Impact of heme iron from red meat on colorectal carcinogenesis and relevance of DNA repair

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Dietary factors are well known to increase the risk to develop colorectal cancer (CRC), which is the third most common tumor entity in Germany. Various studies suggest that the intake of heme iron, as relevant constituent of red meat, plays an important role in colorectal carcinogenesis. However, the underlying mechanisms are only partially understood and may involve a) an increased proliferation of the colon crypts linked to microbial dysbiosis, b) the generation of genotoxic N-nitroso compounds (NOC) in the colorectum and c) the induction of lipid peroxidation. NOC are alkylating agents, which cause premutagenic DNA adducts such as O6-methylguanine (O6-MeG) and O6-carboxymethylguanine (O6-CMG). In turn, lipid peroxidation products such as malondialdehyde and hydroxynonenal (HNE) give rise to premutagenic DNA lesions such as pyrimidopurinone (M1G) and HNE-G adducts. This raises the issue whether heme iron from red meat exhibits tumor initiating and/or tumor promoting potential in the colorectum and which DNA repair pathway is involved in the protection against heme iron-associated CRC formation. O6-MeG and O6-CMG are substrates for direct damage reversal by O6-methylguanine-DNA methyltransferase (MGMT). M1G and HNE-G adducts undergo nucleotide excision repair, which essentially involves xeroderma pigmentosum complementation group A (XPA) protein. Transgenic mouse models with deficiencies in MGMT and XPA are available in our group, which will allow studying the causal role of these DNA adducts in heme iron-triggered colorectal carcinogenesis. First, the tumor initiating and tumor promoting properties of dietary heme iron will be analyzed in wildtype animals in comparison to an iron balanced control diet. To this end, a non-invasive mini-endoscopy unit will be used, by which tumor formation and progression is monitored over time in a quantitative manner, which is complemented by histopathological analysis of the whole colorectum. Furthermore, the dose-response relationship in heme iron-triggered CRC formation and the impact of DNA repair deficiencies will be assessed. Next, we will analyze critical heme iron-induced DNA damage in colorectal tissue as well as other endpoints such as cell death induction, cell proliferation and MGMT promoter methylation. Finally, the contribution of intestinal inflammation in heme-associated colorectal carcinogenesis will be analyzed.