Health
The accumulation of age-associated changes in a biochemical process that helps control genes may be responsible for some of the increased risk of cancer seen in older people, according to a National Institutes of Health study.
Scientists have known for years that age is a leading risk factor for the development of many types of cancer, but why aging increases cancer risk remains unclear.
Researchers suspect that DNA methylation, or the binding of chemical tags, called methyl groups, onto DNA, may be involved. Methyl groups activate or silence genes, by affecting interactions between DNA and the cell's protein-making machinery.
Zongli Xu, Ph.D., and Jack Taylor, M.D., Ph.D., researchers from the National Institute of Environmental Health Sciences (NIEHS), part of NIH, identified DNA methylation sites across the human genome that changed with age.
They demonstrated that a subset of those sites – the ones that become increasingly methylated with advancing age – are also disproportionately methylated in a variety of human cancers. Their findings were published online in the journal Carcinogenesis.
“You can think of methylation as dust settling on an unused switch, which then prevents the cell from turning on certain genes,” Taylor said. “If a cell can no longer turn on critical developmental programs, it might be easier for it to become a cancer cell.”
Xu and Taylor made the discovery using blood samples from participants in the Sister Study, a nationwide research effort to find the environmental and genetic causes of breast cancer and other diseases. More than 50,000 sisters of women who have had breast cancer are participating in the study.
The researchers analyzed blood samples from 1,000 women, using a microarray that contained 27,000 specific methylation sites. Nearly one-third of the sites showed increased DNA methylation in association with age.
They then looked at three additional data sets from smaller studies that used the same microarray and found 749 methylation sites that behaved consistently across all four data sets.
As an additional check, they consulted methylation data from normal tissues and seven different types of cancerous tumors in The Cancer Genome Atlas, a database funded by the National Cancer Institute and the National Human Genome Research Institute.
Taylor said that DNA methylation appears to be part of the normal aging process and occurs in genes involved in cell development. Cancer cells often have altered DNA methylation, but the researchers were surprised to find that 70-90 percent of the sites associated with age showed significantly increased methylation in all seven cancer types.
Taylor suggests that age-related methylation may disable the expression of certain genes, making it easier for cells to transition to cancer.
The research also determined how fast these methylation events accumulate in cells. They occur at a rate of one per year, according to Xu.
“On your 50th birthday, you would have 50 of these sites [from the subset of 749] that have acquired methyl groups in each cell,” Xu said. “The longer you live, the more methylation you will have.”
For future work, Xu and Taylor want to examine more samples, using a newer microarray that will explore methylation at 450,000 genomic methylation sites.
The additional samples and larger microarray, which will provide 16 times more genomic coverage, will allow them to address whether environmental exposures during adulthood or infancy affect methylation profiles.
These additional studies will help scientists better understand why methylation happens as people march toward their retirement years.
DNA methylation is one of several epigenetic mechanisms that can control gene expression without changes in DNA sequence. This study is part of a broader research effort, funded by NIEHS, to understand how environmental and other factors affect epigenetic mechanisms in relation to health.
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Previous studies have shown the certain pesticides can increase the risk for developing Parkinson's disease. Now, UCLA researchers have now found that the strength of that risk depends on an individual's genetic makeup, which in the most pesticide-exposed populations could increase the chances of developing the debilitating disease by two- to six-fold.
In a previous study published January 2013 in the Proceedings of the National Academy of Sciences, the UCLA research team discovered a link between Parkinson's and the pesticide benomyl, a fungicide that has been banned by the U.S. Environmental Protection Agency.
That study found that benomyl inhibited an enzyme called aldehyde dehydrogenase (ALDH), which converts aldehydes highly toxic to dopamine cells into less toxic agents, and therefore contributed to the development of Parkinson's.
In this study, UCLA researchers tested a number of other pesticides and found 11 that also inhibit ALDH and increase the risk of Parkinson's, and at much lower levels than those at which they are currently being used, said study lead author Jeff Bronstein, a professor of neurology and director of movement disorders at UCLA.
Bronstein said the team also found that people with a common genetic variant of the ALDH2 gene are particularly sensitive to the effects of ALDH-inhibiting pesticides, and were two to six times more likely to develop Parkinson's than those without the variant when exposed to these pesticides.
The results of the epidemiological study appear Feb. 5, 2014 in the online issue of Neurology, the medical journal of the American Academy of Neurology.
“We were very surprised that so many pesticides inhibited ALDH and at quite low concentrations, concentrations that were way below what was needed for the pesticides to do their job,” Bronstein said. “These pesticides are pretty ubiquitous, and can be found on our food supply and are used in parks and golf courses and in pest control inside buildings and homes. So this significantly broadens the number of people at risk.”
The study compared 360 patients with Parkinson's in three agriculture heavy Central California counties to 816 people from the same area who did not have Parkinson's.
Researchers focused their analyses on individuals with ambient exposures to pesticides at work and at home, using information from the California Department of Pesticide Regulation.
In the previous PNAS study, Bronstein and his team determined the mechanism that leads to increased risk. Exposure to pesticides starts a cascade of cellular events, preventing ALDH from keeping a lid on DOPAL, a toxin that naturally occurs in the brain. When ALDH does not detoxify DOPAL sufficiently, it accumulates, damages neurons and increases an individual's risk of developing Parkinson's.
“ALDH inhibition appears to be an important mechanism by which these environmental toxins contribute to Parkinson's pathogenesis, especially in genetically vulnerable individuals,” said study author Beate Ritz, a professor of epidemiology at the Fielding School of Public Health at UCLA. “This suggests several potential interventions to reduce Parkinson's occurrence or to slow its progression.”
In this study, the research team developed a lab test to determine which pesticides inhibited ALDH. Then the researchers found that those participants in the epidemiologic study with a genetic variant in the ALDH gene were at increased risk of Parkinson's when exposed to these pesticides. Just having the variant alone, however, did not increase risk of the disease, Bronstein said.
“This report provides evidence for the relevance of ALDH inhibition in Parkinson's disease pathogenesis, identifies pesticides that should be avoided to reduce the risk of developing Parkinson's disease and suggests that therapies modulating ALDH enzyme activity or otherwise eliminating toxic aldehydes should be developed and tested to potentially reduce Parkinson's disease occurrence or slow its progression particularly for patients exposed to pesticides,” the study states.
The study was funded in part by the National Institute of Environmental Health Sciences (P01ES016732, R01ES010544, 5R21ES16446-2 and U54ES012078), the National Institute of Neurological Disorders and Stroke (NS038367), the Veterans Administration Healthcare System, the Michael J. Fox Foundation, the Levine Foundation, the Parkinson Alliance, the National Defense Science and Engineering Graduate Fellowship and the Ruth L. Kirschstein Institutional National Research Service Award in Molecular Toxicology (T32ES015457).
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