Estrogen signaling in livers of male mice with hepatocellular carcinoma induced by exposure to arsenic in utero
Estrogen signaling in livers of male mice with hepatocellular carcinoma induced by exposure to arsenic in utero
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DOI：
10.1093/jnci/djh070
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发表时间：
2004-03-17
影响因子：
10.3
通讯作者：
Diwan, BA
中科院分区：
文献类型：
--
作者：
Waalkes, MP;Liu, J;Diwan, BA
背景资料：怀孕的小鼠暴露于无机砷诱导肿瘤的光谱，包括肝细胞癌（HCC），在其成年后代类似的成年小鼠暴露于雌激素化合物诱导。为了研究子宫内砷暴露是否会导致雌激素信号转导的改变，我们检测了子宫内砷诱导肝癌的成年雄性小鼠肝脏中雌激素受体α（ER-α）、细胞周期蛋白D1（一种雌激素反应性肝癌基因）和几种细胞色素P450基因（具有性别二态性肝脏表达模式）的表达。研究方法：使用定量实时逆转录-聚合酶链反应来评估成年雄性小鼠肝脏中的基因表达，暴露的小鼠; n = 8）或没有（即，对照小鼠; n = 5）在子宫内暴露于砷。使用甲基化特异性聚合酶链反应测定肝组织中ER-α和细胞周期蛋白D1基因启动子部分的DNA甲基化状态。统计检验是双侧的。结果如下：暴露小鼠肝脏中ER-α mRNA水平比对照小鼠高3.1倍（95%置信区间[CI] = 2.0倍至4.3倍），细胞周期蛋白D1水平高3.0倍（95% CI = 1.7倍至4.3倍）。暴露小鼠显示出几种细胞色素P450基因的雌性化表达模式，表达雌性主导的CYP 2A 4（与对照组相比P = .017）和CYP 2B 9（P < .001）基因的水平分别为对照小鼠的8.7和10.5倍，表达雄性主导的CYP 7 B1的水平约为对照小鼠的四分之一（P = .0012）。与对照小鼠相比，暴露小鼠肝脏DNA中ER-α基因启动子的甲基化程度降低（约90%）;暴露或对照小鼠中细胞周期蛋白D1基因启动子均未甲基化。结论：雌激素信号通路的改变可能在宫内砷暴露诱发肝癌中发挥作用。具体而言，ER-α的过度表达，可能通过启动子区低甲基化，在这些小鼠的肝脏可能与砷的肝癌性。
Background: Exposure of pregnant mice to inorganic arsenic induces a spectrum of tumors, including hepatocellular carcinoma (HCC), in their adult offspring similar to that induced by exposing adult mice to estrogenic compounds. To investigate whether arsenic exposure in utero causes altered estrogen signaling, we examined expression of estrogen receptor-alpha (ER-alpha), cyclin D1 (an estrogen-responsive hepatic oncogene), and several cytochrome P450 genes (with sexually dimorphic liver expression patterns) in livers from adult male mice with in utero arsenic-induced HCC. Methods: Quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate gene expression in livers of adult male mice that had (i.e., exposed mice; n = 8) or had not (i.e., control mice; n = 5) been exposed to arsenic in utero. DNA methylation status of portions of the ER-alpha and cyclin D1 gene promoters in liver tissue was measured using methylation-specific polymerase chain reaction. Statistical tests were two-sided. Results: ER-alpha mRNA levels were 3.1-fold (95% confidence interval [CI] = 2.0-fold to 4.3-fold) higher in livers of exposed mice than in those of control mice, and cyclin D1 levels were 3.0-fold (95% CI = 1.7-fold to 4.3-fold) higher. Exposed mice showed a feminized expression pattern of several cytochrome P450 genes, expressing the female-dominant CYP2A4 (P = .017 versus control) and CYP2B9 (P < .001) genes at 8.7 and 10.5 times, respectively, the level in control mice and expressing the male-dominant CYP7B1 at approximately one-fourth the level in control mice (P = .0012). Exposed mice exhibited reduced (by approximately 90%) methylation of the ER-alpha gene promoter in liver DNA as compared with control mice; the cyclin D1 gene promoter was not methylated in either exposed or control mice. Conclusion: Altered estrogen signaling may play a role in induction of HCC by arsenic exposure in utero. Specifically, overexpression of ER-alpha, potentially through promoter region hypomethylation, in livers of such mice may be linked to the hepatocarcinogenicity of arsenic.