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Xenoestrogens and Women's Health
by Sandra Steinbraber and Kathryn Patton

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Manufactured from cholesterol by a woman's ovaries each month, the hormone calledestrogen circulates in the blood, passes easily in and out of all organs and tissues andis eventually metabolised by enzymes in the liver.

Certain tissues in a woman's body, however, contain receptors that latch onto estrogenmolecules as they float through her body. During the few hours when estrogen molecules arebound to the receptors, the cells of these "target tissues" are stimulated toproliferate. The cells of the vagina, the uterus and the breast all contain large numbersof estrogen receptors. In the presence of estrogen, they grow.

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

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

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

that human breast tissue proliferates in the presence of nonylphenol, possibly placingit on the path to tumour formation. Soto and Sonnenschein's research is now focused onquantifying the estrigenicity of nonylphenol and other substances. These chemicals arebeing termed xenoestrogens: substances foreign to the human body that, directly orindirectly, act like estrogens.Xenoestrogens are a hot area of research right now amongbiochemists, epidemiologists, cancer researchers and endocrinologists. Because of theirability to interfere with the normal process of hormonal regulation in women's bodies,xenoestrogens are being implicated in many reproductive disorders, ranging frominfertility and endometriosis to breast and ovarian cancer.And, as increasing numbers ofchemicals are demonstrated to function as xenoestrogens, scientists are beginning to learnjust how amazingly estrogenic the industrialised world is. Nonylphenol, for example, isnot 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 isalso an ingredient in spermicides.The banned pesticide DDT is a xenoestrogen. So is theunbanned pesticide endosulphan. So is atrazine, the most commonly used weed killer in UScornfields. So is DES, the drug given to millions of women from 1948 to 1972 to preventmiscarriages (which it didn't). And so are dozens of different combustion products emittedfrom coal-burning power plants and automobile exhaust pipes.

To understand the impact of xenoestrogens on women's health - we have discoveredthrough our investigation - one has to become a bit of an endocrinologist, chemist, andhistorian.

A Pentagon and Three Hexagons

Like all steroid hormones (primarily reproductive relatedhormones), estrogen has a "backbone" made up of 17 carbon atoms arranged asthree hexagons interlocked with a pentagon. Estrogen can exist in one of several modifiedforms, and each form has its own chemical name. The most potent form produced by theovaries is called estradiol.Blood levels of estradiol rise steadily during the first halfof 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. Thesecarrier proteins regulate and slow down the entry of estradiol molecules into surroundingtissues. This feature turns out to be important because many xenoestrogens are not carriedon these molecules and can therefore enter cells more quickly and at lowconcentration.When estradiol enters the cell of a target tissue such as the breast or thelining of the uterus and is bound by an estorgen receptor, the story becomes moremysterious.  Just 10 years ago, scientists learned that these receptors arethemselves attached to the coiling strands of DNA where our genes lie like beads on astring.

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 bemanufactured; the rate of cell division may accelerate. The exact mechanisms of action isstill an ongoing subject of research. What is known for sure is that at some point, thereceptor is "processed" and the estrogen molecule released.

Meanwhile, in the liver, estradiol molecules carried in by the bloodstream are brokendown. There are two different chemical routes that estradiol molecules can take here. Thefirst one alters carbon atom number 2 and converts estradiol into a compound called2-hydroxyestrone. The second pathway alters carbon atom number 16, producing a metabolitecalled 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 toestrogen 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 16pathway, 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 governmentsto solve wartime problems. The pesticide DDT, for example, was perfected and developed asa means to control body lice and, therefore, typhus. Herbicides 2,4-D and 2,4,5-F weredeveloped as chemical defoliants for fighting jungle warfare.These new chemicals weresynthetic, meaning they are derived from petroleum and manufactured in a laboratory. Wholenew 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 thenatural world, they are almost never found bonded together.At the end of the war, the USgovernment helped the petrochemical industry to find private markets for their products.DDT was used for mosquito and agricultural pest control. Chemical defoliants were used innational forests to control shrubs. Lawn, garden and household insecticides weredeveloped. Detergents replaced soaps. Plastics replaced celluloid.

...And 50 Years Later

Because they derive from oil, most of these synthetic products are, like steroidhormones, fat-soluble. This means that, rather than leaving the body (as they would ifthey were water-soluble), these synthetic products accumulate in areas of the body wherefat 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 chemicalsshared these properties with steroid hormones, one might reasonably wonder why theirpotential to wreak havoc with our reproductive systems was not considered sooner.There aredoubtless many reasons. Sexism would be one starting point. The prevailing ideology of theCold War would be another. Rachel Carson was one of the first scientists to raisequestions about DDT. Her 1962 book, Silent Spring, was accused by industry chemists ofthreatening the Free World's food supply.But yet another answer resides in the nature ofestrogenicity itself: it is a far sneakier conceptthan even many scientists concerned withthe issue had imagined.

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

Second, xenoestrogens have many modes of operation. Not all of them latch on toestrogen receptors. Some simply stimulate the manufacture of more estrogen receptormolecules. More receptors mean an amplified response to the estradiol naturally floatingthrough a woman's body, which may place her at a higher risk for breast cancer.Still otherxenoestrogens 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 andmore 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 aBritish surgeon reported that removal of the ovaries sometimes caused breast tumours toshrink.Since then, many different studies indicate that a woman's risk of breast cancer isrelated to her lifetime exposure to estrogen. Early first menstruation, late menopause,and late or no childbirth are all considered risk factors. However, these factors explainonly a portion of the increasing rates of breast cancer, which in North  America hasnearly tripled since 1950.The first well-documented study that

established a preliminary link between pesticide exposure and breast cancer came onlyrecently. 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 thatwomen diagnosed with breast cancer had significantly higher concentrations of DDT in theirblood than women without breast cancer.At the same time, other researchers began reportingtheir results on how DDT and estrogen affect the growth of breast cells in laboratorycultures. Dr. Leon Bradlow at Cornell University reported at a breast cancer conference inOctober 1995 that pesticide residues induce "anchorage independence" in breasttumour cultures. This means that tumour cells can continue dividing even when detachedfrom other cells, a feature that allows breast cancer to spread in the body.  Wolffand Bradlow are currently collaborating on a project that investigates exactly howxenoestrogens like DDT place breast tissue on the pathway to tumour formation. Soto ispresently working on developing an assay that would allow a woman's total body burden onxenoestrogens to be measured. This may provide the most comprehensive indicator to date ofthe relationship between environmental estrogens and breast cancer.

Xenoestrogens and Ovarian Cancer

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

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

Further research on the precise actions of herbicides in the ovaries is also needed.Inthe meantime, what should the fate of triazine herbicides by? Germany banned theagricultural 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 comesfrom animal studies. Wildlife biologist Dr. Theo.  Colburn had conducted long-termand intensive studies of animals living in the Great lakes Basin. This are is highlycontaminated with organochlorines from chemical industries and pulp and paper mills, whichuse great amounts of chlorine bleach. He research documents that many animal speciesliving near water - eagles, mink, fish and various shore birds - are unable to reproducesuccessfully due to high body burdens of various xenoestrogens.Colburn is currently atwork on elucidating what she calls "the human/wildlife connection". She isparticularly interested in considering a possible link between estrogenic pollutants andfalling 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.  Thisdisease causes pieces of the uterine lining to attach and grow outside the uterus, causingpain and often infertility. Exposure to PCB's has been shown to cause endometriosis infemale monkeys.In November 1995, researchers reported that monkeys exposed to dioxin alsodevelop significantly higher levels of endometriosis. Dioxin is a contaminant in manypesticides and is also formed during many industrial processes that use chlorine.Strangely enough, unlike other xenoestrogens, dioxin seems to counteract rather thanmagnify the effects of estradiol. Some researchers believe that dioxin may blockade theestrogen receptors, preventing estrogen molecules from attaching.The US EnvironmentalProtection Agency is planning further research on the possible link between dioxin andendometriosis in women.

Xenoestrogens and Political Action

The flurry of research interest now surrounding xenoestrogens didnot just develop on its own. Indeed, most scientific investigations do not just happen.Which questions are deemed important, which projects receive funding, which studies arefollowed up - these are all political issues.  In the case of xenoestrogens, manyenvironmental and women's health activists have been at work behind the scenes - andsometimes in the streets - to insist that particular questions be asked and answered. Forexample, the Endometriosis Association, a women's advocacy group, sponsored the study ondioxin mentioned above.In October 1995, Long Island activists convened their ownscientific conference on breast cancer and the environment. In the same month, theAmerican Public Health Association called for the elimination of chlorine inmanufacturing, citing its' role in the creation of xenoestrogens and the threat to women'shealth.There are other signs of change. Breast cancer activists in San Francisco succeededin adding a panel on breast cancer and the environment to the program at the annualmeeting of the American Association for the Advancement of Science in February 1994. Greenpeace and the Women's Environment and Development Organisation (WEDO) headed by BellaAbzug, recently met with women's health activist in Austin, Texas, to launch a jointinitiative called "Women, Cancer and the Environment".

Ana Soto's accidental discovery and her subsequent research shed light on possibleenvironmental intervention to prevent breast cancer. Soto said she hoped that her workwill help develop a more ecological view of human health, understanding that pollutants inwater, 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 ofxenoestrogens by only looking at genes... Banned pesticides are still found in the fishthat we eat."

Sandra Steingrabe is a visiting scholar at North-eastern University with a PhD inbiology. She is the author of "Post Diagnosis", a book of poetry on women'scancers, and is currently writing a book on cancer and the environment to be published byAddison Wesley in 1996.

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

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

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