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)存在下并由亚砷酸盐甲基转移酶(AS3MT)催化的一系列生化反应之后。然而,甲基化的程度和模式在暴露于砷的个体中不同,导致不同的易感性.这种个体间差异的机制是神秘的。在本病例对照研究中,我们招募了有和没有砷诱导的皮肤损伤的暴露个体(WSL和WOSL),和一个未暴露的队列,每人有120个人。使用ELISA,与WOSL相比,我们观察到WSL中SAM水平降低(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。qRT-PCR显示关键调控基因如MTHFR显著下调(p<0.01),地铁,WSL队列中SAM生物发生途径的MAT2A和MAT2B。甲基化特异性PCR显示AS3MT的启动子高度甲基化(WSL与WOSL:p<0.01),导致其随后的转录抑制(WSL与WOSL: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之间呈负相关。一起来看,这些结果表明,SAM生物发生的减少以及SAM的更高利用率导致甲基供体的可用性降低。这些以及AS3MT的表观遗传下调可能是砷暴露个体中更高的易感性的原因。
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.