Evaluation of environmental chemical effects on genome and gene expression

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有相当大的担忧。那些具有雌激素活性的化学物质被称为异种雌激素或内分泌干扰物。它们被认为模仿或干扰雌激素的功能，其中许多已知具有雌激素受体结合活性。为了比较生理性雌激素(雌二醇)和被怀疑为非生理性雌激素的化学物质(己烯雌酚；壬基酚)的作用，我们使用DNA微阵列分析了雌激素和化学物质诱导的子宫基因表达模式。虽然雌二醇和己烯雌酚以相同的方式诱导了许多基因的反应，但不同的基因组对每种雌激素的敏感性程度不同，导致了不同的剂量-反应模式。这些结果表明，每种雌激素对子宫基因表达有相似但不同的影响。与子宫和化学物质相似的影响相比，在肝脏中，雌激素化学物质(壬基酚)对基因表达的影响比雌二醇更明显。这表明，在肝脏中，壬基酚可以激活另一组不同于雌激素反应基因的基因。这些结果表明，壬基酚对子宫基因表达的影响与雌二醇非常相似，但对肝脏组织中的基因表达无明显影响。因此，为了阐明烷基酚的不同作用，应考虑组织特异性效应。此外，为了从基因组水平上了解雌激素激活基因的机制，采用染色质免疫沉淀法鉴定雌激素受体的直接靶点。分析免疫沉淀DNA片段与基因活化谱的相关性。

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.