**9. Genotoxicity of arsenic**

Several studies have documented the elevated inter individual variability in receptiveness of arsenic toxicity underlying genetic factor as a cause of variability. The genotoxicity of arsenic cause deoxyribonucleic acid modification such as chromosomal aberrations, mutation, micronuclei formation, deletion, sister chromatid exchange [68]. Numerous studies have been done to explain the genotoxic effect of arsenic, over and above stimulation of oxidative stress and distorted DNA repair [69]. For the purpose of understanding several studies confirmed the manipulation of genetic polymorphism in gene coding enzymes involved in mechanism of arsenic metabolism and detoxification [70]. It has been demonstrated that arsenic does not affect DNA directly and is considered a poor mutagen, as regardless of its low mutagenicity it affects the mutagenicity of other carcinogens. For illustration, an elevated increase in mutagenicity of arsenic with ultraviolet light has been observed in mammalian cells [71]. Progression of experimentation proposed that arsenic genotoxicity is associated with the generation of reactive oxygen species during its biotransformation [68]. The generation of reactive oxygen species is able to break DNA strands, cross links and chromosomal aberration [72]. One of the mechanisms of arsenic destroys to DNA is base adjustment in particular 8-oxoguanine is one of the most frequently formed DNA nuclease modifications which are a mutagenic miscoding lesion that lead to G: C to T: A transverse [73].

Moreover arsenic can induce DNA strand breaks even at low concentration [70], as single strand breaks are caused by reactive oxygen species on DNA base directly or indirectly during base excision repair mechanism [74]. As it was observed that human fibroblast cells demonstrate single strand break and chromatid substitute interfering with polyadenosinediphosphate ribose polymerase activity which is a protein important for single strand DNA break and double strand DNA break repair process (**Figure 2**) [75]. Recent studies revealed that chronic arsenic exposure induces oxidative DNA damage, reduced thymic functions and subsequent immunosuppression in childhood [76]. Arsenic is well known inducer of chromosomal aberration which involves both clastogenic and a euploidogenic [77]. Recent studies documented cytogenetic monitoring by using chromosomal aberration and micronuclei assay in order to observe genotoxic effects of arsenic in human and animal population [78]. Inhibition of DNA repair is considered one of the most important effects of genotoxicity of arsenic. Nucleotide excision repair and base excision repair are the two process of DNA repair which are inhibited by reactive oxygen species of arsenic [79]. Earlier studies revealed that arsenic exposure may hinder the nucleotide excision repair mechanism of DNA repair but in recent studies it is observed that it also inhibit the base excision repair mechanism (**Figure 2**) [80]. Changes in DNA repair mechanisms have been confirmed in human exposed population, as arsenic exposure was linked with reduced expression of excision repair to at low dose. They have found that arsenic metabolites can affect several processes in the cell [81–83]. Particularly cellular activity of human 8-oxoguanine DNA glycosylase was the most sensitively affected by dimethylmonoarsenic acid [80]. Recently, epidemiological studies revealed that arsenic may affect single nucleotide polymorphism in genes of DNA repair pathways [84]. Arsenic causes DNA damage and changes cellular capacity for DNA repair. Consequently alterations in DNA repair capacity is associated to the presence of polymorphisms in DNA repair genes which are related to risk of developing disturbance induced by arsenic [85].
