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Metal's Mayhem: Cadmium mimics estrogen's effects, thwarts DNA repair

12:15pm, July 16, 2003
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Trace amounts of cadmium can mimic estrogen's effects on cells and alter the reproductive system of female rats, a new study shows. The finding may expand the rap sheet on cadmium–already fingered in lung cancer and kidney damage–to include reproductive disorders and possibly hormone-related malignancies such as breast cancer.

Meanwhile, a separate report reveals that cadmium also disrupts DNA repair inside cells, offering an explanation for its cancer-causing effects in cigarette smoke and industrial pollution. Cadmium is a white metal used in alloys, batteries, metal coatings, and pigments.

In the August Nature Medicine, molecular biologist Mary Beth Martin of Georgetown University in Washington, D.C., and her colleagues report that female rats injected with cadmium chloride grew thicker uterine linings and larger mammary glands, effects that mirror the animals' normal responses to an estrogen boost. These changes arose even though the rats had had their ovaries removed and so were making none of their own estrogen.

The findings validate earlier cell-culture studies showing that cadmium binds to a receptor molecule on cells that normally binds estrogen. When the metal does so, it sets off a genetic chain reaction and growth processes similar to those induced by the hormone itself, Martin says.

The rats also showed evidence of extra amounts of two proteins typically activated by estrogen–the progesterone receptor protein and C3, an immune system protein.

Revealing another estrogen-mimicking effect, cadmium-exposed female rats with intact ovaries bore female pups that gained weight quicker than usual and reached puberty earlier than normal.

The rat findings indicate that cadmium can rev up unwanted cell growth by mimicking estrogen, says Martin. Her group is planning experiments to determine whether such an endocrine disruption by cadmium may be a cause of breast cancer.

In the other new study, researchers found that low concentrations of cadmium cause an extremely high rate of genetic mutation in yeast. But rather than damage DNA directly, the metal appears to cause mutations by inhibiting a cell's DNA-repair mechanism.

Normally in any organism, some cells die off naturally and others multiply to take their places. However, errors commonly arise in this replication process, which is why DNA has built-in repair mechanisms. Among them is DNA-mismatch repair, a mutation-avoidance system that suppresses tumor formation, says study coauthor Dmitry A. Gordenin, a geneticist at the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.

However, in yeast cells exposed to cadmium, this DNA-repair process goes awry. Cadmium exposure pushed the mutation rate up as much as 2,000-fold in these cells, Gordenin says.

DNA-mismatch repair is guided by specific genes and the proteins they encode. In the July Nature Genetics, Gordenin and his colleagues say they don't know which proteins are affected by cadmium but that the evidence of mutations is unmistakable.

Cadmium is present in soil and therefore in many foods. In people, it lingers in the body for decades, tending to accumulate in the kidneys, liver, lungs, and prostate. Once inside a person, it binds chemically to certain molecules in tissues and so isn't readily excreted.

Cadmium is one of the major contaminants of tobacco smoke, says Gordenin. "Smokers definitely accumulate more cadmium in their lungs" than nonsmokers do, he says, and the new research suggests one of the mechanisms by which smoking leads to lung cancer.

These studies are "both extremely important steps in [determining] cadmium's role in the human body," says John A. McLachlan of Tulane University in New Orleans. They add to a growing body of knowledge about pollutants that mimic hormones and thus have an impact on health, he says.


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