Short-Term And Long-Term Carcinogenic Effects Of Food Contaminants (4-Hydroxynonenal And Pesticides) On Colorectal Human Cells: Involvement Of Genotoxic And Non-Genomic Mechanisms

Simple Summary One's environment, including diet, play a major role in the occurrence and the development of colorectal cancer (CRC). In this study, we are interested in two western diet associated food contaminants: 4-hydroxynonenal (HNE), a major lipid peroxidation product neoformed during digestion, and a mixture of pesticides to which we are commonly exposed to via fruit and vegetable consumption. The aim of this study was to analyse the impact of acute and long-term exposure to these contaminants, alone or in combination, on colorectal carcinogenesis. We used in vitro models of human colonic cells, either exhibiting or not different genetic susceptibilities to CRC. After acute exposure, we did not observe major alteration. However, long-term exposure to contaminants induce malignant transformation with different cellular mechanisms, depending on genetic susceptibility and contaminants alone or in mixtures. To investigate environmental impacts upon colorectal carcinogenesis (CRC) by diet, we assessed two western diet food contaminants: 4-hydroxynonenal (HNE), a major lipid peroxidation product neoformed during digestion, and a mixture of pesticides. We used human colonic cell lines ectopically eliciting varied genetic susceptibilities to CRC: the non-transformed human epithelial colonic cells (HCECs) and their five isogenic cell lines with the loss of APC (Adenomatous polyposis coli) and TP53 (Tumor protein 53) and/or ectopic expression of mutated KRAS (Kristen-ras). These cell lines have been exposed for either for a short time (2-24 h) or for a long period (3 weeks) to 1 mu M HNE and/or 10 mu M pesticides. After acute exposure, we did not observe any cytotoxicity or major DNA damage. However, long-term exposure to pesticides alone and in mixture with HNE induced clonogenic transformation in normal HCECs, as well as in cells representing later stages of carcinogenesis. It was associated with genotoxic and non-genomic mechanisms (cell growth, metabolic reprogramming, cell mobility and epithelial-mesenchymal transition) depending on genetic susceptibility. This study demonstrated a potential initiating and promoting effect of food contaminants on CRC after long-term exposure. It supports that these contaminants can accelerate carcinogenesis when mutations in oncogenes or tumor suppressor genes occur.