Scientists are developing new ways to selectively boost gene expression in the brain, in the hope of treating psychiatric and neurological disease. A growing pool of evidence shows that compounds that target this mechanism can improve learning and memory in rodents. But existing drugs, which were not developed for this purpose, are relatively weak and unselective, and their long-term safety is not yet clear. Over the past few years, neuroscientists have begun to recognize the importance of epigenetics--molecular processes that change the expression of genes without altering DNA--in the brain, and in memory in particular. One of the key regulators of epigenetics is a group of enzymes known as histone deacetylases (HDACs), which trigger DNA to wind more tightly around neighboring proteins, ultimately dampening gene expression.
While scientists don't yet know exactly how epigenetic regulation affects memory, the theory is that certain triggers, such as exercise, visual stimulation, or drugs, unwind DNA, allowing expression of genes involved in neural plasticity. That increase in gene expression might trigger development of new neural connections and, in turn, strengthen the neural circuits that underlie memory formation. "Maybe our brains are using these epigenetic mechanisms to allow us to learn and remember things, or to provide sufficient plasticity to allow us to learn and adapt," says John Satterlee, program director of epigenetics at the National Institute on Drug Abuse, in Bethesda, MD.
The findings suggest that scientists will need to develop compounds that act selectively on the different HDAC enzymes, perhaps inhibiting some and activating others. At this point, little is known about the specific functions of the nearly 20 different enzymes. But Tsai says that her group has identified one enzyme that appears to be specifically involved in memory. The researchers are also developing more selective compounds.
Fetal Exposure to Carcinogens May Lead to Cancer Decades Later
A new study suggests that exposure of a fetus to common carcinogens during the late stages of pregnancy may be even more harmful than exposure after birth, causing long-lasting genetic damage that could lead to cancer in childhood, young adulthood or even middle age.
The findings, done in experiments with laboratory mice exposed to high levels of a class of carcinogen that’s commonly found in the environment, are consistent with other studies that also point to the particular vulnerability of fetuses to cancer-causing compounds, especially in late stages of gestation.
The results were just published in Toxicology and Applied Pharmacology, a professional journal, by researchers from the Linus Pauling Institute at Oregon State University. The studies were supported by the National Institutes of Health.
“The study of epigenetics and imprinting has shown that exposure to agents during early stages of development can program gene expression, such that susceptibility to disease in later life is impacted,” the authors wrote in the report. “Studies in human populations find high exposures to environmental chemicals associated with . . . birth weight, behavioral endpoints and cancer.”
The toxic environmental chemical used in these experiments was one kind of polycyclic aromatic hydrocarbon, or PAH, a group of chemicals that scientists believe represent a “re-emerging” environmental concern.
PAHs are associated with the burning of fossil fuels such as coal and petroleum, and are increasingly common air pollutants, especially in some places such as China where use of coal for power production is soaring. But they can also get into soils, be taken up by plants and make their way into the human food chain. And cancer is the number one cause of disease-related death in children, with lymphomas and leukemias – some of the types of cancer produced in these animal experiments – at the top of the list.
“What was surprising about our findings is that PAHs appeared to be even more carcinogenic when the exposure was in late-stage pregnancy, instead of nursing,” said David Williams, professor and director of the Marine/Freshwater Biomedical Sciences Center at OSU. “Significantly more damage was done in two days of in-utero exposure than by three weeks of exposure through breast milk. This suggests the fetus in late gestation is very susceptible to carcinogens.”
An alternative explanation, Williams said, would be that little of the PAH partitions into the milk, although this PAH is very fat soluble, as are other environmental chemicals of concern in breast milk, such as DDT, PCBs and dioxin. The researchers are investigating these possibilities, as well as performing studies with actual environmental PAH mixtures collected in Beijing by Staci Simonich, an associate professor in the OSU Department of Environmental and Molecular Toxicology.
The idea that exposure to carcinogens during early development can set the stage for cancer years later is gaining more credence as the science of “epigenetics” reveals how genes can undergo permanent changes, based on toxic insults, nutrition or other factors, Williams said. Other laboratory studies have shown nutritional interventions that can help prevent some of the damage from carcinogens.
And research of this type may help explain why some people exposed to carcinogens during adulthood get cancer, and others with similar exposure do not.
While the risk of birth defects through genetic damage is often observed in the very early stages of pregnancy, Williams said, the risk of carcinogens and cancer appears to be linked more to the late stages, and to infancy, when detoxification systems are not yet fully developed.
“Carcinogens have to be metabolized in order to affect the fetus, and the enzymes necessary to do that are not really developed until later stages of pregnancy,” Williams said. “If nothing else, this suggests that avoidance of toxic chemicals and a healthy diet is very important throughout a pregnancy, not just at first.”
The diet that might provide some protection against toxins, Williams said, is essentially the same as that usually recommended anyway – lots of fresh fruits and vegetables, especially cruciferous vegetables such as broccoli, cauliflower and kale that have high levels of indole-3-carbinol, which appears to have cancer chemopreventive properties. More research is needed before it can be determined if dietary supplements would be appropriate, Williams said.
More than 800,000 Americans have leukemia, lymphoma or myeloma, the researchers noted in their report. There are an estimated 135,000 new cases of these cancers and 50,000 deaths every year.
“In order to devise the most efficacious approaches to chemoprevention, we need to know when the greatest period of sensitivity is,” the scientists wrote in this study. “We now show that, in this model, in- utero exposure carries the greatest risk."
Steve - these are two very well-respected research bodies. We will continue to see more data regarding the importance of epigenetics, especially during fertility and pregnancy stages.
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