Polymorphisms of the AS3MT gene are associated with arsenic methylation capacity and damage to the P21 gene in arsenic trioxide plant workers

Abstract

Epidemiological evidence suggests that the metabolic profiles of each individual exposed to arsenic (As) are related to the risk of cancer, coronary heart disease, and diabetes. The arsenite methyltransferase ( AS3MT) gene plays a key role in As metabolism. Several single nucleotide polymorphisms in the AS3MT gene may affect both enzyme activity and gene transcription. AS3MT polymorphisms are associated with the proportions of monomethylarsenic acid (MMA) and dimethylarsenic acid (DMA) in urine as well as the incidence of cancer. P21 protein is a cyclin-dependent kinase inhibitor. Mutations of the P21 gene have been found in cancer patients. In our study, we investigate whether polymorphisms of the AS3MT gene alter As methylation capacity and adversely affect the P21 gene in arsenic trioxide plant workers. The DNA damage was examined by the quantitative polymerase chain reaction. Restriction fragment length polymorphism was used to analyze the genotype of the AS3MT gene. The results showed that DNA damage in P21 gene fragments was greater in those individuals exposed to high levels of As. There was a strong positive correlation between the DNA damage to P21 gene fragments and the percentage of MMA in urine. However, DNA damage in P21 gene fragments was negatively associated with the percentage of DMA in urine (%uDMA), primary methylation index (PMI), and secondary methylation index. We found that subjects with the rs7085104 GG or GA allele were associated with higher %uDMA and PMI and less DNA damage. The subjects with the rs11191454 GG+GA or GA allele were also associated with higher %uDMA and PMI and less DNA damage. Our results suggest that rs1191454 and rs7085104 in the AS3MT gene affect the As-induced DNA damage by altering individual metabolic efficiency.

Metabolic Changes and Their Associations with Selected Nutrients Intake in the Group of Workers Exposed to Arsenic

“…In addition, in various nontumorigenic cell lines, treatment with N-acetyl-D-glucosamine for 3 days resulted in genome instability [ 35 ]. In a study by Ni et al [ 36 ] on a group of workers exposed to iAs, DNA damage to the P21 gene fragments was observed, which was associated with the reduced methylation of iAs (positively associated with the percentage of MMA and negatively with the percentage of DMA in the urine). The results of the aforementioned study indicated that iAs exposure is associated with an increase in N-acetyl-D-glucosamine signal intensity.…”

Arsenic Methyltransferase and Apolipoprotein E Polymorphism in Pregnant Women Exposed to Inorganic Arsenic in Drinking Water in Western Romania

“…Inorganic As metabolism can be influenced by genetic differences, which may predispose individuals to adverse health outcomes related to iAs exposure [ 12 ]. Previous studies have shown that polymorphisms in the AS3MT gene may be associated with reduced gene expression and enzymatic activity, which were correlated with urinary MMA and DMA levels [ 13 ]. Other studies reported that single-nucleotide polymorphisms (SNPs) in the AS3MT gene were related to iAs exposure in drinking water and were associated with lower percentages of MMA and higher percentages of DMA in urine [ 14 , 15 , 16 ].…”