Toxicity of processed red meat: Endogenous synthesis of different heme species and their potential implication in colon cancer formation

• Applicant: Dr. Tina Kostka
• Subject Area: Toxicology, Laboratory Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495865234

Epidemiological studies show a correlation between the consumption of processed meat and the incidence of colorectal cancer. Although the causes and mechanisms have not yet been clearly identified, nitrosylated heme, which is formed when curing salts are added to meat, was long considered to be one of the most important factors. However, this hypothesis has been put to question, for the first time, by the preliminary work of the applicant. In addition, these results brought the substance β-hematin as a possible endogenously formed carcinogen into focus, which was completely unknown in a food (toxicology)-related context until then, although adverse effects of this compound on macrophages and pneumocytes have been described. Moreover, scientific literature shows that β-hematin can be formed in mammalian organs under certain conditions. Therefore, a human exposure, e.g., after consumption of processed meat, would be possible. In the context of the pro-carcinogenic effects of processed meat, β-hematin has not yet been considered. There are no studies on its occurrence as a component of human diet and digestion, nor have the toxic effects on the intestinal epithelium been analyzed. It is therefore the aim of the present project to close these research gaps.It is envisaged to link, for the first time, β-hematin with human nutrition and its endogenous formation as a degradation product of different heme species, which will be demonstrated by using in vitro digestion techniques. The focus is thereby on the detection of structural changes, as well as the formation of new heme-based substances specific to the individual compartments of the human digestive system (oral cavity, stomach, small intestine and colon). Firstly, the interplay of putatively important factors in β-hematin formation (e.g., the presence of a lipid layer, an acidic pH, and nitrosylated heme as a precursor for β-hematin) will be examined individually and in combination. Digestion would be performed using both individual heme species, but also with processed red meat and meat in combination with nitrite-rich vegetables. In the second step, the potentially toxic effects of the endogenously occurring heme species would be analyzed individually and in combination, taking into account physiologically relevant concentrations. Established tumor cell lines of the human colon, either in the form of differentiated epithelial cells or as co-culture with macrophages, will serve as models. The aim is to investigate the compound-specific induction of oxidative stress, DNA damage, an inflammatory response, damage to membrane integrity as well as to investigate the signal transduction pathways underlying these effects. Ultimately, effective preventive measures can be developed as an alternative to a vegetarian diet only when substances actually present in the digestive system, their endogenous activation, their respective distribution within the intestines and their toxic effects are known.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Tuba Esatbeyoglu