Cellular mechanism of arsenic toxicity
A number of epidemiological studies have found that persistent exposure of Arsenic to the human population can lead to different types of cancers including that of bladder, lung, skin, liver, and kidney. Even though the mechanism of action of Arsenic toxicity is not well understood, oxidative stress caused by Arsenic exposure is predicted to be a contributing factor.
The levels of Reactive oxygen species (ROS) play a key role in normal cell signaling and its alteration can result in aberrant expression of genes that are activated by redox mechanisms.
Notably, genes associated with redox mechanisms include those regulating cellular proliferation, differentiation, and apoptosis. ROS generation can also influence cell proliferation by deregulating the expression of cell cycle proteins like NF-kB, c-Myc, and HO-1. Arsenite can lead to caspase activation and cell cycle alteration in MCF-7 cells thereby inducing apoptosis. The consequences of ROS production can further lead to DNA damage which typically involves the conversion of 2-deoxyguanine to 8-hydroxyl-2-deoxyguanine (8-OHdG) and has been used as a marker of DNA oxidative stress. Therefore increased production of ROS can lead to the development of tumors and cancerous processes.
In humans, arsenic is known to target the liver and its exposure can cause the development of liver lesions, fatty infiltration, and hepato-cellular carcinomas. Hepato-cellular lesions including neoplasia were reported in mice after repeated injections of Arsenate. In addition to this, organic arsenic exposure to pregnant mice caused high occurrence of hepatocellular carcinomas in adult offspring. Therefore we can say that Arsenic has the potential to induce liver carcinogenesis in both human and non-human species.
In mammalian liver, Arsenic methylation by an incompletely characterized methyltransferase using S adenosylmethionine (SAM) as a methyl donor to MMA and DMA occurs at a high level. This can lead to depletion of SAM in normal cellular reactions. SAM is a global methyl donor, required for DNA methylations and its depletion can lead to hypomethylation of DNA resulting in alteration of gene expression like c myc, c met, cyclin D1 and induction of carcinogenesis.
DNA methylation is an epigenetic modification that plays an important role in controlling the expression of various genes. Methylation generally occurs at cytosine residues located in symmetrical CpG nucleotide sequences and its alteration, both in the global and regional levels has been associated with oncogenesis. Methylation of CpG islands in the promoter region