Chronic arsenic exposure is known to produce arsenicosis and cancer. To ascertain whether perturbation of methylation plays a role in such carcinogenesis, the degree of methylation of p53 and p16 gene in DNA obtained from blood samples of people chronically exposed to arsenic and skin cancer subjects was studied. Methylation-specific restriction endonuclease digestion followed by polymerase chain reaction (PCR) of gene p53 and bisulfite treatment followed by methylation-sensitive PCR of gene p16 have been carried out to analyze the methylation status of the samples studied. Significant DNA hypermethylation of promoter region of p53 gene was observed in DNA of arsenic-exposed people compared to control subjects. This hypermethylation showed a dose-response relationship. Further, hypermethylation of p53 gene was also observed in arsenic-induced skin cancer patients compared to subjects having skin cancer unrelated to arsenic, though not at significant level. However, a small subgroup of cases showed hypomethylation with high arsenic exposure. Significant hypermethylation of gene p16 was also observed in cases of arsenicosis exposed to high level of arsenic. In man, arsenic has the ability to alter DNA methylation patterns in gene p53 and p16, which are important in carcinogenesis.
Chronic arsenicosis, a major public health concern in India and Bangladesh, is mainly caused by ingestion of arsenic (As) contaminated ground water. Although this problem has been studied extensively, the mechanism of toxicity remains unknown. This paper investigates the process of trivalent arsenicals binding to hemoglobin (Hb) in chronic arsenicosis patients and consequent modification in the structure-function activity of Hb. In this work peroxidase activity, thermal denaturation profile, oxygen releasing capacity and hydrodynamic diameter have been evaluated for the Hb collected from subjects suffering with chronic arsenicosis. Increased peroxidative activity suggests altered oxidative status of Hb in the diseased state. The thermal denaturation profile indicates the Hb molecule to be more susceptible to unfolding in the pathologic state. The enhanced oxygen releasing capacity and significant reduction in hydrodynamic diameter of Hb is also observed in the diseased condition, suggesting conformational alterations in the Hb molecule. Finally, trivalent arsenic is found to bind with freshly isolated Hb from arsenicosis patients, binding affinity constant being 0.256 μM⁻¹. The binding is positively cooperative with a Hill coefficient of +2.961 and isosbestic points at specific wavelengths. Thus, our work explores the structure-function property of Hb in chronic arsenicosis subjects and reveals that the molecule is modified in such a way that comparatively weak binding with oxygen and strong binding with arsenic occur simultaneously. This association may play a crucial role in exerting the pathway for arsenic toxicity.
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