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Benzo pyrene-induced DNA adducts and gene expression profiles in target and non-target organs for carcinogenesis in mice

机译:苯并芘诱导的DNA加合物和基因表达谱系在靶和非靶器官中的小鼠中的致癌作用

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Background Gene expression changes induced by carcinogens may identify differences in molecular function between target and non-target organs. Target organs for benzo[a]pyrene (BaP) carcinogenicity in mice (lung, spleen and forestomach) and three non-target organs (liver, colon and glandular stomach) were investigated for DNA adducts by 32P-postlabelling, for gene expression changes by cDNA microarray and for miRNA expression changes by miRNA microarray after exposure of animals to BaP. Results BaP-DNA adduct formation occurred in all six organs at levels that did not distinguish between target and non-target. cDNA microarray analysis showed a variety of genes modulated significantly by BaP in the six organs and the overall gene expression patterns were tissue specific. Gene ontology analysis also revealed that BaP-induced bioactivities were tissue specific; eight genes (Tubb5, Fos, Cdh1, Cyp1a1, Apc, Myc, Ctnnb1 and Cav) showed significant expression difference between three target and three non-target organs. Additionally, several gene expression changes, such as in Trp53 activation and Stat3 activity suggested some similarities in molecular mechanisms in two target organs (lung and spleen), which were not found in the other four organs. Changes in miRNA expression were generally tissue specific, involving, in total, 21/54 miRNAs significantly up- or down-regulated. Conclusions Altogether, these findings showed that DNA adduct levels and early gene expression changes did not fully distinguish target from non-target organs. However, mechanisms related to early changes in p53, Stat3 and Wnt/β-catenin pathways may play roles in defining BaP organotropism.
机译:由致癌物质诱导的背景基因表达变化可以识别目标和非靶器官之间的分子功能的差异。针对小鼠(肺,脾脏和林瘤)和三种非靶器官(肝脏,结肠和腺体)的苯并[a]芘(BAP)致癌物体进行DNA加合物,通过 3 3 3蛋白(肺癌)和三个非靶器官(肝脏,结肠和腺胃)进行DNA加合物-PostLabling,用于基因表达通过cDNA微阵列的改变和MiRNA表达通过MiRNA微阵列在暴露于动物曝光后通过MiRNA微阵列进行变化。结果在所有六个器官中发生BAP-DNA加合物的形成,该水平在目标和非靶标不区分。 CDNA微阵列分析显示通过六个器官中的烘位显着调节各种基因,并且整个基因表达模式是组织特异性的。基因本体分析还显示出诱导的BAP诱导的生物活化是组织特异性;八个基因(TubB5,FOS,CDH1,CYP1A1,APC,MYC,CTNNB1和CAV)显示出三个靶标和三个非靶器官之间的显着表达差异。另外,若干基因表达改变,例如TRP53活化和Stat3活性,提出了两种靶器官(肺和脾)的分子机制中的一些相似之处,其在其他四个器官中未发现。 miRNA表达的变化通常是组织特异性的,涉及总共21/54 miRNA显着上调或下调。结论中,这些发现表明,DNA加合水平和早期基因表达的变化并未完全区分非靶器官的靶标。然而,与P53,STAT3和Wnt /β-catenin途径的早期变化有关的机制可以在定义绕组有机谱中发挥作用。

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