Epigenetic Modifications of DAPK and p16 Genes Contribute to Arsenic-Induced Skin Lesions and Nondermatological Health Effects
Epigenetic Modifications of DAPK and p16 Genes Contribute to Arsenic-Induced Skin Lesions and Nondermatological Health Effects
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DOI：
10.1093/toxsci/kft163
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发表时间：
2013-10-01
影响因子：
3.8
通讯作者：
Giri, Ashok K.
中科院分区：
文献类型：
--
作者：
Banerjee, Nilanjana;Paul, Somnath;Giri, Ashok K.
在印度西孟加拉邦，超过2600万人通过饮用水接触到高浓度的砷，导致包括癌症在内的几种有害终点。为了阐明启动子甲基化在砷诱导的皮肤和非皮肤健康效应中的作用，研究人员检测了p16和DAPK基因的甲基化状态。进行了一项病例对照研究，涉及72名砷诱发皮肤病变的个体（病例）和50名没有皮肤病变的个体（对照组），他们通过饮用水接触了类似的砷。甲基化状态通过基因组DNA的亚硫酸盐转化和甲基化特异性PCR来确定。实时荧光定量PCR和Western blot检测基因的表达情况。从流行病学调查数据确定启动子甲基化状态与非皮肤病健康影响之间的关联。与对照组相比，在这些病例中，在DAPK和p16基因的启动子中发现了显著的高甲基化，导致这些病例中这两个基因的下调。与对照组相比，死亡相关蛋白激酶的表达减少了3.4倍，p16的基因表达减少了2.2倍，在癌组织中的表达最低。这些基因的启动子高甲基化也与砷引起的皮肤病变、周围神经病变、眼部和呼吸系统疾病的高风险相关。这项研究首次尝试将肿瘤抑制基因的表观遗传修饰与长期暴露于砷的人群的皮肤和非皮肤健康结果联系起来。
Over 26 million people in West Bengal, India, are exposed to very high levels of arsenic through drinking water, leading to several deleterious endpoints including cancers. To elucidate the role of promoter methylation in arsenic-induced dermatological and nondermatological health effects, methylation status of p16 and DAPK genes was determined. A case-control study was conducted involving 72 individuals with arsenic-induced skin lesions (cases) and 50 individuals without skin lesions (controls), having similar arsenic exposure through drinking water. Methylation status was determined by bisulfite conversion of genomic DNA and methylation-specific PCR. Expression of the genes was determined by real-time PCR and Western blot analysis. Associations between the promoter methylation status and nondermatological health effects were determined from epidemiological survey data. Significant hypermethylation was found in the promoters of both DAPK and p16 genes in the cases compared with the controls resulting in downregulation of both the genes in the cases. There was a 3.4-fold decrease in the expression of death-associated protein kinase and 2.2-fold decrease in gene expression of p16 in the cases compared to the controls, the lowest expression being in the cancer tissues. Promoter hypermethylation of the genes was also associated with higher risk of developing arsenic-induced skin lesions, peripheral neuropathy, ocular and respiratory diseases. This study for the first time makes an attempt to correlate epigenetic modifications of the tumor suppressor genes with dermatological and nondermatological health outcomes in a population chronically exposed to arsenic.