Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol
Persistent gene expression in mouse vagina exposed neonatally to diethylstilbestrol
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DOI：
10.1677/jme.0.0320663
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发表时间：
2004-06-01
影响因子：
3.5
通讯作者：
Iguchi, T
中科院分区：
文献类型：
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作者：
Miyagawa, S;Suzuki, A;Iguchi, T
发育过程中暴露于合成雌激素己烯雌酚（DES），可诱发人类和实验动物的癌变。在小鼠中，新生儿DES治疗诱导阴道上皮持续增殖和角化，甚至在没有卵巢的情况下，导致晚年癌变。为了了解这种持续细胞增殖和分化的机制，我们使用DNA微阵列和实时定量RT-PCR表征了新生儿des暴露小鼠阴道中的基因表达模式。我们发现，在新生儿des暴露小鼠阴道中，与细胞信号相关的基因（介导持续增殖和分化的候选基因）发生了改变，与免疫系统相关的基因减少。我们还注意到白介素-1 （IL-1）相关基因的高表达伴随着JNK1的磷酸化。此外，IGF-1及其结合蛋白的表达被调节，导致IGF-1受体和Akt磷酸化，Akt是IGF-1信号传导的下游因子之一。这使得我们表征了IL-1和IGF-1信号通路组分的表达和磷酸化状态，这些信号通路组分可能激活新生儿暴露于DES的小鼠阴道中的磷酸化级联反应。这些发现有助于深入了解暴露于DES的新生儿小鼠阴道中的持续激活。
Developmental exposure to a synthetic estrogen, diethylstilbestrol (DES), induces carcinogenesis in human and laboratory animals. In mice, neonatal DES treatment induces persistent proliferation and keratinization of the vaginal epithelium, even in the absence of the ovaries, resulting in cancerous lesions later in life. To understand the mechanisms underlying this persistent cell proliferation and differentiation, we characterized the gene expression patterns in the neonatally DES-exposed mouse vagina using DNA microarray and real-time quantitative RT-PCR. We found that genes related to cellular signaling, which are candidates for mediating the persistent proliferation and differentiation, were altered, and genes related to the immune system were decreased in the neonatally DES-exposed mouse vagina. We also noted high expression of interleukin-1 (IL-1)-related genes accompanied by phosphorylation of JNK1. In addition, expression IGF-1 and its binding proteins was modulated and led to phosphorylation of IGF-1 receptor and Akt, which is one of the downstream factors of IGF-1 signaling. This led us to characterize the expression as well as the phosphorylation status of IL-1 and IGF-1 signaling pathway components which may activate the phosphorylation cascade in the vagina of mice exposed neonatally to DES. These findings give insight into persistent activation in the vagina of mice exposed neonatally to DES.