Specificity of mutation spectrum and gene expression profiles induced by environmental carcinogens

人类划独木舟被认为是由遗传和环境因素的综合影响。然而，迄今为止，尚未明确这些环境因素对人类致癌作用的影响以及这些化合物对人类的低剂量效应。在本研究中，我们重点研究了杂环胺（HCAs），这是一种由加热肉类和鱼类产生的致突变和致癌化合物，并使用我们的间歇性HCA喂养方案，研究了五种结肠致癌HCAs（PhIP，IQ，MeIQ，Glu-P-1和MeIQx）和三种非致癌HCAs（Trp-P-2，AαC和MeAαC）在HCA诱导的结肠病变中的组织病理学特征的时间变化。还分析了这些HCA诱导的结肠病变（包括ACF、异型增生ACF、微腺瘤、腺瘤和结肠癌）中的遗传改变。在暴露于这些化合物中的每一种后，结肠上皮中的化学特异性和基因表达谱的差异被 ...更多信息 结果表明，PhIP、IQ和MeIQ诱发的结肠病变在Apc或β-catenin基因上显示出一些化学特异性的突变谱。特别是，从鸟嘌呤（G）核苷酸延伸的一个G缺失，如5 '-GGG-3'，是特异性的PhIP诱导的病变，并可能是有用的PhIP的签名型突变。HCA诱导的结肠上皮细胞基因表达谱在不同的HCA中也有不同的模式。有趣的是，基因表达谱的层次聚类分析显示，AαC和MeAαC（两种非致癌HCA）与其他六种HCA（包括非致癌Trp-P-2）聚为一个不同的簇。更令人惊讶的是，在34个通常由致癌MeIQ、Glu-P-1和MeIQx上调的基因中，32个在Trp-P-2处理的结肠上皮中也上调。此外，86个基因中的82个通常由MeIQ，Glu-P-1和MeIQx下调，也下调Trp-P-2暴露的样品。综合以上结果，推测Trp-P-2可能是一种潜在的结肠癌致癌物。目前正在进行进一步的研究，以重新评估Trp-P-2在长期实验中对结肠的致癌潜力，使用我们的“间歇性HCA喂养方案”。“少

Human canoers are believed to be caused by combined effects of heritable and environmental factors. To date, however, identification of these environmental factors responsible for human carcinogenesis and low-dose effects of these compounds on humans have not been clarified yet. La this study, we focused on heterocyclic amines (HCAs), which are mutagenic and carcinogenic compounds produced by heating meat and fish, and investigated chronological changes in histopatholgical features of HCA-induced lesions in the colon using our intermittent HCA-feeding protocol with five colon carcinogenic HCAs, namely PhIP, IQ, MeIQ, Glu-P-1 and MeIQx, and three non-carcinogenic HCAs, namely Trp-P-2, AαC and MeAαC. Genetic alterations in colonic lesions, including ACF, dysplastic ACF, microadenomas, adenomas and colon cancers, induced with these HCAs were also analyzed. Chemical-specificity and differences in gene expression profiles in colonic epithelium after exposure to each of these compounds were … More examined, and the implication of the data for prediction of carcinogenic potentials in the colon were also evaluated.As a result, colonic lesions induced by PhIP, IQ and MeIQ demonstrated some chemical-specific types of mutation spectra in the Apc or β-catenin gene. Especially, one G deletion from guanine (G) nucleotide stretches, such as 5'-GGG-3', was specific to PhIP-induced lesions, and could be useful as a signature-type mutation for PhIP. As for gene expression profiles induced in colonic epithelium by HCA, distinct patterns were also observed among various HCAs. Interestingly, hierarchical clustering analysis of gene expression profiles revealed that AαC and MeAαC, two of the non-carcinogenic HCAs, were grouped into a distinct cluster from the other six HCAs, including non-carcinogenic Trp-P-2. More surprisingly, of 34 genes commonly up-regulated by carcinogenic MeIQ, Glu-P-1 and MeIQx, 32 were also up-regulated in Trp-P-2-treated colon epithelium. Furthermore, eighty-two of 86 genes commonly down-regulated by MeIQ, Glu-P-1 and MeIQx were also down-regulated in Trp-P-2-exposed samples. Taking all our results together, Trp-P-2 was speculated to be a candidate colon carcinogen. Further studies are currently ongoing to re-evaluate the carcinogenic potential of Trp-P-2 on the colon in a long-term experiment using our "intermittent HCA-feeding protocol." Less