Das Ankita, Sanyal Tamalika, Bhattacharjee Pritha, Bhattacharjee Pritha
Department of Environmental Science, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, West Bengal, India.
Department of Environmental Science, University of Calcutta and Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, West Bengal, India.
Environ Res. 2021 Jul;198:111184. doi: 10.1016/j.envres.2021.111184. Epub 2021 Apr 22.
Methylation of arsenic compounds in the human body occurs following a series of biochemical reactions in the presence of methyl donor S-adenosylmethionine (SAM) and catalyzed by arsenite methyltransferase (AS3MT). However, the extent and pattern of methylation differs among the arsenic exposed individuals leading to differential susceptibility. The mechanism for such inter-individual difference is enigmatic. In the present case-control study we recruited exposed individuals with and without arsenic induced skin lesion (WSL and WOSL), and an unexposed cohort, each having 120 individuals. Using ELISA, we observed a reduction in SAM levels (p < 0.05) in WSL compared to WOSL. Linear regression analysis revealed a negative correlation between urinary arsenic concentration and SAM concentration between the study groups. qRT-PCR revealed a significant down-regulation (p < 0.01) of key regulatory genes like MTHFR, MTR, MAT2A and MAT2B of SAM biogenesis pathway in WSL cohort. Methylation-specific PCR revealed significant promoter hypermethylation of AS3MT (WSL vs. WOSL: p < 0.01) which resulted in its subsequent transcriptional repression (WSL vs. WOSL: p < 0.001). Linear regression analysis also showed a negative correlation between SAM concentration and percentage of promoter methylation. Taken together, these results indicate that reduction in SAM biogenesis along with a higher utilization of SAM results in a decreased availability of methyl donor. These along with epigenetic down-regulation of AS3MT may be responsible for higher susceptibility in arsenic exposed individuals.
人体内砷化合物的甲基化发生在甲基供体S-腺苷甲硫氨酸（SAM）存在的一系列生化反应过程中，并由亚砷酸盐甲基转移酶（AS3MT）催化。然而，甲基化的程度和模式在砷暴露个体之间存在差异，导致易感性不同。这种个体间差异的机制尚不清楚。在本病例对照研究中，我们招募了有和没有砷诱导皮肤病变的暴露个体（有皮肤病变组和无皮肤病变组），以及一个未暴露队列，每组各有120人。使用酶联免疫吸附测定法（ELISA），我们观察到有皮肤病变组的SAM水平相比无皮肤病变组有所降低（p < 0.05）。线性回归分析显示，研究组之间尿砷浓度与SAM浓度呈负相关。定量逆转录聚合酶链反应（qRT-PCR）显示，有皮肤病变队列中SAM生物合成途径的关键调控基因如亚甲基四氢叶酸还原酶（MTHFR）、甲硫氨酸合成酶（MTR）、蛋氨酸腺苷转移酶2A（MAT2A）和蛋氨酸腺苷转移酶2B（MAT2B）显著下调（p < 0.01）。甲基化特异性PCR显示AS3MT启动子显著高甲基化（有皮肤病变组与无皮肤病变组比较：p < 0.01），这导致其随后的转录抑制（有皮肤病变组与无皮肤病变组比较：p < 0.001）。线性回归分析还显示SAM浓度与启动子甲基化百分比呈负相关。综上所述，这些结果表明，SAM生物合成减少以及SAM利用率提高导致甲基供体可用性降低。这些因素以及AS3MT的表观遗传下调可能是砷暴露个体易感性较高的原因。
