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

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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