Environmental Factor, April 2011, National Institute of Environmental Health Sciences
Fry outlines a systems level approach to understanding arsenic
By Melissa Kerr
As her studies progress, Fry said she looks forward to "really digging down into the effects of early-life exposure to arsenic and long-term health consequences." (Photo courtesy of Steve McCaw)
Duke's ITEH Seminar Series of lectures are well attended by students and faculty with interest in environmental health issues. (Photo courtesy of Steve McCaw)
Arsenic has a worldwide reputation as a poison, but research has also shown it to be an effective treatment for cancer. During a seminar at Duke University Feb. 25, NIEHS grantee(http://tools.niehs.nih.gov/portfolio/index.cfm?action=portfolio.grantdetail&grant_number=R01ES019315) Rebecca Fry, Ph.D., explored both aspects of this chemical as part of the Integrated Toxicology and Environmental Health (ITEH) Seminar Series.
Fellow NIEHS grantee Ed Levin, Ph.D., welcomed Fry and hosted her presentation, "A Systems Level Approach to the Two Faces of Arsenic: Cancer Causation, Cancer Treatment." Fry is an assistant professor in the Environmental Sciences and Engineering department at the University of North Carolina at Chapel Hill (UNC-CH) and an NIEHS Outstanding New Environmental Scientist awardee. Levin is director of the Training Core of the Duke University Superfund Research Center.
The face of a medicine
Fry opened with a discussion of Trisenox, a clinical version of arsenic trioxide that has been successfully used to treat acute promyelocytic leukemia. This cancer affects blood and bone marrow and is caused by a gene created by a particular translocation of two chromosomes. Trisenox cleaves the gene, Fry explained, so that the cancer can be effectively treated. To identify novel mechanisms by which arsenic may influence tumor growth, Fry and her team examined data representing differential responses of 60 different tumor cell lines to arsenic trioxide. They found a striking range of responses, from a high level of sensitivity in leukemia cells to far more resistance in colon cancer cells.
In Fry's search for specific genes that underlie sensitivity of tumor cells to arsenic trioxide, she and her team found that the pathway of NRF2, a transcription factor involved in cell survival signals, had significantly higher expression within the arsenic-resistant cell lines. Through this association and subsequent laboratory testing, she established that by controlling NRF2 expression, "We can change a tumor cell that is resistant to arsenic trioxide to one that is sensitive to arsenic trioxide-induced killing."
The face of a poison
Fry also highlighted the second face of arsenic, that of a cancer causing agent. Inorganic arsenic is considered a Group 1 carcinogen by the International Agency for Research on Cancer. Chronic exposure results in cancer of the skin, bladder, and liver, among others. Although the U.S. Environmental Protection Agency (EPA) limit for arsenic is 10 parts per billion (ppb), Fry explained, "More than 40 million people in Southeast Asia alone are exposed to greater than 50 ppb, a level that dramatically increases cancer risk."
Another disturbing discovery was that exposure to arsenic prenatally increased the chance of acquiring cancer, even if the subject was not exposed chronically after birth. According to Fry, the nuclear factor-kappaB (NF-κB) pathway, a pathway that regulates inflammatory responses, is impaired in children prenatally exposed to the chemical.
Fry said that a major thrust of her research is to understand cellular mechanisms that control the gene expression change in that pathway. She cited evidence that arsenic is associated with epigenetic modifications in gene expression. To that end, she is looking at DNA methylation of cytosine (see text box).
Building on earlier studies in Thailand, Fry's current research follows people in the Zimapan Valley of Mexico who consume arsenic-contaminated water. Up to 34 percent of this population have arsenic-induced skin lesions, and arsenic levels there can reach as high as 1,000 ppb - 100 times the EPA and World Health Organization limits. Her team collaborates with UNC-CH biochemist Miroslav Styblo, Ph.D., also an NIEHS grantee(http://tools.niehs.nih.gov/portfolio/index.cfm?action=portfolio.grantdetail&grant_number=R01ES015326), to answer a central question: "If we look across the genome, can we find novel genes that are epigenetically altered and associated with arsenic exposure?"
Fry's results show that as the exposure to arsenic increased, the level of DNA methylation increased in 182 out of 183 candidate genes. Strikingly, the results show again the NF-κB pathway to be differentially methylated in adults with signs of arsenic poisoning. Her work establishes a new connection between the hypermethylation of several tumor suppressors and chronic arsenic poisoning or arsenicosis.
(Melissa Kerr studies chemistry at North Carolina Central University. She is currently an intern in the NIEHS Office of Communications and Public Liaison.)
Silencing tumor suppressor genes through DNA methylation
Fry's research probes the epigenetic consequences of arsenic exposure in human populations. Methyl groups, when attached to specific bases, result in a modification in gene expression. Fry has focused her attention on CpG (cytosine-phosphate-guanine) islands within the DNA. The methylation of CpG sites is associated with gene silencing.
"Gene members of the NF-κB pathway," Fry explained, "are enriched for differential methylation," highlighting epigenetic modification in people with signs of arsenic poisoning. Her group identified 17 tumor suppressor genes with increased hypermethylation in the subjects with arsenicosis.
Fry's research suggests that arsenic exposure leads to dramatic changes in epigenetic programming. "These changes could well link arsenic to increased mortality from lung cancer and liver cancer." Fry will continue to examine the role of these epigenetically altered sites as biomarkers of exposure and disease.