News

Blame it on bad repairs

Biplab Das

doi:10.1038/nindia.2008.184 Published online 17 April 2008

Ashok Kumar Giri (left sitting) with fellow researchers.

Why don't some people show any signs of arsenic-induced toxicity despite drinking water laced with the deadly element while some others develop excessive horn-like growths (hyperkeratosis) on skin? The answer, as it appears now, lies in their genes.

A research team from Kolkata has discovered that people with a faulty DNA repair system develop hyperkeratosis when exposed to arsenic. This means their DNA can't protect itself from the onslaught of reactive oxygen species (ROS) that results from arsenic getting into the system and its subsequent metabolism. This triggers a cascade of events leading to the development of arsenic-induced skin lesions.

In India and neighbouring Bangladesh, more than 100 million people are at risk of arsenic poisoning. In nine districts of West Bengal, about 6 million people are exposed to arsenic, of whom only 15 - 20 per cent exhibit arsenic-induced skin lesions. This has long intrigued scientists. They have suspected the role of genes in individual susceptibility to arsenic toxicity.

Once ingested, arsenic is converted in the liver into a methylated form that is excreted via the urine. The researchers say that arsenic and its methylated metabolites generate ROS, which inflict damage on DNA. In previous studies, the Kolkata team found chromosomal aberrations like breaks, deletions and exchanges in chromosomes of peripheral blood lymphocytes among such arsenic-exposed people.

However, what makes a person vulnerable to arsenic-induced skin lesions and subsequent risk of cancer remained a matter of conjecture. To find out what really happens, the researchers selected 60 arsenic exposed people from Murshidabad, a severely arsenic affected district of West Bengal. Of them, 30 had arsenic-induced pre-malignant hyperkeratosis and thirty without any arsenic-induced skin lesion. None of them had skin cancer.

The exposed people had been drinking arsenic-contaminated water for ten years or more and were matched with unexposed subjects aged between 15-70 years from East Midnapur district. Water and other biological samples such as blood, urine, nail and hair were collected from all the participants. Individuals without skin lesions drank water with mean arsenic content of 205.04 parts per billion (ppb) and people with skin lesions drank water containing 224.10 ppb arsenic, which was not significantly different.

The study found that within the exposed group, people with precancerous hyperkeratosis had significantly higher incidence of chromosomal aberrations (CA) than those without skin lesions. It has long been known that DNA damage results in CA. The researchers suspected that faulty DNA repair system might play a role in DNA damage that might result in high incidence of CA among people with skin lesions.

To study the status of DNA repair system, the researchers collected blood samples from 24 exposed people (12 with skin lesions and 12 without skin lesions) and the blood cells were irradiated with gamma rays. The treated cells were allowed to undergo repair for one hour, enough to detect DNA repair efficiency.

"The study showed that individuals with hyperkeratosis had lower capacity to repair DNA damage," says lead researcher Ashok Kumar Giri, Deputy Director of the molecular and human genetics division of Indian Institute of Chemical Biology.

The main finding of the study is that DNA repair deficiency plays an important role in susceptibility to develop arsenic-induced premalignant skin lesions, the precursor to skin cancer, Giri says.

In a previous study, Giri and his colleagues found that a specific variation in ERCC2 gene (excision repair cross-complementing rodent repair deficiency, complementation group 2, which normally repairs DNA damage) leads to reduced ability to repair arsenic-induced DNA damage. Reduced ERCC2 activity might certainly be one of the several factors that ultimately cause hyperkeratosis in exposed population, he adds.


References

  1. Banerjee, M. et al. DNA Repair Deficiency Leads to Susceptibility to Develop Arsenic-induced Premalignant Skin Lesions. Int. J. Cancer. (2008) AOP. Article
  2. Banerjee, M. et al. Polymorphism in the ERCC2 codon 751 is associated with arsenic-induced premalignant hyperkeratosis and significant chromosome aberrations. Carcinogenesis 28, 672-676 (2007)