Chemicals can turn genes on and off; new tests needed, scientists say.
By Bette Hileman
Environmental Health News
Aug. 3, 2009
Each of us starts life with a particular set of genes, 20,000 to 25,000 of them. Now scientists are amassing a growing body of evidence that pollutants and chemicals might be altering those genes—not by mutating them, but by sending subtle signals that silence them or switch them on at the wrong times.
Last week, several dozen researchers and experts convened by the National Academies tackled this complicated topic, called epigenetics, at a two-day workshop in Washington, D.C. They discussed new findings that suggest chemicals in our environment and in our food can alter genes, leaving people vulnerable to a variety of diseases and disorders, including diabetes, asthma, cancer and obesity. They also considered whether regulatory agencies and industry should start testing the thousands of chemicals in use today for these effects.
“There is little doubt these epigenetic effects are important. The next question is how we test for effects," said William H. Farland, professor of environmental and radiological health sciences at Colorado State University. "We don’t need to abandon current approaches to chemical testing. When testing chemicals in animals, we may just need to add some new endpoints."
Animal studies indicate that some environmental chemicals cause epigenetic changes that trigger breast and prostate cancer, obesity, diabetes, heart disease, asthma, Alzheimer’s, Parkinson’s disease and learning disabilities, she said. And some new human studies are now adding to the evidence.
“There is a huge potential impact from these exposures, partly because the changes may be inherited across generations. You may be affected by what your mother and grandmother were exposed to during pregnancy,” Birnbaum said.
What a pregnant mother eats and the chemicals she is exposed to can affect her offspring without causing mutations in the DNA, the experts said. Instead, such exposures can disrupt the way that genes behave, according to both animal and human studies. These changes, in turn, can be passed on to the next generations.
Some environmental chemicals enable methyl groups (carbon atoms with three hydrogen atoms attached) to attack genes, which turns them off or mutes them, at a time when they should be turned on. When genes are turned off, they can’t direct the manufacture of proteins that are essential for proper cell function. Chemicals also can uncoil parts of the chromosome, causing genes to be expressed, or turned on, at inappropriate times.
An example is asthmatic children. Wan-Yee Tang, a researcher at the University of Cincinnati, found that children in New York City exposed in the womb to high levels of polycyclic aromatic hydrocarbons (PAHs), common air pollutants from traffic, were much more likely to have asthma than those who were not exposed. By studying cord blood, she found that a particular gene (ACSL3) was methylated in the asthmatic children and unmethylated in the unexposed children, and concluded that the abnormal methylation patterns probably caused the asthma.
The finding could in part explain why worldwide asthma rates have skyrocketed in much of the world, reaching epidemic proportions among children. In the boroughs of New York City with the worst air pollution, about 25 percent of children are asthmatic.
Epigenetic changes also have been observed in children conceived with assisted reproductive technologies, said Richard Meehan of the Medical Research Council in Scotland.
One of the disorders that occurs at a higher rate in these children is Beckwith-Wiedemann syndrome, which is characterized by abdominal wall defects and a higher risk of certain childhood cancers. The culture medium where fertilized eggs are grown for several days before implantation probably causes the syndrome, he said. It appears that all the different media used for the eggs might be problematic because they contain chemicals that stimulate the addition of methyl groups to the cells.
The scientists at the workshop said it’s important to understand epigenetics not only to figure out which chemicals might endanger public health, but to find new ways to prevent or treat diseases.
Scientists are just now beginning to figure out normal methylation patterns in the genome so they can learn what is abnormal, said Karl T. Kelsey, professor of community heath and pathology at Brown University in Rhode Island. As a result of this new understanding, epigenetic therapies have been developed for some types of cancers, and some have been successful in clinical trials, he said. Unlike traditional cancer drugs, which kill cells, the new drugs simply change how the cells act.
Research with rats shows that gene-altering chemicals can change animals’ brains—in some cases, in a beneficial way.
Moshe Szyf, a pharmacology and therapeutics professor at McGill University Medical School in Montreal, found that rats that received healthy doses of maternal licking as pups grew up to be calmer than pups who had inattentive mothers. The maternal grooming brought about a chemical change in the part of the pup’s brain that produces stress hormones, he said.
The rats reared by attentive mothers had different levels of corticoid gene expression and lower levels of stress hormones than those reared by inattentive mothers. Szyf found he could cure the stressed rats by injecting a chemical called TSA into their brains, which reversed the inappropriate methylation caused by inattentive mothering.
This understanding of epigenetics may lead to new medications for treating human problems. By using approaches similar to those used in the rat study, Szyf is hoping to find drugs that will help alleviate human psychiatric conditions.
Szyf also studied the preserved brains of suicide victims and of people who died suddenly from causes other than suicide. He found that certain genes in the suicide victims were methylated, or turned off. In contrast, those same genes were not methylated in the victims who died by other means. Abnormal methylation patterns could cause depression in some people, he said.
Some compounds, such as nickel, chromium and arsenic, are well-known carcinogens—not because they are toxic to cells but because of their epigenetic effect, said Max Costa, a New York University professor of environmental medicine and pharmacology. They increase DNA methylation, which results in gene silencing and cell transformation and leads to cancer, he explained.
Researchers at the meeting spent a great deal of time discussing whether and how to test chemicals for their ability to cause epigenetic changes.
Most researchers there agreed that compounds need to be tested for epigenetic effects. But practical testing of the 80,000 or so chemicals in commerce would require rapid screens that would prioritize the compounds into high, medium, and low-risk groups. Those at high risk for epigenetic effects could then be subjected to more definitive and expensive tests.
John M. Greally, associate professor at the Albert Einstein College of Medicine in New York City, pointed out that no single test is ideal for detecting epigenetic effects.
“All of the assays have drawbacks,” he said. For example, one assay requires immediate sample processing so it cannot be used on stored samples.
Nevertheless, many researchers said that testing chemicals for epigenetic changes can begin soon.
“The fact that we don’t know a great deal about this area doesn’t mean it’s daunting,” said George Daston, research fellow at Procter & Gamble. “We just need to build on what we have. Microassays already show how chemical exposures change the gene expression in certain parts of the genome. The fact that we don’t know a lot doesn’t mean we can’t start testing quickly.”
Birnbaum, who formerly was head of experimental toxicology at the U.S. Environmental Protection Agency, said regulators and industry don’t have to start from square one.
“We’re already marching down this road,” said Birnbaum. “The National Toxicology Program is already talking about including some epigenetic studies in the program.”
The most important public health issue that arises from epigenetics, Birnbaum told Environmental Health News, is that the current environment may not be the crucial factor to consider when examining what causes diseases.
“Asking heart attack victims what they ate this year or last may be far less important than what they were exposed to in the womb and shortly after birth,” she said.