Evaluation of environmental chemical effects on genome and gene expression

评估环境化学对基因组和基因表达的影响

基本信息

批准号：
15310043
负责人：
WATANABE Hajime
金额：
$ 10.11万
依托单位：
Okazaki Research Facilities, National Institute of Natural Sciences (2004)Okazaki National Research Institutes (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Recently, there has been considerable concern about potential endocrine-disrupting effects of chemicals released into the environment. Those chemicals that have estrogenic activity are termed xenoestrogens or endocrine disrupters. They are thought to mimic or disturb the function of estrogen and many are known to possess estrogen receptor binding activity.To compare the effects of physiological estrogen (estradiol) and chemicals suspected as non-physiological estrogens (diethylstilbestrol ; nonylphenol), we used DNA microarray analysis to examine the uterine gene expression patterns induced by the estrogens and chemicals. Although estradiol and diethylstilbestrol induced many genes to respond in the same way, different groups of genes showed varying levels of sensitivity to each estrogen, resulting in different dose-response patterns. These results suggested that each estrogen has a similar but distinct effect on uterine gene expression.In contrast to the similar effects of estrogen and chemicals observed in the uterus, in liver, gene expression was more markedly affected by estrogenic chemical (nonylphenol) than by estradiol. This indicated that in the liver, nonylphenol could activate another set of genes that is distinct from estrogen-responsive genes. These results indicate that nonylphenol has very similar effects to estradiol on gene expression in uterine but not in liver tissue, indicating that tissue-specific effects should be considered in order to elucidate the distinct effects of alkylphenols. In addition, in order to understand gene activation mechanism by estrogen in genomic level, chromatin immunoprecipitation was performed to identify direct target of estrogen receptor. Correlation between immunoprecipitated DNA fragment and gene activation profile was analyzed.

最近，人们对释放到环境中的化学物质潜在的内分泌干扰作用产生了相当大的担忧。那些具有雌激素活性的化学物质被称为异雌激素或内分泌干扰物。它们被认为可以模仿或干扰雌激素的功能，并且许多已知具有雌激素受体结合活性。为了比较生理雌激素（雌二醇）和疑似非生理雌激素的化学物质（己烯雌酚；壬基酚）的作用，我们使用了 DNA 微阵列分析以检查雌激素和化学物质诱导的子宫基因表达模式。尽管雌二醇和己烯雌酚诱导许多基因以相同的方式做出反应，但不同组的基因对每种雌激素表现出不同程度的敏感性，导致不同的剂量反应模式。这些结果表明，每种雌激素对子宫基因表达都有相似但不同的影响。与子宫中观察到的雌激素和化学物质的类似作用相反，在肝脏中，基因表达受雌激素化学物质（壬基酚）的影响比雌二醇更显着。。这表明在肝脏中，壬基酚可以激活另一组与雌激素反应基因不同的基因。这些结果表明，壬基酚对子宫中基因表达的影响与雌二醇非常相似，但在肝组织中则不然，这表明应考虑组织特异性影响，以阐明烷基酚的独特影响。此外，为了在基因组水平上了解雌激素激活基因的机制，进行染色质免疫沉淀以鉴定雌激素受体的直接靶点。分析了免疫沉淀 DNA 片段和基因激活谱之间的相关性。