermicides.The banned pesticide DDT is a xenoestrogen. So is the unbanned pesticide endosulphan. So is atrazine, the most commonly used weed killer in US cornfields. So is DES, the drug given to millions of women from 1948 to 1972 to prevent miscarriages (which it didn’t). And so are dozens of different combustion products emitted from coal-burning power plants and automobile exhaust pipes.

To understand the impact of xenoestrogens on womens’ health – we have discovered through our investigation – one has to become a bit of an endocrinologist, chemist, and historian.

A Pentagon and Three Hexagons

Like all steroid hormones (primarily reproductive related hormones), estrogen has a “backbone” made up of 17 carbon atoms arranged as three hexagons interlocked with a pentagon. Estrogen can exist in one of several modified forms, and each form has its own chemical name. The most potent form produced by the ovaries is called estradiol.  Blood levels of estradiol rise steadily during the first half of a woman’s menstrual cycle. All cells of the body are permeable to estradiol. However,most estradiol is carried in the blood on special sex-hormone binding proteins. These carrier proteins regulate and slow down the entry of estradiol molecules into surrounding tissues. This feature turns out to be important because many xenoestrogens are not carried on these molecules and can therefore enter cells more quickly and at low concentration. When estradiol enters the cell of a target tissue such as the breast or the lining of the uterus and is bound by an estorgen receptor, the story becomes more mysterious.  Just 10 years ago, scientists learned that these receptors are themselves attached to the coiling strands of DNA where our genes lie like beads on a string.

When attached to estradiol, the receptor triggers a change in gene expression.  Depending on the type of tissue, some genes may be turned on; different proteins may be manufactured; the rate of cell division may accelerate. The exact mechanisms of action is still an ongoing subject of research. What is known for sure is that at some point, the receptor is “processed” and the estrogen molecule released.

Meanwhile, in the liver, estradiol molecules carried in by the bloodstream are broken down. There are two different chemical routes that estradiol molecules can take here. The first one alters carbon atom number 2 and converts estradiol into a compound called2-hydroxyestrone. The second pathway alters carbon atom number 16, producing a metabolite called 16-beta-estriol.The proportion of 2 to 16 turns out to be critical. The16-metabolite is still estrogenic: it can recirculate through a woman’s body and bind to estrogen receptors just like its parent, estradiol.

Moreover, 16 is capable of directly damaging the DNA strand.In contrast, the2-metabolite is minimally estrogenic and is non-toxic to DNA. Clearly, a low 16 to 2 ratiois desirable. Some xenoestrogens act to skew this balance away from 2 and towards the 16 pathway, as we shall see.

The Dawn of Xenomania…

Now enter xenoestrogens. And to explain their entry, we need a bit of chemical history.

During World War II, legions of organic chemists were put to work by their governments to solve wartime problems. The pesticide DDT, for example, was perfected and developed as a means to control body lice and, therefore, typhus. Herbicides 2,4-D and 2,4,5-F were developed as chemical defoliants for fighting jungle warfare. These new chemicals were synthetic, meaning they are derived from petroleum and manufactured in a laboratory. Whole new classes of chemicals not found in nature were thus created.

Organochlorines, of which DDT and PCB’s are two, are made by attaching chlorine atomsto carbon chains, for example. While chlorine and carbon are common elements of the natural world, they are almost never found bonded together. At the end of the war, the US government helped the petrochemical industry to find private markets for their products. DDT was used for mosquito and agricultural pest control. Chemical defoliants were used in national forests to control shrubs. Lawn, garden and household insecticides were developed. Detergents replaced soaps. Plastics replaced celluloid.

…And 50 Years Later

Because they derive from oil, most of these synthetic products are, like steroid hormones, fat-soluble. This means that, rather than leaving the body (as they would if they were water-soluble), these synthetic products accumulate in areas of the body where fat content is high – for example, breasts. Moreover, any of them, like steroid hormones,consist of interlocking hexagonal rings of carbon atoms. Given that these new chemicals shared these properties with steroid hormones, one might reasonably wonder why their potential to wreak havoc with our reproductive systems was not considered sooner.There are doubtless many reasons. Sexism would be one starting point. The prevailing ideology of the Cold War would be another. Rachel Carson was one of the first scientists to raise questions about DDT. Her 1962 book, Silent Spring, was accused by industry chemists of threatening the Free World’s food supply.But yet another answer resides in the nature of estrogenicity itself: it is a far sneakier concept than even many scientists concerned with the issue had imagined.

First, the estrogen receptor is turning out to be far less specific than anyone imagined. Carbon compounds quite different-looking from estradiol are able to attach to it. Soto points out that scientists cannot predict whether a chemical can attach to estrogen receptors purely from the shape of the molecule. Estrogen receptors are like locks that accept many different keys. DDT for example, has only two hexagonal rings and yet is able to bind directly to the receptor.

Second, xenoestrogens have many modes of operation. Not all of them latch on to estrogen receptors. Some simply stimulate the manufacture of more estrogen receptor molecules. More receptors mean an amplified response to the estradiol naturally floating through a woman’s body, which may place her at a higher risk for breast cancer.Still other xenoestrogens act in the liver to accelerate the metabolism of estradiol toward the16-metabolite

and away from the 2 pathway. More 16-beta-estriol means more bio-available estrogen and more damage to DNA. The weed killer atrazine seems to have this effect.

Xenoestrogens and Breast Cancer

The first clue that estrogens might play a role in breast cancer came in 1896 when a British surgeon reported that removal of the ovaries sometimes caused breast tumours to shrink.  Since then, many different studies indicate that a woman’s risk of breast cancer is related to her lifetime exposure to estrogen. Early first menstruation, late menopause,and late or no childbirth are all considered risk factors. However, these factors explain only a portion of the increasing rates of breast cancer, which in North  America has nearly tripled since 1950.The first well-documented study that

established a preliminary link between pesticide exposure and breast cancer came only recently. In April 1993, 31 years after the publication of Carson’s Silent Spring, biochemist Dr. Mary Wolff at Mount Sinai School of Medicine in New York reported that women diagnosed with breast cancer had significantly higher concentrations of DDT in their blood than women without breast cancer.  At the same time, other researchers began reporting their results on how DDT and estrogen affect the growth of breast cells in laboratory cultures. Dr. Leon Bradlow at Cornell University reported at a breast cancer conference in October 1995 that pesticide residues induce “anchorage independence” in breast tumour cultures. This means that tumour cells can continue dividing even when detached from other cells, a feature that allows breast cancer to spread in the body.  Wolff and Bradlow are currently collaborating on a project that investigates exactly how xenoestrogens like DDT place breast tissue on the pathway to tumour formation. Soto is presently working on developing an assay that would allow a woman’s total body burden on xeno estrogens to be measured. This may provide the most comprehensive indicator to date of the relationship between environmental estrogens and breast cancer.

Xenoestrogens and Ovarian Cancer

Recent studies also link xenoestrogens to ovarian cancer. Because the raw material for estrogen production is cholesterol, the ovary, like the breast, is are pository of fat-soluble contaminants. Dioxin, for example, has been found in the fluid surrounding human eggs extracted for test-tube fertilization.Studies done in 1989 showed that estrogen increases the rate of growth of ovarian tumour cells by 50% compared to those not treated with estrogen.In the same year, Italian researchers studying the health and habits of women farmers in northern Italy discovered that women farmers exposed to triazine herbicides, such as atrazine, had a three- to- four-times higher risk for ovarian cancer.Both these lines of research suggests that triazine herbicides may be acting as xenoestrogens in the ovaries, a hypothesis that has been supported by more recent research.

However, many of the existing reports suffer from small sample sizes, difficulty determining actual exposures, and lack of control groups.

Further research on the precise actions of herbicides in the ovaries is also needed.  In the meantime, what should the fate of triazine herbicides by? Germany banned the agricultural use of atrazine in 1991. In the Midwestern United States, atrazine continuesto run off farm fields and into ground and surface water.

Xenoestrogens and Fertility

Much of what is known about xenoestrogens’ impact on fertility and reproduction comes from animal studies. Wildlife biologist Dr. Theo.  Colburn had conducted long-term and intensive studies of animals living in the Great lakes Basin. This are is highly contaminated with organochlorines from chemical industries and pulp and paper mills, which use great amounts of chlorine bleach. He research documents that many animal species living near water – eagles, mink, fish and various shore birds – are unable to reproduce successfully due to high body burdens of various xenoestrogens.  Colburn is currently at work on elucidating what she calls “the human/wildlife connection”. She is particularly interested in considering a possible link between estrogenic pollutants and falling sperm counts in men. She also suspects xenoestrogens could be contributing to the400% increase in ectopic (outside the uterus) pregnancies between 1970 and 1987.

A separate line of research is focused on xenoestrogens and endometriosis.  This disease causes pieces of the uterine lining to attach and grow outside the uterus, causing pain and often infertility. Exposure to PCB’s has been shown to cause endometriosis in female monkeys.In November 1995, researchers reported that monkeys exposed to dioxin also develop significantly higher levels of endometriosis. Dioxin is a contaminant in many pesticides and is also formed during many industrial processes that use chlorine.Strangely enough, unlike other xenoestrogens, dioxin seems to counteract rather than magnify the effects of estradiol. Some researchers believe that dioxin may blockade the estrogen receptors, preventing estrogen molecules from attaching.The US Environmental Protection Agency is planning further research on the possible link between dioxin and endometriosis in women.

Xenoestrogens and Political Action

The flurry of research interest now surrounding xenoestrogens did not just develop on its own. Indeed, most scientific investigations do not just happen.Which questions are deemed important, which projects receive funding, which studies are followed up – these are all political issues.  In the case of xenoestrogens, many environmental and womens’ health activists have been at work behind the scenes – and sometimes in the streets – to insist that particular questions be asked and answered. For example, the Endometriosis Association, a women’s advocacy group, sponsored the study ondioxin mentioned above. In October 1995, Long Island activists convened their own scientific conference on breast cancer and the environment. In the same month, the American Public Health Association called for the elimination of chlorine in manufacturing, citing its’ role in the creation of xenoestrogens and the threat to womens’ health.There are other signs of change. Breast cancer activists in San Francisco succeeded in adding a panel on breast cancer and the environment to the program at the annual meeting of the American Association for the Advancement of Science in February 1994. Greenpeace and the Womens’ Environment and Development Organization (WEDO) headed by Bella Abzug, recently met with womens’ health activist in Austin, Texas, to launch a joint initiative called “Women, Cancer and the Environment”.

Ana Soto’s accidental discovery and her subsequent research shed light on possible environmental intervention to prevent breast cancer. Soto said she hoped that her work will help develop a more ecological view of human health, understanding that pollutants in water, soil, air – and even plastic tubes – eventually find their way into our bodies.”Molecular biology is not enough. We can’t understand the additive effects of xenoestrogens by only looking at genes… Banned pesticides are still found in the fish that we eat.”

Sandra Steingrabe is a visiting scholar at North-eastern University with a PhD in biology. She is the author of “Post Diagnosis”, a book of poetry on womens’ cancers, and is currently writing a book on cancer and the environment to be published by Addison Wesley in 1996.

Kathryn Patton has participated in cancer research projects at the University of Washington Medical Centre and is considering a career in oncology.

Reprinted from Sojourner: The Womens’ Forum. Subscription is $21 per year for 12issues. 42 Seaverns Avenue, Boston, Massachusetts USA 02130.

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