Our prior work showed that brief exposure of pregnant C3H mice to inorganic arsenic-induced hepatocellular carcinoma (HCC) formation in adult male offspring. The current study examined the early hepatic events associated with this oncogenic transformation. Pregnant mice were exposed to a known carcinogenic dose of arsenic (85 ppm) in the drinking water from gestation days 8 to 18. The dams were allowed to give birth and liver samples from newborn males were analyzed for arsenic content, global DNA methylation and aberrant expression of genes relevant to the carcinogenic process. Arsenic content in newborn liver reached 57 ng/g wet weight, indicating arsenic had crossed the placenta, reached the fetal liver and that significant amounts remained after birth. Global methylation status of hepatic DNA was not altered by arsenic in the newborn. However, a significant reduction in methylation occurred globally in GC-rich regions. Microarray and real-time RT-PCR analysis showed that arsenic exposure enhanced expression of genes encoding for glutathione production and caused aberrant expression of genes related to insulin growth factor signaling pathways and cytochrome P450 enzymes. Other expression alterations observed in the arsenic-treated male mouse newborn liver included the overexpression of cdk-inhibitors and stress response genes including increased expression of metallothionein-1 and decreased expression of betaine-homocysteine methyltransferase and thioether S-methyltransferase. Thus, transplacental exposure to arsenic at a hepatocarcinogenic dose induces alterations in DNA methylation and a complex set of aberrant gene expressions in the newborn liver, a target of arsenic carcinogenesis.

中文翻译：

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经胎盘暴露于致癌剂量无机砷的新生小鼠肝脏中异常 DNA 甲基化和基因表达。

我们之前的工作表明，怀孕的 C3H 小鼠短暂暴露于无机砷会诱导成年雄性后代形成肝细胞癌 (HCC)。目前的研究检查了与这种致癌转化相关的早期肝脏事件。从妊娠第 8 天到第 18 天，怀孕小鼠的饮用水中暴露了已知致癌剂量的砷（85 ppm）。母鼠被允许分娩，并对新生雄性的肝脏样本进行了砷含量、整体 DNA 甲基化和异常的分析。与致癌过程相关的基因的表达。新生儿肝脏中的砷含量达到57纳克/克湿重，表明砷已穿过胎盘，到达胎儿肝脏，并且在出生后仍有大量砷残留。新生儿肝脏 DNA 的整体甲基化状态并未因砷而改变。然而，全球范围内富含 GC 的区域甲基化显着减少。微阵列和实时 RT-PCR 分析表明，砷暴露增强了编码谷胱甘肽生成的基因的表达，并导致与胰岛素生长因子信号通路和细胞色素 P450 酶相关的基因的异常表达。在砷处理的雄性小鼠新生肝脏中观察到的其他表达变化包括 cdk 抑制剂和应激反应基因的过度表达，包括金属硫蛋白-1 表达增加以及甜菜碱同型半胱氨酸甲基转移酶和硫醚 S-甲基转移酶表达减少。因此，经胎盘暴露于致癌剂量的砷会诱导新生肝脏中 DNA 甲基化的改变和一组复杂的异常基因表达，而新生肝脏是砷致癌的目标。