# Arsenic: A Review on a Great Health Issue Worldwide
## 7 Arsenic Epigenetic Modifications  
Exposure to heavy metals (Cd, Cr, Hg, Fe, Ni, Pb, and TI) and metalloids (like As) is correlated with a risk of skin, lung, liver, urinary tract, prostate, and hematopoietic cancers [59; 60; 61; 62]. Chromosomal instability and epigenetic modifications may also play important roles in the arsenic carcinogenicity. Epigenetics refer to inherited changes in gene expression not involving a change in the nucleotide sequence of DNA. Epigenetics may be conditioned by different environmental factors and their dysregulation is involved in many diseases [63]. Eukaryotic DNA is packaged in the form of chromatin with the nucleosomes as a basic repeating unit. Each nucleosome consists of 147 DNA base pairs wrapped around histones H2A, H2B, H3, and H4 that aggregate each other forming the histone octamer. The N-terminal end of these histones may undergo a variety of post-translational modifications promoted by specific enzymes with acetylation and deacetylation, methylation and demethylation, phosphorylation, citrulination, sumoylation, biotinylation, and ubiquitination processes. These covalent reactions influence the chromatin structure facilitating gene transcription [64; 65] or its inhibition [66]. Histone acetylation modification is regulated by two classes of enzymes: histone acetyl-transferase and histone deacetylase. In this modification reaction, in the presence of acetyl coenzyme A, an acetyl group is transferred on lysine amino acid residue which loses its ability to bind the DNA phosphate groups. [PERSON] et al. (2009) [67] showed that exposure to MMA(III) and As(III) in human bladder cells reduced histone 4 lysine 16 (H4K16) acetylation suggesting that chronic arsenic exposure could contribute to bladder cancer. Lysine or arginine on N-terminal end of H3 and H4 may undergo a methyl reversible modification. [PERSON] et al. (2008, 2009) [68; 69] published that arsenite (As III) can act on histone modification modulating the methylation of H3. These authors showed that human lung carcinoma A549 cells exposed to As(III) increased H3K9 demethylation (H3K9 me2) and decreased H3K27 trimethylation (H3K27 me3). In addition, microRNAs (miRNAs) act on epigenetic mechanisms. These small non-coding molecules (20-25 nucleotides in length) are implicated in the post-transcriptional regulation of protein expression by binding to a complementary region on target RNA silencing their  
Figure 2: Effect of arsenic on pyruvate dehydrogenase complex. Arsenic and organic arsenicals form an adduct with the two -SH groups of dihydroplioamide that alter the function of dihydroplioyl dehydrogenase affecting the respiratory chain and the oxidative phosphorylation (E\({}_{1}\): pyruvate decarboxylase; E\({}_{2}\): dihydroplioyl transacetylase; E\({}_{3}\): dihydroplioyl dehydrogenase. TPP: thiamine pyro phosphate; FAD: flavin adenine dinucleotide; FADH\({}_{2}\): reduced FAD; NAD\({}^{+}\): nicotinamide adenine dinucleotide; NADH: reduced NAD\({}^{+}\); CoASH: Coenzyme A). This figure is an elaboration based on information retrieved from ref. [54; 55]. translation. MiRNAs are transcribed within the nucleus from DNA but not translated in proteins [70]. A majority of research on arsenic-induced miRNA expression changes have been conducted in vitro using human bladder carcinoma (T24) and human liver carcinoma (Hep-G2) cell lines. Hep-G2 cells treated for 24 h in the of 4 uM arsenic trioxide (As\({}_{2}\)O\({}_{3}\)) showed upregulation of miR-24, miR-29a, miR-30a, and miR-210. Among these four miRNAs, miR-29a had a positive effect in liver cancer therapy by inhibiting cells growth and inducing apoptosis [71]. [PERSON] et al. (2018) [72] investigated the effects of arsenic exposure (inorganic arsenic, monomethyl arsenic acid, and dimethyl arsenic acid detected in urine) on the expression of AS3 MT (arsenite methyltransferase), 3 miRNA, and 17 relative mRNA in 43 workers producing arsenic trioxide.