Arsenite methyltransferase (AS3MT) polymorphisms and arsenic methylation in children in rural Bangladesh

Loma, Jessica De; Skröder, Helena; Raqib, Rubhana; Vahter, Marie; Broberg, Karin

doi:10.1016/j.taap.2018.08.020

Cited by 22 publications

(11 citation statements)

References 67 publications

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“…When the arsenic species levels were compared between groups according with their genotyping, As V and MMA V levels were significantly higher in the cases carriers of the As3MT gene variants, which suggests that the gene variants modify arsenic metabolism. Similar to our results, De Loma, Skroder, Raqib, Vahter, and Broberg (2018) evaluated the associations between As3MT polymorphisms and arsenic methylation efficiency and found higher %iAs and %MMA, and lower %DMA in urine, among rs1046778 TT carriers compared with CC carriers. Antonelli, Shao, Thomas, Sams, and Cowden (2014) concluded that their data support the hypothesis that As3MT polymorphisms alter in vivo metabolite concentrations.…”

Section: Discussionsupporting

confidence: 89%

Association between the polymorphism of three genes involved in the methylation and efflux of arsenic (As3MT, MRP1, and P‐gp) with lung cancer in a Mexican cohort

Recio-Vega

Hernandez-Gonzalez

Michel-Ramirez

et al. 2020

J of Applied Toxicology

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Lung cancer is the most common neoplasm and the primary cause‐related mortality in developed and in most of nondeveloped countries. Epidemiological studies have demonstrated that even at low arsenic doses, the lungs are one of the main target organs and that chronic arsenic exposure has been associated with an increase in lung cancer development. Among the risk factors for cancer, arsenic methylation efficiency (As3MT) and the clearance of arsenic from cells by two members of the ATP‐binding cassette (ABC) transporter family (multidrug resistance protein 1 [MRP1] and P‐glycoprotein [P‐gp]) play an important role in processing of arsenic and decreasing its intracellular levels. This study aimed to evaluate the association between chronic exposure to arsenic with polymorphism of three proteins involved in arsenic metabolism and efflux of the metalloid in subjects with lung cancer. Polymorphism in As3MT, MRP1, and P‐gp modified the arsenic metabolism increasing significantly the AsV urinary levels. A significant association between MRP1 polymorphisms with an increase in the risk for cancer was found. The high inorganic arsenic urinary levels registered in the studied subjects suggest a reduction in the efficiency of As3MT, MRP1, and P‐gp firstly because of gene polymorphisms and secondarily because of high internal inorganic arsenic levels. MRP1 polymorphism was associated with a twofold increase in the risk of lung cancer.

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Section: Discussionsupporting

confidence: 89%

Association between the polymorphism of three genes involved in the methylation and efflux of arsenic (As3MT, MRP1, and P‐gp) with lung cancer in a Mexican cohort

Recio-Vega

Hernandez-Gonzalez

Michel-Ramirez

et al. 2020

J of Applied Toxicology

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“…Genetic factors such as gene polymorphisms related to arsenic metabolism are used to determine arsenic concentrations in the human body (Chernoff et al, 2020). Arsenic methylation efficiency in children and adults is affected by AS3MT variation (Antonelli et al, 2014;De Loma et al, 2018). AS3MT is mainly expressed in human adrenal glands, liver, heart, kidney, and brain (Su et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Arsenite methyltransferase (AS3MT) catalyzes transfer of a methyl group from S-adenosyl-L-methionine (SAMe) to trivalent arsenic resulting in biomethylation of arsenic in vivo and in vitro, thus it plays a critical role in arsenic metabolism (Lin et al, 2002;Liu et al, 2020). AS3MT (previously called CYT19) gene variation affects arsenic methylation activity in children and adults (Antonelli et al, 2014;De Loma et al, 2018). AS3MT gene is associated with various diseases including Borst-Jadassohn intraepidermal carcinoma of dermal system, liver injury, schizophrenia, and attention deficit or hyperactivity disorder (Li et al, 2016;Zhao et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

AS3MT Polymorphism: A Risk Factor for Epilepsy Susceptibility and Adverse Drug Reactions to Valproic Acid and Oxcarbazepine Treatment in Children From South China

Fan

Chen

et al. 2021

Front. Neurosci.

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Epilepsy is a common neurologic disorder characterized by intractable seizures, involving genetic factors. There is a need to develop reliable genetic markers to predict the risk of epilepsy and design effective therapies. Arsenite methyltransferase (AS3MT) catalyzes the biomethylation of arsenic and hence regulates arsenic metabolism. AS3MT variation has been linked to the progression of various diseases including schizophrenia and attention deficit or hyperactivity disorder. Whether genetic polymorphism of AS3MT contributes to epilepsy remains unclear. In this study, we investigated the association of AS3MT gene polymorphism with susceptibility to epilepsy in children from south China. We also explored the effect of AS3MT variation on the safety of antiepileptic drugs. Genotypic analysis for AS3MT rs7085104 was performed using samples from a Chinese cohort of 200 epileptic children and 244 healthy individuals. The results revealed a genetic association of AS3MT rs7085104 with susceptibility to pediatric epilepsy. Mutant homozygous GG genotype exhibited a lower susceptibility to childhood epilepsy than AA genotype. Carriers of AS3MT rs7085104 AA genotype exhibited a higher risk of digestive adverse drug reactions (dADRs) in children when treated with valproic acid (VPA) or oxcarbazepine (OXC). Additionally, bioinformatics analysis identified eight AS3MT target genes related to epilepsy and three AS3MT-associated genes in VPA-related dADRs. The effects of AS3MT on epilepsy might involve multiple targets including CNNM2, CACNB2, TRIM26, MTHFR, GSTM1, CYP17A1, NT5C2, and YBX3. This study reveals that AS3MT may be a new gene contributing to epileptogenesis. Hence, analysis of AS3MT polymorphisms will help to evaluate susceptibility to pediatric epilepsy and drug safety.

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“…Author details 1 Yunnan Center for Disease Control and Prevention, Kunming, China. 2 School of Public Health, Southwest University, Nanjing, China, 3 School of Public Health, Kunming Medical University, Kunming,China.…”

Section: Ethics Approval and Consent To Participatementioning

confidence: 99%

“…Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in the methylation metabolism of arsenic (1)(2)(3). It promotes methyl transfer to form methyl arsenate and dimethyl arsenate, which play an important role in the formation and development of toxicity (4).…”

Section: Introductionmentioning

confidence: 99%

The Novel Role of Arsenic (+3 oxidation state) Methyltransferase in Arsenic Genotoxicity

Sun¹,

Cheng

et al. 2021

Preprint

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Background: Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in methylation metabolism of arsenic. It is closely related to DNA methylation, but little is known about the novel molecular mechanisms.Methods: 79 workers and 41 individuals in the control group were recruited. Arsenic, relative indexes, 28 relative RNAs, and base modifications of exon 5-8 of p53 were detected. Enzyme linked immunosorbent assay(ELISA) was performed to detect the expression of AS3MT protein in all subjects. A series of methods were used to analyze the relationships between them. The AS3MT protein was detected in A549 and 16HBE cells after treated using sodium arsenite, MMA and DMA for 48 hours. Small interfering RNA (siRNA) transfection was used to investigate the role of AS3MT in arsenite-induced tumorigenesis. The cell proliferation and apoptosis were assessed with MTT assay, EdU assay, HO/PI double staining and JC-1 assay. The real-time quantitative PCR (qRT-PCR) and Western Blot analyses were used to evaluate the expression of genes. The p53 luciferase reporter gene assay and Co-immunoprecipitation (Co-IP) were used to identify the interactions of target proteins.Results: AS3MT RNA is closely related to p53, a series of ncRNAs and mRNAs, and likely to have causal correlations. Base modifications of p53, miR-548 and miR-190 have significant distinctive effects, but arsenic may play limited roles. AS3MT is over expression in lung cancer patients who have not exposed to arsenic, human lung adenocarcinoma and bronchial epithelial cells with arsenic treatment for 48h. AS3MT protein is induced in arsenic exposed population. Down regulation of AS3MT inhibit proliferation and promotes apoptosis of cells. Mechanistically, AS3MT specifically bind with c-Fos, and block the binding ability between c-Fos and c-Jun. Additionally, knockdown of AS3MT mediated by siRNA enhance the phosphorylation level of p53 Ser392 through activating p38 MAPK. These probably lead to activation of p53 signaling and up regulation in downstream targets, such as p21, Fas, Puma and Bax.Discussion: Here showed that AS3MT RNA plays a great role in the genotoxicity and carcinogenesis which started by arsenic, but influenced by other factors. Up regulation of AS3MT can directly act on cell, and affect cell proliferation and apoptosis through activation of p53 signaling and up regulation in downstream targets.

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Arsenite methyltransferase (AS3MT) polymorphisms and arsenic methylation in children in rural Bangladesh

Cited by 22 publications

References 67 publications

Association between the polymorphism of three genes involved in the methylation and efflux of arsenic (As3MT, MRP1, and P‐gp) with lung cancer in a Mexican cohort

Association between the polymorphism of three genes involved in the methylation and efflux of arsenic (As3MT, MRP1, and P‐gp) with lung cancer in a Mexican cohort

AS3MT Polymorphism: A Risk Factor for Epilepsy Susceptibility and Adverse Drug Reactions to Valproic Acid and Oxcarbazepine Treatment in Children From South China

The Novel Role of Arsenic (+3 oxidation state) Methyltransferase in Arsenic Genotoxicity

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