Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
Arch Toxicol. 2020 Mar;94(3):927-937. doi: 10.1007/s00204-020-02665-x. Epub 2020 Feb 12.
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.
妊娠 CD-1 小鼠从妊娠第 8 天到第 18 天在饮用水中接受 200ppm 的二甲基砷酸（DMA），并在 84 周龄时评估后代的肿瘤形成情况。DMA 使雄性后代的肺腺癌（10.0%）和总肿瘤（33.3%）的发生率与雄性对照后代（分别为 1.9%和 15.1%）相比升高。DMA 还使雄性后代的肝细胞癌（10.0%）的发生率与雄性对照后代（0.0%）相比升高。DMA 及其代谢物在胎盘处理的新生小鼠的肺部中被检测到。胎盘 DMA 暴露增加了新生和 6 周龄雄性小鼠肺部上皮细胞的增殖。微阵列和实时 PCR 分析检测到新生和 6 周龄 DMA 处理的小鼠肺部中角蛋白 8（Krt8）的高表达。Western blot 分析表明，DMA 增加了雄性小鼠肺部组蛋白 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 的小鼠和对照小鼠之间异染色质形成存在差异。值得注意的是，ChIP-seq 分析还发现 DMA 处理的小鼠中异染色质形成的区域较低，其中一个区域包含 Krt8 基因，与微阵列分析的结果一致。雄性后代的肺部腺瘤和腺癌中也检测到 Krt8 的高表达。总的来说，这些数据表明胎盘 DMA 处理增强了雄性小鼠的肺部和肝脏致癌作用。在肺部，DMA 导致组蛋白 H3K9 的异常甲基化、Krt8 表达增加和细胞增殖增强。
