Environmental Estrogens -
Is Male Sexual Development Under Threat?

Over the last few years, intense debate has centred over the potential effects that a number of chemical compounds can have on male sexual development. These compounds, refered to as environmental estrogens, include a number of different chemical compounds found in the environment such as the pesticide DDT, biphenol A (a biproduct in the production of plastics), PCBs which have been extensively used as industrial coolants and flavanones which occur naturally in plants.

In an Editorial article which appeared in The Lancet medical journal in 1995, it was claimed that the involvment of a male factor in infertility amongst couples had increased from 10% to 25%. Moreover, there appear to have been increases in the incidence of testicular cancer. The potential involvement of environmental estrogens in the onset of this observed male infertility was discussed in a 1995 workshop in Copenhagen at the request of the Danish Environmental Protection Agency. Among the subjects that were raised during this workshop was the possibility that over-exposure of developing male fetuses to high levels of environmental estrogens during pregnancy might be an important factor in determining subsequent male reproductive health. Thus the current effects of environmental estrogens might not be known for another 20 to 40 years. The Lancet Editorial article also pointed out that for most chemical pollutants, no proper studies have been carried out concerning their estrogenic effects. Moreover, while DDT has been banned as an organochlorine pesticide, it can and most probably will remain in human and animal tissues for generations.

The incidence of male reproductive problems appears to be geographically determined with different countries having different decreases in sperm counts. Cryptoorchidism appears to be most common in caucassians than in blacks and asians. The 1995 Danish workshop outlined a number of chemical compounds that could act as environmental estrogens such as DDT, dieldrin, aldrin, polychlorinated biphenyls (PCBs), dioxins, furans, alkylphenol polyethoxylates (APEs) and phyto-Oestrogens (present in plants). The Lancet Editorial article came to the conclusion that initial studies on environmental estrogens should concentrate on their effects on male foetal development and concommitantly on the over-exposure of women to such compounds.

When do environmental estrogens affect sexual development in male fetuses? In a 1993 letter to The Lancet medical journal, Ursula Mittwoch, Ann Burgess and Paul Baker from Queen Mary's and Westfield college in London, pointed out that during male sexual development in Eutherian mammals, the developing fetus is exposed to very high concentrations of estrogen. Paradoxically, the male fetus is able to develop testis and male genitalia without any apparent feminising effects from this estrogen. Mittwoch and her colleagues have therefore hypothesised that the male fetus must have an accleleration of gonadal development so that masculinity of the fetus is established well in advance of the intense Oestrogen exposure. Mittwoch and her colleagues have clearly demonstrated in a rat model that the male gonads develop at a much faster rate than female gonads supporting their accelerated male development hypothesis. Moreover, this result supports the theory that exposure of developing fetuses to environmental estrogens, would have to occur very early on in development, out-running the accelerated masculinisation of a developing fetus.

Alkylphenol Polyethoxylates as environmental estrogens
According to John Sumpter and Susan Jobling from the Department of Biology and Biochemistry at Brunel University in the UK, the annual production of the main alkylphenol polyethoxylate (APE) compounds is estimated at 100,000 tons in Europe and 300,000 tons worldwide. These detergents may accumulate in rivers and sewage plants. Sumpter and Jobling have referred to a study which detected the presence of APEs in New Jersey drinking water at a concentration of 1 mg/l. At such levels of exposure, Sumpter and Jobling believe that APEs could be having serious consequences on sexual development in male fetuses.

In response to fears raised over the presence of environmental estrogens and their potential influence on male sexual development, Stephen Safe, from the Texas A and M University, pointed out in a letter to The Lancet Medical Journal that man is also exposed to a number of anti-estrogenic compounds. These compounds include polynuclear aromatic hydrocarbons (produced from cigarette smoke) and a number of organochlorines.

DDE and the risk of breast cancer
In 1993 Mary Wolff of the Mount Sinai Medical school in New York announced that breast cancer was four times more common in women who had been exposed to the chemical compound DDE than women without such exposure. DDE, which is a breakdown product of DDT, appears to be present at low levels in some women even though DDT itself was banned in the US in the 1970s. This result created alarm and led to a call to ban all use of organochlorine compounds in addition to DDT. Evidence had already shown that such organochlorine compounds could act as week estrogens and that it was precisely this action that could cause breast cancer.

Only a year after, a group led by Nancy Krieger at the Kaiser Foundation Research Institute in California, published a paper concluding that no such link existed. This second study involved 150 women who had developed breast cancer. More specifically, Krieger claimed that there was no link between the serum levels of DDE and the risk of breast cancer. However, Krieger added that the proper reaction to the results of the Kaiser study should be to carry out more research.

In a letter to the Science magazine, Larry Hansen from the University of Illinois and Heiko Jansen from the University of Cincinnati, provided an explanation for the disagreements between the Wolff and Kaiser studies concerning the association of DDE with breast cancer. While the Kaiser study had been carried out on women who were known to have been exposed to higher DDE concentrations, Hansen and Jansen point out that the anti-estrogen compound Dioxin could have prevented the estrogenic effects of DDT.

Feminisation of fish and changes in sperm counts - what is the cause ?
Over the last few years, a number of studies have been published describing an apparent decrease in human sperm counts as well as a feminisation of certain types of fish. These studies have linked falling sperm counts with the presence of environmental estrogenic compounds. However, during the 1994 annual meeting of the Society of Toxicology, Stephen Safe criticised the hype that had been created over the presence of estrogens in the environment. This came as the Environmental Protection Agency (EPA) announced that it was planning to carry out research into the effects of estrogen-like compounds, such as dioxin, on human reproduction and development.

Lawrence Reiter, director of the EPA laboratories in North Carolina, stated that the potential effect of estrogens in the environment on human reproduction represents an issue as serious as Global warming. EPA toxicologist Earl Gray has counteracted the comments made by Stephen Safe. According to Earl Gray, "there are many man-made and natural chemicals in the environment that have the ability to alter the endocrine system".

DES -- an indication that something is wrong.
Dielthylstilbestrol (DES), a synthetic estrogen, was used until 1971 to prevent miscarriages in pregnant women. However, it has since been banned following a study linking DES to vaginal cancer. Since 1971, a number of similar studies have linked several synthetic chemicals with problems in reproductive development. For example, animal studies on male rats have shown that male rats exposed to DDT are more likely to develop testicular cancer. However, while such studies are very worring, John Gierthy, at the New York State Department of Health, argues that it is dangerous to make conclusions on the threat to human health purely on results obtained in the lab.

Ginsburg and colleagues at the Royal Free hospital school of Medicine in London, have reported a decrease in sperm density in men from 101 million per ml to 96 million per ml between 1984 and 1989. The same study also recorded decreases in sperm motility as well as abnormal sperm morphology within a group in the Thames Water Area of London. These results would appear to indicate that geographical localisation is a highly important factor in determining male reproductive problems. Ginsburg and colleagues also referred to a study in which the presence of Polychlorinated Biphenyls has been detected in male semen samples. Moreover, in this study an inverse correlation between the concentration of polychlorinated biphenyls and sperm motility was described.

Animal wildlife sends a cautionary message
In recent years, a number of wildlife studies have been published which support the theory that estrogens in the environment pose a severe threat to human reproductive health.

Louis Guillette, a reproductive physiologist at the University of Florida, claims to have found a link between a DDT spill and a possible reduction in penis sizes in young alligators. Other studies have also suggested a possible link between synthetic compounds such as PCBs and reproductive problems in animal wildlife. Frederick Von Saal, a reproductive biologist at the University of Missouri adds that because the reproductive biology in many of these animals is similar to that in humans, these results suggest that humans exposed to certain levels of synthetic, estrogen-like compounds might suffer fertility problems and even cancer.

However EPAs toxicologist Linda Birnbaum argues that environmental estrogens bind very weakly to estrogen receptors. It is therefore unlikely that such environmental estrogens could exert an effect.

In many of the wildlife studies, the levels of environmental estrogen exposure were very high, much higher than humans would ever be exposed to. Moreover Neil Maclusky, a reproductive endocrinologist at the University of Toronto, has added that humans have mechanisms for "mopping up" circulating estrogens.

Are environmental estrogens really harmless?
In a letter to the Science magazine in October 1994, Larry Hansen from the University of Illinois and Heiko Jansen from the University of Cincinnati, pointed out that while environmental estrogen compounds such as the PCBs had weaker binding affinities to estrogen receptors than the naturally occuring female estrogen, their concentrations in human blood are generally much higher than the female estrogen (2-8ng/ml compared to 0.03-0.5ng/ml). Moreover female estrogen tends to be bound up in plasma proteins or associated to what Hansen and Jansen refer to as 'disarming groups'. The higher concentrations and lower binding to plasma proteins of environmental estrogens means that such environmental estrogens are capable of exerting adverse effects on male foetal sexual development.

Clinton Administration shows concern over male fertility problems
In July of 1996, the Clinton Administration announced the formation of a panel to investigate the involvement of environmental estrogens in the onset of male fertility problems. One of the panel members, Bob Kavlock, who is also a toxicologist at the EPA, was very firm on his views about the seriousness of the problem. "If human sperm counts really have declined by half over the last 40 years, we need to know about it now -- we cannot wait another 40 years to find out". With a total budget of 10 million dollars spent by the EPA each year on what it calls Endocrine Disrupter Research (which includes environmental estrogens), the EPA announced that most of the research would concentrate on developing methods for environmental estrogen detection.

So what does the future hold? As the 21st century approaches, we can only hope that a potential epidemic in male infertility will be prevented by current studies into environmental estrogens such as DDE. While the results do not show a conclusive correlation between the presence of environmental estrogens and the onset of male infertility worldwide, it would be imprudent to stop research into such a possible link. After all, it is better to be safe than sorry.

© 1998 Roberto Deyes and Carolina Mora Mendes.
Printed with Permission.
The Mad Scientist Network
Washington University School of Medicine
St. Louis, Missouri, USA
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