Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure.
Global gene expression associated with hepatocarcinogenesis in adult male mice induced by in utero arsenic exposure.
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在子宫砷暴露中诱导的成年雄性小鼠中与肝癌发生有关的全球基因表达。
DOI：
10.1289/ehp.8534
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发表时间：
2006-03
影响因子：
10.4
通讯作者：
中科院分区：
文献类型：
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作者：
我们之前的工作表明，子宫内接触无机砷会导致成年雄性小鼠的肝细胞癌（HCC）。为了进一步探索经胎盘砷肝癌发生的分子机制，我们进行了第二次砷经胎盘癌研究，并使用全基因组微阵列更广泛地分析了砷诱导的异常基因表达。简单地说，怀孕的C3H小鼠从妊娠第8天到18天饮用含有85 ppm砷的亚砷酸钠或未改变的水。经胎盘砷暴露后，成年男性后代HCC发生率增加4倍，肿瘤多样性增加3倍。尸检时取正常肝脏和肝脏肿瘤样本进行基因组分析。子宫内砷暴露导致砷暴露的肝脏样本中2010个基因的表达显著改变（p < 0.001），砷诱导的HCC中2540个基因的表达显著改变。匠心途径分析显示，基因表达的显著改变发生在许多生物网络中，而Myc在其中一个主要网络中起着关键作用。实时逆转录聚合酶链反应和Western blot分析所选基因/蛋白的一致性为90%。砷改变的基因表达包括癌基因和HCC生物标志物的激活，以及细胞增殖相关基因、应激蛋白、胰岛素样生长因子和参与细胞间通讯的基因的表达增加。肝脏女性化的证据是雌激素相关基因的表达增加和编码性别相关代谢酶的基因表达改变。这些新发现与砷诱导HCC的生物学和组织学一致，从而表明多种遗传事件与经胎盘砷肝癌的发生有关。
Our previous work has shown that exposure to inorganic arsenic in utero produces hepatocellular carcinoma (HCC) in adult male mice. To explore further the molecular mechanisms of transplacental arsenic hepatocarcinogenesis, we conducted a second arsenic transplacental carcinogenesis study and used a genomewide microarray to profile arsenic-induced aberrant gene expression more extensively. Briefly, pregnant C3H mice were given drinking water containing 85 ppm arsenic as sodium arsenite or unaltered water from days 8 to 18 of gestation. The incidence of HCC in adult male offspring was increased 4-fold and tumor multiplicity 3-fold after transplacental arsenic exposure. Samples of normal liver and liver tumors were taken at autopsy for genomic analysis. Arsenic exposure in utero resulted in significant alterations (p < 0.001) in the expression of 2,010 genes in arsenic-exposed liver samples and in the expression of 2,540 genes in arsenic-induced HCC. Ingenuity Pathway Analysis revealed that significant alterations in gene expression occurred in a number of biological networks, and Myc plays a critical role in one of the primary networks. Real-time reverse transcriptase–polymerase chain reaction and Western blot analysis of selected genes/proteins showed > 90% concordance. Arsenic-altered gene expression included activation of oncogenes and HCC biomarkers, and increased expression of cell proliferation–related genes, stress proteins, and insulin-like growth factors and genes involved in cell–cell communications. Liver feminization was evidenced by increased expression of estrogen-linked genes and altered expression of genes that encode gender-related metabolic enzymes. These novel findings are in agreement with the biology and histology of arsenic-induced HCC, thereby indicating that multiple genetic events are associated with transplacental arsenic hepatocarcinogenesis.