Environmental estrogens affect breast development in male rats.

May 27, 2009

Latendresse JR, TJ Bucci, G Olson, P Mellick, CC Weiss, B Thorn, RR Newbold and KB Delclos. 2009. Genistein and ethinyl estradiol dietary exposure in multigenerational and chronic studies induce similar proliferative lesions in mammary gland of male Sprague-Dawley rats. Reproductive Toxicology doi:10.1016/j.reprotox.2009.04.006.




2009_0522soymilkbeans
mc559, Flickr
 

A five-generation rat study provides the clearest evidence to date that exposure to low levels of environmental estrogens can increase the risk of abnormal cell growth in the male breast.  Abnormalities which could have the potential to become cancerous developed in the mammary gland tissue of male rats that were exposed to either the soy-based phytoestrogen genistein or ethinyl estradiol – an estrogen used in birth control pills. The findings support a growing concern that exposure to low levels of estrogen in the environment might increase the risk of breast cancer.

 

 

Context

Phytoestrogens are a class of estrogen-like compounds produced by plants, most notably beans and other legumes. A kind of phytoestrogen called isoflavones are commonly found in soy and soy based foods, including soy milk, tofu and soy infant formula. Genistein is a well known isoflavone.

Exposure in people varies depending on what they eat and drink. Infants reared on soy formula consume approximately 6-9 milligrams per kilogram of isoflavones per day. Adults eating a traditional soy-rich Asian diet or meeting the US Food and Drug Administration recommendation of 25 grams of soy protein per day consume roughly less than half of that.

Genistein can mimic the hormone estrogen and cause similar responses and effects, which can be beneficial or possibly harmful depending on at what age it is eaten. For example, prior studies have found that it can affect the development of the reproductive system in laboratory animals.

Ethinyl estradiol (EE) is the most commonly used estrogen in birth control pills. A developing fetus can become exposed to EE when a woman on the pill becomes pregnant, which happens to a small percentage of women each year.  Most of these woman do not know they are pregnant and continue taking their birth control pills. The potential long-term consequences of exposure to EE during fetal development in humans are largely unknown.

EE is also considered an environmental contaminant because it frequently turns up in rivers, lakes and tap water. Presumably EE gets into the water supply from human sewage and by disposing of birth control pills and other pharmaceuticals by "flushing" them.

Hyperplasia in the breast is defined as an increased number of cells.  In some cases these cells may appear abnormal, a condition called atypical hyperplasia.  These atypical cells may ultimately develop into a cancerous tumor, but it is important to recognize that not all people with atypical hyperplasia will develop breast cancer.

Breast cancer is more common in women than men. In the US, men account for about one percent of the 194,300 newly diagnosed cases per year, according to the National Cancer Institute.

Researchers from the National Institutes of Health and the US Food and Drug Administration conducted a five-generation study to determine if mammary gland tissue in rats exposed to low doses of estrogenic compounds would develop abnormally. They compared  different exposure times and exposures over multiple generations.

Rats were fed diets containing low doses of either ethinyl estradiol (EE)  (0, 2, 10, or 50 parts per billion) or genistein (0, 5, 100 or 500 parts per million) for different lengths of times and at different ages for 5 generations.

In the first generation, exposure began in adolescence and ended during adulthood. Animals in the next two generations – F2 and F3 – were exposed their entire lifetime, beginning at conception and ending two years later. Exposure in the fourth group (F4 generation) began at conception and ended at weaning.

The final F5 group were never directly exposed to either EE or genistein. The group was included in the study to determine if effects could be transmitted from parent to offspring. If so, this would indicate some kind of genetic change that could be passed on to future generations.

The researchers examined the mammary glands of male rats in each generation at different stages of early adulthood. They looked for signs of abnormal growth, termed hyperplasia, by examining and comparing the size and density of the glands.
 

A number of abnormal tissue growths in the mammary glands of the male rats were noted, including hyperplasia. Severity increased with dose and duration of exposure. Some of the changes occurred at very low doses of EE (2 ppb). Effects of genistein were similar to EE but generally weaker.

Very few animals developed tumors.  However, the tissues were collected when the rats were young adults, so it is possible that some of them could have developed cancer later.

The male rats in the F4 group – those exposed only until weaning – had fewer breast gland and tissue abnormalities than the animals in the other groups exposed throughout their lives. This suggests that the effects might be less severe or even reversible if exposure is reduced or eliminated.

An additional important finding was that no transgenerational effects were observed. Therefore, effects in the parent were not transmitted to the offspring. Abnormalities were only seen in animals directly exposed to EE or genistein.

A complete description of all effects found in both the male and female animals from this large and long-range study are available in additional published reports (Delclos 2001; Delclos 2009).
 

Overall, the comprehensive data from this study indicate that the male mammary gland may be particularly sensitive to environmental estrogens.

The findings suggest that chronic exposure to estrogenic compounds, even at low levels, increases the risk of developing hyperplasia in the mammary gland.  The tissue changes – called lesions – are less severe when exposure is short. These results suggest the effects may be reversible if exposure is reduced.

In humans, hyperplasia is sometimes considered a risk factor for developing breast cancer. However, very few of the animals in this study developed cancer. Therefore, the data do not show a direct link between exposure to environmental estrogens and breast cancer.

Past studies consistently show that genistein and other soy isoflavones can act like estrogen in the body. The data from this mammary gland study provide further evidence that genistein is an endocrine disruptor.

The effects of genistein found in this study are significant because it, and other isoflavones, is a component of soy food, which is widely thought to be healthy. In 1999, the Food and Drug Administration approved the health claim that consuming 25 grams of soy per day can reduce the risk of heart disease. Because of these and other potential health benefits, people in the US are eating more soy foods and taking more soy supplements.

Prior studies in humans and laboratory animals, however, show mixed results.  Some human studies have found that people in Asian countries eating a low fat, soy-rich diet have lower rates of breast cancer. Other studies in laboratory animals conclude that soy-based phytoestrogens may contribute to reproductive and developmental abnormalities.

EE is becoming a more prevalent environmental pollutant. There is growing concern about its presence in wastewater and drinking water supplies. EE can affect reproductive development in fish and other aquatic wildlife, raising concerns that it may also cause subtle, but functionally significant, effects in humans. 

This study provides cruical evidence that exposure to EE, even at very low levels, could have subtle but potentially harmful effects in the developing male mammary gland. 

Resources

Benign Breast Conditions. Imaginis.

Delclos, KB, TJ Bucci, LG Lomax, JR Latendresse, A Warbritton, CC Weis and RR Newbold. 2001. Effects
of dietary genistein exposure during development on male and female CD (Sprague-Dawley)
rats
. Reproductive Toxicology 15(6):647-63.

Delclos, KB, CC Weis, TJ  Bucci, GR Olson, P Mellick, N Sadovovab, JR Latendresseb, B Thorna and RR Newbold. 2009. Overlapping but disinct effects of genistein and ethinyl estradiol in female Sprague-Dawley rats in
multigenerational reproductive and chronic toxicity studies
. Reproductive Toxicology 27(2):117-132.

Flores, A and EM Hill. 2008. Formation of estrogenic brominated ethinylestradiol in drinking water: implications for aquatic toxicity testing. Chemosphere 73:1115-1120

Jefferson WN, E Padilla-Banks and RR Newbold. 2007. Disruption of the female reproductive system by the phytoestrogen genistein. Reproductive Toxicology 23: 308-316.

Kuhnle GG, C Dell'Aquila, SM Aspinall, SA Runswick, AA Mulligan and SA Bingham. 2008. Phytoestrogen content of beverages, nuts, seeds, and oils. Journal of Agricultural and Food Chemistry 56: 7311-7315.

Phytoestrogens. e.hormone, Tulane University.

Phytoestrogens and Breast Cancer Fact Sheet. Program on Breast Cancer and Environmental Risk Factors, Cornell University. Revised July 2001.

Setchell KDR, L Zimmer-Nechemias, J Cai and JE Heubi. 1997. Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet 350: 23-27.

What are the risk factors for breast cancer? American Cancer Society.

 

 

 

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