Early Environmental Exposure May Set Stage for Cancer

Rat study found it triggered disease in those with genetic predisposition

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HealthDay Reporter

TUESDAY, May 31, 2005 (HealthDay News) -- Researchers think they have discovered why some people who are genetically prone to cancer develop the disease, and some do not.

In experiments with rats, scientists found that exposure to synthetic estrogen in the womb can permanently "reprogram" cells in a way that determines whether cancer will develop in adulthood. Their report appears in this week's issue of the Proceedings of the National Academy of Sciences.

"We found that very early life exposures seem to have a very profound effect on determining which individual will get cancer as an adult," said lead researcher Cheryl Walker, a professor in the Department of Carcinogenesis at the University of Texas M.D. Anderson Cancer Center in Houston.

"We were interested in those people who might be genetically predisposed to cancer," Walker said. "But not all genetically susceptible people actually develop cancer. In fact, the rate of cancer in those that have these genetic defects can be very high or very low, and we don't know why that is."

That means there are most likely environmental influences that set these genes in motion, Walker explained. "Our work found that environmental exposure that occurs early in life, a long time before the cancer develops, might be determining which of these genetically susceptible individuals will develop cancer as an adult," she said.

In their experiments, Walker and her colleagues used an animal model that had a similar genetic defect that is found in some people susceptible to tumors. In this case it was uterine leiomyoma, the same kind of benign fibroid tumors that many women have.

In rats engineered to be susceptible to benign uterine tumors, Walker's team treated some with diethylstilbestrol (DES), a banned anti-miscarriage drug.

Usually, about 65 percent of rats with this genetic defect develop the tumors as adults. In the experiment, some rats were exposed to DES three to five days after birth.

By the time the DES-exposed rats reached adulthood, almost all had developed tumors. Moreover, there were more and larger tumors in the DES-exposed rats, compared with unexposed rats that had the genetic defect. In contrast, rats that did not have the genetic defect but were exposed to DES did not develop tumors.

"This environmental exposure, during a critical developmental time, had a profound effect on the uterus," Walker said. "In fact, what it did was it reprogrammed the way the normal uterus responds to the female hormone estrogen. This is a new type of gene/environment interaction."

Walker believes this interaction is the mechanism that is also involved in human cancer. "If we want to understand how the environment contributes to cancer, we can't just look at adult exposures," she said. "We are going to have to look at early life exposures."

Walker also cautioned that looking at environmental causes of cancer that result from gene mutations is not the whole story. "In this study, we have not induced mutations; we have reprogrammed the tissue in such a way that it is responding differently. It is that reprogrammed tissue, combined with the genetic alteration, that drives tumor development."

One expert finds the study interesting, but not entirely convincing.

"We knew from earlier studies that early exposure to DES is linked to cancers of the female genital tract, so this is not completely surprising," said Dr. Archibald S. Perkins, an associate professor of pathology and molecular, cell and developmental biology at Yale University.

What is new here is that the impact of early hormonal exposure can depend on the presence of genetically inherited traits, indicating that certain individuals will be affected, while others will not, Perkins said. "This study also starts to uncover the mechanism by which these brief exposures lead to later effects," he noted.

However, what the implication might be for people isn't clear. "Whether this study has implications for exposure to environmental agents, such as pesticides, is not clear since such environmental agents are likely present at very low levels, while the DES levels the rats were exposed to were quite high," Perkins said. "That would be the obvious concern, however, that environmental agents could cause, in the susceptible individual, a change in some target organ that would only become evident much later."

More information

The American Cancer Society can tell you more about cancer.

SOURCES: Cheryl Walker, Ph.D., professor, department of carcinogenesis, University of Texas M.D. Anderson Cancer Center, Houston; Archibald S. Perkins, M.D., Ph.D., associate professor, pathology and molecular, cell and developmental biology, Yale University, New Haven, Conn.; May 30-June 3, 2005, Proceedings of the National Academy of Sciences

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