Abstract
Colorectal neoplasia is the third most common cancer worldwide. Environmental factors such as diet are known to be involved in the etiology of this cancer. Several epidemiological studies have suggested that specific neo-formed mutagenic compounds related to meat consumption are an underlying factor involved in the association between diet and colorectal cancer. Heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) are known mutagens and possible human carcinogens formed at the same time in meat during cooking processes. We studied the genotoxicity of the model PAH benzo(a)pyrene (B(a)P) and HCA 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), alone or in mixture, using the mouse intestinal cell line ApcMin/+, mimicking the early step of colorectal carcinogenesis, and control Apc+/+ cells. The genotoxicity of B(a)P and PhIP was investigated using both cell lines, through the quantification of B(a)P and PhIP derived DNA adducts, as well as the use of a genotoxic assay based on histone H2AX phosphorylation quantification. Our results demonstrate that heterozygous Apc mutated cells are more effective to metabolize B(a)P. We also established in different experiments that PhIP and B(a)P were more genotoxic on ApcMin/+ cells compared to Apc+/+. Moreover when tested in mixture, we observed a combined genotoxicity of B(a)P and PhIP on the two cell lines, with an increase of PhIP derived DNA adducts in the presence of B(a)P. Because of their genotoxic effects observed on heterozygous Apc mutated cells and their possible combined genotoxic effects, both B(a)P and PhIP, taken together, could be implicated in the observed association between meat consumption and colorectal cancer.
Highlights
Colorectal cancer is one of the most common cancers in the western world [1]
Colon cancer is described as a multistep process [10] in which mutation in the adenomatous polyposis coli (Apc) gene is considered to be the earliest event in the initiation of colorectal carcinogenesis [11]
In vitro studies on colorectal carcinogenesis have usually been performed on carcinoma cell lines, which are not the best suited to investigate the biological effect of xenobiotics since normal or premalignant epithelial cells are the primary targets of these compounds [13]
Summary
Colorectal cancer is one of the most common cancers in the western world [1]. The implication of dietary habits in colorectal carcinogenesis is suggested by several epidemiological studies [2,3], with a possible link between colorectal carcinogenesis and the presence in the diet of heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) [4,5,6]. PAHs and HCAs have been shown to induce tumors in different animal models [7,8,9]. Min mice (ApcMin/+), which retain the heterozygous Apc genotype have been shown to be more sensitive to the carcinogenic potential of 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP, an extensively studied HCA) than control C57BL/6J mice (Apc+/+) [12]. Several in vitro studies have been published regarding the characterization of tumor-promoting factors for colon carcinogenesis. In such studies, the cellular model used plays a crucial role in understanding the relationship between mutagenic compounds and the etiology of cancer. Intestinal cell lines derived from C57BL/6J mice (Apc+/+) and Min mice (ApcMin/+) which retains the heterozygous
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