Toxicogenomic analysis of aberrant gene expression in liver tumors and nontumorous livers of adult mice exposed in utero to inorganic arsenic
Toxicogenomic analysis of aberrant gene expression in liver tumors and nontumorous livers of adult mice exposed in utero to inorganic arsenic
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DOI：
10.1093/toxsci/kfh055
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发表时间：
2004-02-01
影响因子：
3.8
通讯作者：
Waalkes, MP
中科院分区：
文献类型：
--
作者：
Liu, J;Xie, YX;Waalkes, MP
砷是一种已知的人类致癌物质。我们曾报道，怀孕的C3 H小鼠在怀孕期间短暂暴露于饮用水中的亚砷酸盐会导致雄性后代成年后患肝细胞癌（HCC）。肿瘤的形成通常与多个基因表达的变化有关，本研究检测了与经胎盘砷肝癌发生有关的异常基因表达。从妊娠第8至18天，在子宫内暴露于42.5或85 ppm砷（以亚砷酸钠形式）或未改变的水的成年雄性小鼠尸检时采集肝肿瘤和非肿瘤性肝脏样本。提取总RNA并进行微阵列分析。在600个基因中，砷诱导的HCC显示出比自发性肿瘤（7.8%）更高的异常基因表达率（>2倍和p < 0.05，14%）。甲胎蛋白、c-myc、细胞周期蛋白D1、增殖相关蛋白PAG和细胞角蛋白18的过度表达在砷诱导的肝癌中比自发性肿瘤更显著。在砷暴露动物的非肿瘤肝脏样本中，有60个基因（10%）差异表达，包括甲胎蛋白，c-myc，胰岛素样生长因子结合蛋白-1，超氧化物歧化酶，谷胱甘肽S-转移酶和CYP 2A 4的表达增加，CYP 7 B1的表达降低。实时RT-PCR分析在很大程度上证实了这些发现。这种毒理基因组学分析揭示了一些异常的基因表达变化与经胎盘砷致癌作用。值得注意的是，即使在妊娠期砷暴露结束，表达变化也发生在成年期。这些异常表达的基因中的一些可能在砷诱导的肿瘤的发展中发挥作用，至少在肝脏中。
Arsenic is a known human carcinogen. We have reported that brief exposure of pregnant C3H mice to arsenite in their drinking water during gestation induced hepatocellular carcinoma (HCC) in male offspring after they became adults. Tumor formation is typically associated with multiple gene expression changes, and this study examined aberrant gene expression associated with transplacental arsenic hepatocarcinogenesis. Liver tumors and nontumorous liver samples were taken at necropsy from adult male mice exposed in utero to either 42.5 or 85 ppm arsenic as sodium arsenite or unaltered water from day 8 to 18 of gestation. Total RNA was extracted and subjected to microarray analysis. Among 600 genes, arsenic-induced HCC showed a higher rate of aberrant gene expression (>2-fold and p < 0.05, 14%) than spontaneous tumors (7.8%). Overexpression of alpha-fetoprotein, c-myc, cyclin D1, proliferation-associated protein PAG, and cytokeratin-18 were more dramatic in arsenic-induced HCC than spontaneous tumors. In nontumorous liver samples of arsenic-exposed animals, 60 genes (10%) were differentially expressed, including the increased expression of alpha-fetoprotein, c-myc, insulin-like growth factor binding protein-1, superoxide dismutase, glutathione S-transferases, and CYP2A4, and the depressed expression of CYP7B1. Real-time RT-PCR analysis largely confirmed these findings. This toxicogenomic analysis revealed several aberrant gene expression changes associated with transplacental arsenic carcinogenesis. It is indeed remarkable that expression changes occurred in adulthood even though arsenic exposure ended during gestation. Some of these aberrantly expressed genes could play a role in the development of arsenic-induced tumors, at least in the liver.