January 23, 1998

Pollutants’ effect on reproduction investigated

Pollutants' effect on reproduction investigated

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Benjamin Danzo, Ph.D., is studying the effects of pollution on reproduction. Photo by Donna Jones Bailey.

Reports of Florida alligators with shrunken penises, of female birds not reproducing normally, and of feminized male birds have been circulating since the early 1970s, leading to the idea that environmental pollutants were contributing to these reproductive problems.

But until recently, most of the studies conducted on the possible effects of environmental pollutants on reproduction were observational.

A Vanderbilt University Medical Center scientist, however, has taken the research one step further by attempting to determine how these problems occur at the cellular and molecular level.

Benjamin J. Danzo Ph.D., professor of Obstetrics and Gynecology, published a study on the mechanisms by which pollutants can affect reproduction in Environmental Health Perspectives last year. Danzo¹s research was recently selected by Discover magazine to be one of the top science stories of 1997.

³It seemed to me that if pollutants were causing reproductive problems in animals, they were probably interfering with the normal mechanisms of steroid hormone action, since steroids are necessary for the development and function of the male and female reproductive systems,² Danzo said.

³I figured that if these environmental pollutants were acting through steroid-dependent mechanisms, they must be interacting with the estrogen receptor, androgen receptor or with certain steroid binding proteins ‹ androgen-binding protein (ABP), which is produced by the testes, or sex hormone-binding globulin (SHBG), which is produced by the liver.

The first step in the mechanism of steroid hormone action is its binding a receptor or binding protein followed by gene activation or suppression, Danzo explained.

³I thought the environmental pollutants must be either stimulating or inhibiting steroid-dependent genes that were involved in regulating the proper development and function of the male and female reproductive systems,² he said.

Evidence of demasculinizing effects of pollutants in wildlife species led investigators to assume that pollutants were estrogenic, or worked through the estrogen receptor.

Danzo believed that since there were four possible proteins to which the pollutants could bind, it made sense to examine the binding of pollutants to all of them.

With funds from a pilot project grant from the Vanderbilt Center in Molecular Toxicology, Danzo determined the ability of 10 pollutants that had been implicated in disrupting reproductive function to inhibit the binding of radioactive estrogens (female sex hormones) and androgens (male sex hormones) to each of the four types of proteins in a test tube assay.

Of the 10 pollutants tested, five prevented the binding to the androgen receptor, while only two prevented binding to the estrogen receptor. Some pollutants also inhibited binding to ABP and/or SHBG.

³Basically, It showed that all four proteins could bind pollutants, but that the androgen receptor bound most of the pollutants that we looked at,² he said.

This finding was important because it emphasized the importance of environmental androgens as agents that could interfere with normal reproductive processes. It also showed that all four proteins could bind pollutants, thereby providing multiple mechanisms by which the pollutants could disrupt normal reproductive physiology.

³The various pollutants may be agonists (acting as an estrogen or androgen) or antagonists (interfering with steroid hormone action). Both males and females have androgens and all four binding proteins. Therefore, a given pollutant could potentially interfere with reproductive tract development in either sex,² Danzo said.

³A lot of scientists think that the concentration of environmental pollutants isn¹t high enough to cause problems except to animals living in contaminated lakes or to animals that eat animals that live in those lakes and that had acquired high concentrations of pollutants in them.

"However, there have also been cases of reproductive problems in humans that have eaten fish from polluted lakes. There are also some clinical observations indicating that there may be a decrease in sperm counts in human males resulting from exposure to environmental pollutants,² he said.

Danzo said that while people might not be exposed to a high enough concentration of a single pollutant in our general surroundings, there are also many different pollutants around that might interfere with reproductive function. He said that since the pollutants can act through the androgen and the estrogen receptor and through the two steroid binding proteins, ³we have four strikes against us.

³All four of these proteins can be working together to bring about different effects in reproduction, thereby multiplying the effects of even relatively low levels of pollutants.²

Danzo¹s studies have expanded to include animals and molecular biology studies.

³We have seen the effects of pollutants on several parameters of the female reproductive tract, and studies on the male are being conducted. Adult reproductive tracts have been shown to be sensitive to pollutants. However, we expect them to be much more effective in disrupting the reproductive systems of developing males and females because the systems are much more sensitive to steroid hormones during early development," he said.

Collaborating with Danzo in the ongoing studies are Robert J. Matusik, Ph.D., professor of Urologic Surgery, Loren H. Hoffman, Ph.D. professor of Cell Biology, and Marie-Claire Orgebin-Crist, Ph.D., professor of Obstetrics and Gynecology.

Danzo said the research serves as a warning about pollution.

³The main thing that our studies, and others that are coming out now, indicate is that we have to be a lot more careful about the use of chemicals in general. Most new chemical compounds are tested for their ability to cause cancer, since everyone is worried about cancer.

"When people have cancer, most live to reproduce. But if these environmental chemicals are interfering with male and female reproduction, they¹re even more dangerous, because you may not live to reproduce," Danzo said.