[PHNUTR-L] Harmful chemicals may reprogram gene response to estrogen

[Kathrynne Holden, MS, RD]

Colleagues, the following is FYI and does not necessarily reflect my own
opinion. I have no further knowledge of the topic.
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Public release date: 31-May-2005
http://www.eurekalert.org/pub_releases/2005-05/nioe-hcm053105.php

Contact: John Peterson
peterso4 at niehs.nih.gov
919-541-7860
NIH/National Institute of Environmental Health Sciences

Harmful chemicals may reprogram gene response to estrogen

New research shows that exposure to harmful chemicals and drugs during 
critical developmental periods early in life may actually "reprogram" 
the way certain genes respond to the female hormone estrogen. This 
genetic reprogramming may determine whether people with a genetic 
predisposition for a disease actually develop the disease.

The new research shows that when rats with a genetic predisposition to 
uterine tumors also receive an early-life exposure to diethylstilbestrol 
(DES), a synthetic form of estrogen linked to vaginal cancer, the 
incidence of uterine tumors rises to almost 100 percent. By comparison, 
slightly more than half of the unexposed animals, those having only the 
genetic defect, developed the uterine tumors.

DES is a drug that was prescribed for women from 1938 to 1971 to prevent 
miscarriages and premature deliveries. Daughters of women who used DES 
are at increased risk for reproductive tract abnormalities, pregnancy 
complications such as ectopic pregnancies and preterm deliveries, 
infertility, and a rare vaginal and cervical cancer called clear-cell 
adenocarcinoma. Other research conducted by NIEHS scientists indicates 
that women exposed to DES in utero have a higher risk of uterine fibroids.

The National Institute of Environmental Health Sciences, a component of 
the National Institutes of Health, provided funding to researchers at 
the University of Texas M.D. Anderson Cancer Center for the two-year 
study. The study results will be published in the May 2005 issue of the 
Proceedings of the National Academy of Sciences.

The discovery is important because it changes conventional thinking 
about the way in which genetic predisposition and things in the 
environment interact to increase disease risk. Until now, scientists 
thought that exposure to harmful agents in the environment caused damage 
to the gene. This study, however, indicates that an environmental agent 
can actually change or reprogram the gene so that it functions differently.

"This study is telling us that an environmental reprogramming of a 
normal response, combined with an inherited gene defect, work together 
to promote cancer," said NIEHS Director David Schwartz, M.D. "If this 
model is correct, it will help doctors to determine which individuals 
are more likely to develop cancers of the uterus, breast and prostate."

The finding should alert doctors to ask more questions about a patient's 
early-life exposures to chemicals and other harmful agents in order to 
better predict that person's cancer risk.

"Most people with a family history for a particular disease are 
concerned about their recent exposures to harmful agents in the 
environment," said Cheryl Walker, Ph.D., professor of molecular 
carcinogenesis at the M.D. Anderson Cancer Center and lead author on the 
study. "We are just beginning to realize that exposures received decades 
earlier, during critical developmental stages, may be much more 
important in determining who develops cancer as an adult."

The researchers used a special strain of rats with a defect in a gene 
called Tsc-2 (tuberous sclerosis complex 2) that made them more 
susceptible to uterine leiomyomas, benign tumors that are common in 
women over 30 years of age. These rats were then treated with DES during 
days 3, 4 and 5 of life, during a critical period of uterine development.

Once the rats reached adulthood, almost 95 percent had developed the 
uterine tumors. Furthermore, the tumors were much larger and more 
numerous than those in genetically defective rats not receiving the DES 
treatment. "These data suggest that environmental exposures during 
development of the uterus can interact with a preexisting genetic 
susceptibility to increase the risk of disease," said Walker. "We are 
looking at a new kind of gene-environment interaction that determines 
who gets cancer and who doesn't."

According to Walker, the increase in frequency and size of the uterine 
tumors is due to DES' ability to influence estrogen, a female hormone 
that is involved in promoting the growth of tumors by regulating the 
activity of key genes involved in cell growth. "We found that the DES 
treatment somehow 'reprogrammed' how these genes respond to estrogen, 
making them much more responsive to estrogen than normal," said Walker. 
"We realized that the DES exposure enabled estrogen to drive the tumor 
development when combined with a genetic predisposition."

While DES exposure can lead to the development of vaginal and cervical 
cancers, the fact that most DES-exposed women did not develop the 
cancers suggests that genetic predisposition is an important part of the 
equation. "In most cases, we already have tests that can determine if a 
woman has a genetic predisposition for cancer," said Walker.

This is not the first study to suggest that cancer risk is influenced by 
both genetic and environmental factors. A 2003 study of Jewish women 
born with a defect in BRCA1, the gene that is linked to inherited forms 
of breast and ovarian cancer, showed that those women born before 1940 
had a much lower risk of developing breast cancer than women born after 
1940. The researchers believe this discrepancy is due to differences in 
diet, exercise, hormonal factors and chemical exposures.

Walker believes more research needs to be done to test this concept in 
people. "NIEHS is partnering with the National Academy of Sciences to 
fund additional research on early-life exposures and cancer risk in 
human populations," she said.
-- 
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
"Ask the Parkinson Dietitian"  http://www.parkinson.org/
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