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.

中文翻译：

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二甲基ar子酸（DMA）通过组蛋白H3K9修饰增强了在胎盘小鼠模型中的肺癌发生率。

怀孕的CD-1小鼠从妊娠第8-18天开始就在饮用水中接受了200 ppm的二甲基亚砷酸（DMA），并在84周龄的后代中评估了肿瘤的形成。与雄性对照后代（分别为1.9％和15.1％）相比，DMA增加了雄性后代中肺腺癌的发生率（10.0％）和总肿瘤（33.3％）。与雄性对照后代（0.0％）相比，DMA还增加了雄性后代肝细胞癌的发生率（10.0％）。在经胎盘DMA处理的新生小鼠的肺中检测到DMA及其代谢产物。经胎盘DMA暴露可增加新生和6周龄雄性小鼠肺上皮细胞的增殖。芯片和实时PCR分析检测到新生和6周龄DMA处理的小鼠的肺中的角蛋白8（Krt8）的高表达。蛋白质印迹分析表明，在雄性小鼠的肺部，DMA升高了组蛋白H3K9的甲基化水平，但没有提高H3K27的甲基化水平。重要的是，使用H3K9me3抗体进行的染色质免疫沉淀测序（ChIP-seq）分析发现了暴露于DMA的小鼠与对照组之间异染色质形成的差异。值得注意的是，ChIP-seq分析还在DMA处理的小鼠中发现了较低异染色质形成的区域，这些区域之一包含Krt8基因，与通过微阵列分析获得的结果一致。在雄性后代的肺腺瘤和肺腺癌中也检测到Krt8的高表达。总体而言，这些数据表明经胎盘DMA处理可增强雄性小鼠的肺和肝癌发生率。在肺部，DMA导致组蛋白H3K9异常甲基化，Krt8表达增加，