Concerns over Genistein, Part II—Beyond the heart

This is part two of a two-part series. Part I: “Concerns over Genistein, Part I—The heart of the issue” is available at Concerns over Genistein, Part I—The heart of the issue.

DIETARY HORMONES. The protein in soy-based foods tends to be rich in estrogen-mimicking isoflavones, such as genistein. United Soybean Board

For years, soy-based foods have enjoyed a mostly untarnished reputation as healthful offerings. And there’s still plenty to recommend them: They’re rich in protein, can lower cholesterol, and may even help fight cancer. However, emerging research suggests soy’s biological activities are not unalloyed. Soy beans are among plants producing compounds that mimic the activity of estrogens—biologically powerful, female sex hormones.

One recent U.S. study in post-menopausal women linked diets high in genistein—the primary plant estrogen in soy—to a reduction in the ability of blood vessels to dilate and constrict. This vascular impairment is a sign of incipient heart disease (see Concerns over Genistein, Part I—The heart of the issue). Italian researchers now report finding a range of additional perplexing effects attributable to genistein in experiments with male mice. Brief consumption of genistein had potentially beneficial impacts on some tissues, but possibly detrimental effects on others.

In one trial, genistein appeared “to counteract the activity of bad compounds, like pesticides” to which the animals had been exposed, notes research leader Diego Di Lorenzo of the Civic Hospital of Brescia. But in other tests, eating genistein diminished the normal estrogen-triggered functions of a tissue—presumably because genistein, a weak estrogen, substituted for a more potent natural estrogen at these sites.

And, the researchers note, genistein can remain present at “functionally active levels for at least 15 days” after it’s consumed. They reported their findings in the June Toxicological Sciences.

The doses of genistein administered to the rodents were high, Di Lorenzo notes. However, the molecular endocrinologist adds, the intakes, in comparison to body weight, were not beyond the amounts regularly consumed by many people in some Asian nations, such as Japan. For that reason, he says, the new findings give pause.

Males aglow

Ordinarily, the body produces estrogen as needed and then quickly breaks it down. The Italian team wanted to see whether the body could likewise dispose of estrogen mimics. Based on previous studies by others, they had suspected that some of these environmental hormones might accumulate in tissues and then be inappropriately released at some later date. During fasts, for example, the body sustains itself by burning energy previously stored in fat and protein, in the process releasing any stored contaminants.

The researchers conducted their tests in male mice. Although estrogens are ordinarily thought of as female sex hormones, they play pivotal—albeit different—roles in males. Moreover, because males don’t routinely cope with high concentrations of natural estrogen, as females periodically do during their reproductive cycles, large dietary doses of genistein have the potential to evoke proportionately greater changes in males than in females.

For one trial, the researchers fed 30 mice for 3 days with treated chow that gave the animals 50 milligrams of genistein per kilogram of body weight per day. Two other groups of mice got regular chow but also received injections on 3 successive days of either estradiol, the body’s natural estrogen, or beta-HCH, an estrogenic pesticide. A fourth group of mice got regular chow and no injections.

For the next several weeks, all the animals ate untreated chow. Finally, the researchers starved half of the animals in each group for 2 days. This forced the mice to draw down their bodies’ energy reserves, flushing into the bloodstream any stored contaminants.

To better see the effects of estrogen, the researchers employed a genetically engineered strain of rodents. Estrogen receptors in these mice contain a gene that turns on a fluorescent signal in the presence of estrogens—natural or mimics—as long as the animals have also been fed a building block of the fluorescing protein, known as luciferin.

Two weeks after treatment, mice that had received beta-HCH injections showed detectable increases of fluorescence in their livers. This result, not seen in animals from the other groups, suggested that the pollutant was accumulating in this organ. However, after fasting, fluorescence in the beta-HCH animals ratcheted down by 80 percent in the liver, but nearly doubled in the testes. The researchers speculate that some of the excess in the liver, and stockpiles from other sites, got flushed into the bloodstream where it could circulate widely—perhaps turning on primed receptors in the testes.

Fasting in the genistein-treated mice 2 weeks after treatment also mobilized this estrogen mimic to repress normal liver activity of estrogen. It may sound counterintuitive that an estrogen mimic could turn down estrogen activity, but Di Lorenzo explains that if a weak estrogen substitutes for the body’s own potent one, the end result could be that a triggered hormone receptor becomes less active.

Even 30 days after getting beta-HCH or genistein, the mice showed residual estrogenic effects of these hormone mimics.

To establish that these changes were indeed due to the remobilization throughout the body of stored beta-HCH and genistein, the researchers tested the blood of treated animals before and after fasting. Measurable concentrations of both pollutants were found at both times. After a 2-day fast, however, blood concentrations of each pollutant roughly tripled.

Confused yet? If not, wait until you see what additional wrinkles emerge when these hormones and mimics get an opportunity to interact.

In follow-up tests, the Italian team exposed its mice to genistein in combination either with estradiol, beta-HCH, or the now-banned pesticide DDT. In general, the genistein-estradiol pairing led to lower estrogenic activity than occurred with estradiol alone. In the earlier tests, beta-HCH by itself reduced estrogen activity in the testes of nonfasting rodents; when this pollutant was administered along with genistein, the testes response returned to normal.

Co-treatment with genistein did not appreciably alter the testes impacts of either DDT or estradiol. In other organs, however, co-treatment with genistein overcame the 35-percent inhibition of estrogen action linked to DDT treatment.

In sum, then, is genistein good or bad? At present, Di Lorenzo concludes, “We can’t say.” If it inhibits the turning off of normal estrogen action by pesticides like beta-HCH, that would be a good thing. However, if it displaces the body’s natural hormone, diminishing normal estrogen action, that may be detrimental.

ABCs of estrogen action

There’s yet another possible complicating factor: the role of different estrogen receptors.

Until 11 years ago, only one type of estrogen receptor was known. It shows up on cells throughout many parts of the body, and estrogen’s activity, wherever it occurred, was attributed to its interaction with this receptor.

Then, a Swedish team of scientists identified a second type, now called estrogen-receptor beta. Although estrogen-receptor beta often occurs in the same tissues as its better known sibling—now called alpha—the receptor type that dominates not only varies from tissue to tissue but also can trigger quite different functions.

For instance, whereas the alpha receptor can turn on development or reproductive cycling in the breast and uterus, activities that might increase a woman’s cancer risk over time, estrogen’s activation of the beta receptor appears capable of diminishing cell cancer growth—and cancer risk—in those organs.

Unlike the body’s natural estrogen, estrogen mimics don’t necessarily show an equal affinity for both receptor types. That means that significant exposure to genistein or related environmental estrogens could shift the balance of estrogen-driven activities within a tissue from what would occur upon exposure to natural estrogens only.

Di Lorenzo suspects that part of the confusing array of findings associated with the estrogen mimics may trace to their greater or lesser propensity for alpha versus beta receptors. It’s something his team hopes to home in on in future studies.

They also intend to probe a curious effect of genistein that they reported last year. In the December 2006 Endocrinology, they showed that young male mice fed large doses of genistein put on more fat than did untreated males eating the same amount of food. Genistein had no fattening effect in females. Here again, Di Lorenzo notes, the doses of genistein were high, but comparable to what is consumed in some soy-loving cultures or by people who take dietary supplements containing the soy estrogens genistein and daidzein.

This is part two of a two-part series. Part I: “Concerns over Genistein, Part I—The heart of the issue” is available at Concerns over Genistein, Part I—The heart of the issue.

If you would like to comment on this Food for Thought, please see the blog version.

Janet Raloff is the Editor, Digital of Science News Explores, a daily online magazine for middle school students. She started at Science News in 1977 as the environment and policy writer, specializing in toxicology. To her never-ending surprise, her daughter became a toxicologist.

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