Genes and environment interact to promote cancer
Mar 28, 2006 - 5:00:00 AM
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Teasing out which factors most influence human disease risk is difficult without conducting large scale studies, said Joellen Schildkraut, Ph.D., epidemiologist in the department of Community and Family Medicine at Duke. A prime example is the ongoing debate over the role of smoking and the NAT2 gene in promoting bladder cancer. Some studies show that people with a certain version or allele of the NAT2 gene have a 40 percent increased risk for bladder cancer. Adding tobacco smoke to the effects of this allele may increase one's risk to 300 percent, said Schildkraut, but the data sometimes conflict.
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By Duke University Medical Center,
[RxPG] After smoking, radon is considered to be the second leading cause of lung cancer in the United States, said Avner Vengosh, Ph.D., associate professor at Duke's Nicholas School of the Environment and Earth Sciences. Western North Carolina is highly affected, and many homes exceed the EPA's recommended levels of radon.
Radon's risk is not new or unknown, but it illustrates the real danger posed by indigenous substances as well as those artificially created by humans, say Duke scientists. More than 80,000 synthetic chemicals have been introduced worldwide since World War II, with little or no knowledge as to how they affect humans or animals.
Day by day, environmental scientists identify new culprits in the cancer equation in which genes, environment and lifestyle interact to increase cancer risks in some people but not in others.
Their synergy is by no means a simple interaction, said H. Kim Lyerly, Director of the Duke Comprehensive Cancer Center. For example, vitamin A can promote lung cancer growth in some women while it maintains healthy breast cell growth and division in others, said Victoria Seewaldt, M.D., director of the Duke Breast Health Clinic. Chemicals that promote cancer in one fish species do not cause cancer in a closely related species, while populations of another species have adapted to a polluted environment, found Richard Di Giulio, Ph.D., of Duke's Nicholas School. Common nutritional supplements like folic acid, given to pregnant mice, altered their offspri! ngs' coat colors and their adult risk of cancer, found Randy Jirtle, Ph.D. professor of radiation oncology at Duke University Medical Center.
Why these differences exist, and how and when the changes are imposed, are major questions being studied in a partnership between the Duke Comprehensive Cancer Center and Duke's Nicholas School of the Environment and Earth Sciences. The two groups are hosting their joint conference March 30 to 31 to present their latest findings on how the environment impacts cancer. Collectively, their data show that the timing and dose of exposure, combined with an individual's genetic makeup, play critical roles in cancer susceptibility.
The nature-versus-nurture argument is rapidly proving to be irrelevant, because we're finding that the two forces interact in highly specific ways that alter gene behavior, said Jirtle.
Select chemicals may damage or mutate genes at any given time in the lifespan, contributing to a host of human diseases, he said. But another, more subtle, change is emerging as the trigger for many cancers, diseases and even personality traits.Called epigenetic alterations, they occur when chemicals, nutrients or even behaviors elicit a chemical change in the brain or body that activates or silences a gene without changing its fundamental genetic code. The chemical or event mobilizes groups of molecules, called methyl or acetyl groups, to attach to the control region of a gene and alter its usual activity.
Such stealth changes often occur during embryonic or fetal development, but emerging data suggests they set the stage for an adult's susceptibility to a host of diseases and behavioral responses. Moreover, epigenetic changes so named because they sit on top of the gene and leave its sequence unchanged can also be passed down from one generation to the next, said Jirtle, who has extensively studied the phenomenon. They can also be reversible. Methyl groups can be added or knocked off following exposure to various substances.
Finding methylated or acetylated genes is no small task, however. Certain genes are more susceptible to epigenetic alterations than others, but no one knows for certain which genes and when the changes occur. Second, multiple compounds may interact to halt or promote genetic or epigenetic changes. Finally, epigenetic changes may occur so early in prenatal development that gauging its effects in adulthood prove difficult.
There are critical windows of development during which compounds can have a profound impact on disease and wellness, said Lyerly. And one compound may act differently in liver tissue than in breast tissue. Testing a compound during an inactive or inert period of development, or in the wrong tissue, is akin to testing a Porche's speed in Manhattan rush-hour traffic. The device works fine, but the timing and location are wrong.
The scenario grows more complex as multiple chemicals are introduced. A single chemical that proves safe by itself and in low doses may become highly toxic in high doses or when combined with other chemicals.
And, even the lowest detectable limits of a chemical can have dire effects on an organism, said William Schlesinger, Ph.D., Dean of Duke's Nicholas School. Atrazine is a prime example. Less than one part per billion of this widely used corn herbicide de-masculinizes developing frogs or produces dual male-female genitalia. Yet the Environmental Protection Agency's instrumentation often cannot record such minute levels of chemical exposure, he said.
If atrazine is having this effect in animals, we question its effects on humans, said Schlesinger. Are the current standards of exposure high enough to protect the organisms exposed to select chemicals? Our role as environmental scientists is to assess the potential impact of each compound on native organisms and develop models that physician scientists can apply to humans.
Likewise, Duke pharmacologist Mohamed Abou Donia, M.D., has shown that insecticides that are generally safe when used alone or in small amounts can damage the brain, nervous system and testes when combined with other chemicals or certain medications.
Testing each drug alone would fail to produce the synergy that elevates toxicity, he said.
Similarly, certain drugs can sensitize cells to the effects of hormones such as estrogen, progesterone and testosterone. In 2004, Duke researchers showed that an industrial solvent (EGME) and a commonly prescribed drug, Valproic acid, potently boosted estrogen and progestin activity inside cells. The elevated hormone levels are likely responsible for the reproductive failures and breast cancers seen among women exposed to these chemicals, said Duke pharmacologist Donald McDonnell, Ph.D.
Our study demonstrates that these chemicals boost the activity of estrogens and progestins inside cells eight- to 10-fold, said McDonnell. These data should prompt caution for patients who are exposed to either of these chemical compounds while taking any estrogen- or progesterone-containing medications, such as hormone therapy, oral contraceptives or tamoxifen for breast cancer.
Teasing out which factors most influence human disease risk is difficult without conducting large scale studies, said Joellen Schildkraut, Ph.D., epidemiologist in the department of Community and Family Medicine at Duke. A prime example is the ongoing debate over the role of smoking and the NAT2 gene in promoting bladder cancer. Some studies show that people with a certain version or allele of the NAT2 gene have a 40 percent increased risk for bladder cancer. Adding tobacco smoke to the effects of this allele may increase one's risk to 300 percent, said Schildkraut, but the data sometimes conflict.
Ultimately, the knowledge we gain about gene-environment interaction will lead to new drugs and therapies to prevent or treat cancers, and improved environmental regulations that protect humans and animals against toxic exposures, said Schlesinger.
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