Dimethylarsinic acid (DMA) enhanced lung carcinogenesis via histone H3K9 modification in a transplacental mouse model
Dimethylarsinic acid (DMA) enhanced lung carcinogenesis via histone H3K9 modification in a transplacental mouse model
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DOI：
10.1007/s00204-020-02665-x
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发表时间：
2020-02-12
影响因子：
6.1
通讯作者：
Wanibuchi, Hideki
中科院分区：
文献类型：
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作者：
Fujioka, Masaki;Suzuki, Shugo;Wanibuchi, Hideki
怀孕CD-1小鼠从妊娠第8-18天开始在饮用水中注射200ppm的二甲基砷酸(DMA)，并在84周龄的后代中评估肿瘤形成。与男性对照后代(分别为1.9%和15.1%)相比，DMA增加了雄性后代的肺腺癌(10.0%)和总肿瘤(33.3%)的发生率。与男性对照后代(0.0%)相比，DMA还增加了男性后代中肝细胞癌的发生率(10.0%)。经胎盘注射DMA的新生小鼠肺中检测到DMA及其代谢物。经胎盘接触DMA可促进新生和6周龄雄性小鼠肺上皮细胞的增殖。基因芯片和实时定量聚合酶链式反应分析检测到角蛋白8(Krt8)在新生小鼠和6周大的DMA处理的小鼠的肺中都有高表达。Western印迹分析表明，DMA增加了雄性小鼠肺中组蛋白H3K9的甲基化，但不增加H3K27的甲基化。重要的是，使用H3K9me3抗体的染色质免疫沉淀测序(CHIP-SEQ)分析发现，暴露于DMA的小鼠和对照组之间异染色质的形成存在差异。值得注意的是，CHIP-SEQ分析还在DMA处理的小鼠中发现了异染色质形成较低的区域，其中一个区域包含Krt8基因，这与微阵列分析获得的结果一致。Krt8在男性子代肺腺瘤和腺癌中也有高表达。总体而言，这些数据表明，经胎盘DMA治疗增强了雄性小鼠的肺癌和肝癌发生。在肺中，DMA引起组蛋白H3K9的异常甲基化，增加Krt8的表达，促进细胞增殖。
Pregnant CD-1 mice received 200 ppm dimethylarsinic acid (DMA) in the drinking water from gestation day 8-18, and tumor formation was assessed in offspring at the age of 84 weeks. DMA elevated the incidence of lung adenocarcinoma (10.0%) and total tumors (33.3%) in male offspring compared to male control offspring (1.9 and 15.1%, respectively). DMA also elevated the incidence of hepatocellular carcinoma (10.0%) in male offspring compared to male control offspring (0.0%). DMA and its metabolites were detected in the lungs of transplacental DMA-treated neonatal mice. Transplacental DMA exposure increased cell proliferation in the epithelium in the lungs of both neonatal and 6-week-old male mice. Microarray and real-time PCR analyses detected high expression of keratin 8 (Krt8) in the lungs of both neonatal and 6-week-old DMA-treated mice. Western blot analysis indicated that DMA elevated methylation of histone H3K9, but not H3K27, in the lungs of male mice. Importantly, chromatin immunoprecipitation sequencing (ChIP-seq) analysis using an H3K9me3 antibody found differences in heterochromatin formation between mice exposed to DMA and the controls. Notably, ChIP-seq analysis also found regions of lower heterochromatin formation in DMA-treated mice, and one of these regions contained the Krt8 gene, agreeing with the results obtained by microarray analysis. High expression of Krt8 was also detected in adenoma and adenocarcinoma of the lung in male offspring. Overall, these data indicate that transplacental DMA treatment enhanced lung and liver carcinogenesis in male mice. In the lung, DMA caused aberrant methylation of histone H3K9, increased Krt8 expression, and enhanced cell proliferation.