Arsenic more toxic for specific gene variation

By Biplab Das
Published: Thursday 15 March 2007

people with a specific variation in a gene who are exposed to arsenic have greater risk of getting skin lesions and hyperkeratosis, a precursor to skin cancer, say researchers from Kolkata. The gene, called ercc2 (excision repair cross-complementing rodent repair deficiency, complementation group 2), repairs any damage to dna. The findings of the study will be published in the forthcoming issue of Carcinogenesis.

"We found contaminated groundwater to be the principal source of arsenic exposure," says Ashok Kumar Giri of the Indian Institute of Chemical Biology, the lead researcher. "The study will help screen individuals who run the risk of developing cancer for being exposed to high levels of arsenic through contaminated drinking water," he says.

For the study, Giri and his team selected 318 people from Nadia, North 24-Parganas and Murshidabad districts who were exposed to high levels of arsenic--55-625 parts per billion (ppb). The safe limit prescribed by who is 10 ppb. Of the 318 subjects, 165 suffered from hyperkeratosis and the rest had no arsenic-induced skin lesions. Arsenic is a carcinogen and genotoxic chemical, which leaves damaging effects on dna. Normally, cells too fight back by turning on genes and producing proteins that help repair any damage to dna. ercc2 is one such gene.

When blood samples of arsenic-exposed subjects were tested, the research team found a specific genetic variation known as snp, or single nucleotide polymorphism--a change in a single base of the ercc2 gene among individuals who had hyperkeratosis. "This specific variation in the ercc2 gene results in amino acid substitution from lysine to glutamine, giving rise to a ercc2 protein (in arsenic-exposed people having Lys/Lys genotype) with reduced ability to repair arsenic-induced dna damage," explains Giri. It was also found that the ercc2 gene with snp variation is more common in individuals with hyperkeratosis. In another study, the researchers had linked a specific snp in a gene called p53 to increased risk of arsenic-induced keratosis. "p53 can pause cell cycle allowing dna repair," say Susanta Roychoudhuri, co-researcher. The study was published in the journal Mutation Research (Vol 601, No 1-2).

Both the studies raise the possibility of genetic screening for arsenic-exposed people. But according to Giri, "Our study reveals that it is far from being a simple blood test as detection of gene structure requires a lot of sophisticated techniques." Primarily, the results of both the studies obtained are only an indication. "Our results, however, do indicate that people with the particular genetic composition are at a higher risk than those without it. Our objective is to find out what makes a person vulnerable to arsenic toxicity," says Giri.
Present study not enough The exact mechanism of arsenic toxicity, however, still remains unravelled. "Studies such as ours and a conglomeration of such studies, in course of time, will provide clues to unearthing the mechanism of arsenic toxicity in great depth so that we can think of devising ways to combat arsenic-induced toxicity," says Giri. According to him, this technology can be used in a similar way to find out which other genes and snps might be associated with arsenic susceptibility. "As the primary prerequisite to combat any disease is to understand how it works, there is a lot of scope in this type of study and investments in this direction should be profitable."

According to Pradip Sikdar from Kolkata's Indian Institute of Social Welfare and Business Management, "This study will help arsenic researchers to better understand how varying levels of arsenic wreak havoc on exposed people in tropical countries where people drink more water." Sikdar who has earlier worked on sources of arsenic, feels that the three areas of research--source of arsenic contamination, arsenic removal technology and arsenic-induced toxicity due to arsenic exposure--complement each other and are important."Such studies will help researchers to rethink the permissible levels of arsenic in developing countries and deal with debated sources of arsenic contamination with better arsenic removal technology. The present study on arsenic-induced toxicity will not shift the focus from source of arsenic which is still debated upon," adds Sikdar.

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