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Environmental Factor, April 2012

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Study suggests possible therapy for arsenic toxicity

By Angela Spivey

Habibul Ahsan, M.D.

The Environmental Factor has featured stories on studies led by Ahsan in the past — one on arsenic and risk of death in 2010 (see story) and another on arsenic and smoking in 2011 (see story). Pierce was a co-author on the first one and Graziano was a co-author on both. (Photo courtesy of Habibul Ahsan)

Brandon Pierce, Ph.D.

As a ONES awardee, Pierce will receive five years of new investigator support from NIEHS (see story). He and Ahsan have collaborated on a series of studies on arsenic in a Bangladesh cohort. (Photo courtesy of Brandon Pierce)

One of the first large-scale genomic studies conducted in a developing country suggests a possible route for preventing disease in people exposed to arsenic, by improving metabolism of the metal with nutrients or compounds that target a process called methylation. The study also showed that genetic differences may partially explain why some people exposed to arsenic get sick, while others exposed to the same levels do not.

The study, funded by NIEHS and the Superfund Research Program, identified small genetic variants that increase risk for skin lesions in people exposed to arsenic. The variants are found near the enzyme for metabolizing the chemical into a less toxic form, providing strong evidence that efficient metabolism of arsenic through methylation is protective.

The team was led by Habibul Ahsan, M.D., senior author of the study and Louis Block professor of epidemiology at The University of Chicago (UC). NIEHS Outstanding New Environmental Scientist (ONES) awardee Brandon Pierce, Ph.D., also of UC, was first author.

Understanding differences in host susceptibility

“Whatever the source of exposure, different individuals vary with respect to their susceptibility to the toxicity of arsenic,” said Ahsan. “Now that we understand the molecular basis of some of this disease risk, it is conceivable to think of incorporating this information into testing and evaluating, or potentially coming up with successful biomedical interventions."

“This current study shows if you're a better methylator, you're at a lower risk for disease," said co-author Joseph Graziano, Ph.D., professor of environmental health sciences and director of the Superfund Research Program at the Mailman School of Public Health at Columbia University.

Nutrition may be a protective factor

The findings open the possibility of interventions using compounds that boost methylation, such as folic acid, a strategy currently being tested by co-author Mary Gamble, Ph.D., associate professor of environmental health sciences at Columbia.

The researchers conducted the study with participation from almost 3,000 people in Bangladesh exposed to arsenic for decades through their drinking water. About half the country’s population has been accidentally exposed to arsenic, due to the installation of tube wells to tap groundwater sources in the 1970s.

An unbiased search of the genome

In this genome-wide association study, the researchers genotyped the participants to look for small genetic changes known as single nucleotide polymorphisms (SNPs). They identified several SNPs that were common among three groups of people — those with high levels of the most toxic arsenic metabolite, dimethylarsinic acid, people who had skin lesions, and people with reduced expression of the arsenic metabolizing enzyme.

The study also shows that such large-scale genomic studies are possible in a rural population of a developing country and, therefore, have potential for translational impact.

"Many genomic signals that we see are not robust enough or do not pertain to a large population," Ahsan said. "But, in this study, the finding is robust and the impact is massive." The study was published online Feb. 23 in PLoS Genetics.

Citation: Pierce BL, Kibriya MG, Tong L, Jasmine F, Argos M, Roy S, Paul-Brutus R, Rahaman R, Rakibuz-Zaman M, Parvez F, Ahmed A, Quasem I, Hore SK, Alam S, Islam T, Slavkovich V, Gamble MV, Yunus M, Rahman M, Baron JA, Graziano JH, Ahsan H. 2012. Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh. PLoS Genet 8(2):e1002522.

(Angela Spivey is a contract science writer for the NIEHS Superfund Research Program.)

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