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Prenatal Exposure Can Influence Gene Regulation and Later-Life Events

By Dixie Ann Sawin
November 2009

Rebecca Fry, Ph.D.
Fry said that the isolation of a discrete gene set to identify arsenic exposure "lays a foundation for a time when exposures to different drugs or toxicants can be measured from a droplet of a person's blood using specific biomarkers or gene signatures."
(Photo courtesy of Steve McCaw)

There was good turnout of people from throughout the Institute eager to hear about Fry's work in Thailand and Mexico.
There was good turnout of people from throughout the Institute eager to hear about Fry's work in Thailand and Mexico. (Photo courtesy of Steve McCaw)

Dan Shaughnessy, Ph.D.
The NIEHS extramural program was well represented at the talk by such people as Health Science Administrator Dan Shaughnessy, Ph.D., above, and colleagues from DERT. (Photo courtesy of Steve McCaw)

Kevin Gerrish, Ph.D.
Several scientists from the NIEHS intramural program and National Toxicology Program were on hand as well, including Staff Scientist Elena Braithwaite, Ph.D., above, of the Comparative Genomics Group, and Microarray Group Technical Laboratory Manager Kevin Gerrish, Ph.D. (Photo courtesy of Steve McCaw)

On October 14, Rebecca Fry, Ph.D., of the University of North Carolina at Chapel Hill (UNC-CH), presented the second in a series of talks sponsored by the NIEHS Division of Extramural Research and Training (DERT). Hosted by DERT Program Analyst Astrid Haugen, Fry's talk addressed the "Identification of Genetic and Epigenetic Biomarkers of Metal Exposure and Metal-Induced Disease Using Environmental Toxicogenomics and Systems Biology."

In her research, Fry (http://www.sph.unc.edu/?option=com_profiles&Itemid=1892&profileAction=ProfDetail&pid=714233563)Exit NIEHS seeks to characterize genome-wide effects of exposures to arsenic (As), identify specific proteins that could serve as biomarkers of exposure and determine whether prenatal exposure can trigger epigenetic reprogramming in humans. Her current research and earlier work in the same area are supported by NIEHS grants.

Fry began her talk by stressing, "We are continuously exposed to potentially harmful agents in the environment through the food we eat, the water we drink, the air we breathe, but even if we had identical exposures, the responses across individuals would be different." These responses, she continued, are due to "complex gene-environment interactions from the various exposures, our genetic susceptibility, and the age and time at which we are exposed."

Arsenic is a ubiquitous environmental pollutant and known carcinogen, and chronic exposure can lead to cancers, skin bladders and lesions, and death. Worldwide, some 40 million people are exposed to levels of As at least five-fold greater than the allowable limit of 10 parts per billion (ppb) set by the World Health Organization in 1994. Health problems associated with As are most prevalent in developing countries, but there are also many places in the U.S. where the As levels exceed 10 ppb.

Fry highlighted two study populations with high rates of arsenic poisoning or arsenocosis - Ron Pibul, Thailand (see related story(http://www.niehs.nih.gov/news/newsletter/2008/january/changes.cfm)) and Zimapan, Mexico. Due to intensive tin mining in Ron Pibul, the levels of As were as much as 100 times greater than the WHO limit. Analyzing samples from mothers and infants, Fry and her colleagues at MIT and in Thailand identified 170 genes that were associated with As exposure in newborns. Using computational algorithms designed for identifying candidate gene signatures in response to As exposure, the researchers minimized the number of genes required for the analysis to 11 genes that showed 83 percent accuracy in predicting prenatal arsenic exposure.

As part of her research in both populations, Fry is striving to determine how exposure to As impacts the genome and to establish which biological pathways are affected in individuals with arsenocosis. She found that prenatal As exposure is significantly associated with an inflammatory response involving tumor necrosis factor alpha (TNFα) and the inflammation-associated nuclear factor kappa beta (NFkB) pathway. Stress response, cell adhesion, apoptotic, lipid metabolism, signal transduction and transcription pathways were also modulated in response to As exposure.

To answer whether epigenetic changes underlie disease, Fry looked at DNA methylation status in adults with arsenicosis. DNA methylation occurs at cytosine/guanine sites (CpG) across the genome and represents possible heritable changes in methylation. Alterations in methylation are associated with cancer development and exposures to environmental toxicants such as As.

Using a state-of-the-art deep sequencing approach, Fry identified genes that show deregulated DNA methylation. Genes in individuals from the Zimapan population with high-level exposure to As from mining - 21 to 1,000 ppb - showed increased hypomethylation, which may lead to increased gene transcription, and were also associated with the NFkB pathway.

As Fry noted, much more data on the effects of exposure over longer periods will be required to adequately prove the epigenetic effects of prenatal exposures. Her long-term objective is to be able to establish the role of epigenetic alterations that may link prenatal exposure to environmental contaminants with detrimental human health effects.

(Dixie-Ann Sawin, Ph.D., is a post-doctoral research fellow in the NIEHS Laboratory of Neurobiology Neurotoxicology Group on detail as a writer for the Environmental Factor.)



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