By David N. Leff

World leaders from 150 countries converged on Kyoto, Japan, this week to confront the threat of global warming.

Meanwhile, scientists in many countries are tackling a less-celebrated manmade menace to the environment — an apparent worldwide decline in human sperm counts. What carbon dioxide is to the greenhouse effect, the feared falloff in global human fertility is being blamed on a hormone linked to the female menopause — namely, estrogen.

In 1992, University of Copenhagen researchers concluded that exposure to industrial chemicals, notably pesticides, was causing sperm counts, and hence human fertility, to go down. Last month, a team at the California Department of Public Health took a good look at the 61 studies the Danes had analyzed, and reached a similar controversial conclusion.

Endocrinologist Kenneth Korach is scientific director of the environmental disease and medicine program at the National Institute of Environmental Health Sciences, in Research Triangle Park, N. C. "In the last three to five years," he told BioWorld Today, "we have received reports indicating that chemical substances have hormonal activities. So we now term these 'environmental estrogens.'"

Korach continued: "If people or wildlife, animal species in particular, are exposed to these chemicals, that exposure alters their reproductive as well as sex-differentiation endocrine functions, which are obviously controlled by estrogen."

He cited a list of estrogenic-like industrial effluents, which run the gamut from DDT to PCBs (polychlorinated biphenyls) to pesticides and plasticizers. "These materials are being manufactured in tremendous amounts," Korach observed, "and could potentially produce exposures that might have toxicological effects on the normal physiology of exposed individuals."

A controlled survey in Florida, Korach recalled, revealed that alligators inhabiting certain contaminated lakes were shown to have feminization and sex differentiation problems, but those in non-contaminated lakes did not.

Is Estrogen A Testosterone In Drag?

Mainly synthesized in the ovaries, the estrogen hormone kicks in at puberty to help turn a girl into a woman by molding her feminizing female characteristics, such as breast development and menstruation. Similarly, testosterone, secreted in the testis, makes a man out of a boy, deepening his voice, putting hair on his chest (and/or his underarms), and triggering spermatogenesis.

Less well known is the fact that, political correctness aside, estrogen, "the female hormone," is also produced in the male testis, alongside of testosterone, the androgen "male hormone."

What is such a quintessentially feminine hormone doing in the very headwaters of masculinity?

The answer appears in today's Nature, dated Dec. 4, 1997, under an article titled: "A role for oestrogens in the male reproductive system." Korach is one co-author; molecular biologist David Bunick, of the University of Illinois at Urbana, another.

"As we become more worried about estrogenic-like compounds that we work with in the environment," Bunick told BioWorld Today, "this paper offers the first real evidence that estrogen has an important role in male reproduction. It's funny," he added. "This is something that people have ignored, overlooked; yet it was known that the receptor for estrogen is present in various parts of the male reproductive tract."

His paper's key finding is that "estrogen is extremely important to maturation of the sperm."

To reach this experimental conclusion, the Illinois team employed a knockout mouse, lacking estrogen receptor gene function, which Korach had developed in the early 1900s, together with biochemist Dennis Lubahn (the paper's final author).

"We isolated tissue from the male reproductive tracts of those mice," Bunick recounted, "specifically from their efferent ductules. These are a set of, say, three to seven tubes through which the sperm have to pass out of the testis before they enter the epididymis, where they complete their maturation."

These tubules are responsible for absorbing, or reabsorbing, 90 percent of the fluid coming out of the testis, thus concentrating the sperm. The fluid consists mainly of water, but it contains substances that nourish and energize the sperm for their long uphill journey to fertilize their mate.

Collapsed Tubules Denote Estrogenic Function

Bunick and his team isolated the tubules, and cut them into little pieces tied off at both ends. "We sealed the ends in tissue culture," he recounted, "and created a closed system. If they stay alive in our culture system, and if they continue to function and remove water from inside of the tubes' lumen, they should collapse."

Indeed, the Nature paper reports, when they did this in normal tubules from normal animals, the ducts did collapse. "Thus showing that they're carrying out their function, which is to remove water from the inside of the lumen," Bunick pointed out.

Then the team tried the same experiment on Korach's estrogen receptor knockout animal.

"They have no receptors," Bunick pointed out, "so they shouldn't respond to estrogen. And indeed we found that they do not collapse. In fact, they swell a little bit."

To double-check this experiment, they repeated the test using a commercial compound that blocks the estrogen receptor in normal mice. "When we did that, we reproduced the system and the tubules did not collapse, the fluid was not resorbed, showing that estrogen has to be important in sperm maturation. Even if we block the receptor, even if there is estrogen present in the media, we don't get the ductules to function as they're supposed to — that is, removing water from inside the lumen. That's the central focus of our paper."

In a separate study (in the Journal of Andrology, December 1997), the Illinois group reported that the amount of messenger RNA expressed by the estrogen receptor gene in the efferent ductules of male rats "is 3.5 times greater than that in the female reproductive tract."

Morphologist Rex Hess, first author of both papers, observed: "Now that our findings have provided the first recognized physiological function for estrogen in males, the next step in the research is to determine its biochemical action." He added, "We can now say that this female hormone is intimately involved in regulating fertility in the male, because if you block the estrogen receptor's function, as we've shown here, you will have infertility.

"It is very likely," Hess concluded, "that this will be a similar finding in humans." *

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