Author: Jean Marie Winter
Winter, Jean Marie, 2014 Do dietary induced pro-mutagenic DNA adducts increase risk for colorectal cancer?, Flinders University, School of Medicine
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Colorectal cancer (CRC) is a major burden on public health in developed countries with high incidence and mortality rates globally. A major driving force of CRC is related to lifestyle factors, in particular dietary choices. Consumption of red meat has been identified as a risk factor for developing CRC by the World Cancer Research Fund. Increased DNA adducts in the colon via excess endogenous N-nitrosation is one mechanism thought to play a role in colorectal oncogenesis. Haem iron in red meat has also been implicated in development of CRC in humans. A dietary component that can protect against CRC, called resistant starch (RS), is the component of starch undigested in the small intestine and fermented in the colon. It is thought that preferential fermentation of carbohydrate over protein, when RS is incorporated into high protein diets, leads to a reduction in DNA changes that might initiate CRC. Green tea is a common beverage in East Asian countries and evidence from rodent and cell culture studies shows green tea as a preventative agent against CRC, although human studies are somewhat conflicting. The global aim of this thesis is to determine whether dietary-induced DNA adducts by red meat consumption act as bio-markers for risk of CRC. The studies presented will endeavour to validate and extend previous studies demonstrating that red meat can induce pro-mutagenic adducts. Furthermore, RS and green tea will be employed in combination with red meat to ascertain any protective role they might have against pro-mutagenic formation in the colon. The risk of developing CRC with high red meat consumption will also be explored, and RS will be evaluated as a protective food against CRC formation. The hypotheses are that red meat will increase DNA adducts, but that RS and green tea consumption can reduce red meat-induced DNA adducts. Also, red meat and haem from red meat will increase risk for developing CRC, but RS will reduce the CRC risk posed by red meat. In addition to the mouse experiments, the effects of red meat and red meat in combination with RS will be translated to the human setting, by feeding high red meat and high red meat with RS diets to healthy human volunteers. It is hypothesised that red meat will significantly increase DNA adducts in the colorectal tissue of humans consuming a high red meat diet, but that co-consumption with RS will ameliorate these adducts. Red meat and haem increased DNA adducts of the distal colon in all mouse models and in human rectal epithelial tissue. However, there was no clear link between DNA adducts and risk for oncogenesis of the colon in the mouse models tested. RS increased fermentation of beneficial microbial metabolites, but reduced production of potentially toxic fermentation products. RS reduced proliferation rates in the distal colon of wild type and Msh2 knockout mice, but this did not reduce pre-cancerous lesions in the colon. RS supplementation could reduce formation of pro-mutagenic adducts in wild type mice and in humans after short term consumption, but this did not translate over long term RS consumption in the Western diet mouse model. Green tea did not reduce DNA adducts either alone or in the presence of red meat, either in wild type or MGMT knockout mice. In conclusion, chronic consumption of a high red meat diet can generate DNA lesions in colonic epithelial cells and RS consumption can ameliorate this affect in the short term, but this does not lead to consequent changes in risk after long term consumption in the mouse models tested. Consequently, dietary-induced DNA O6MeG and 8-oxo adducts could perhaps be described as a marker for exposure to alkylating and oxidative agents in the diet, including red meat and its associated components such as haem, and not necessarily described as a bio-marker for CRC risk.
Keywords: red meat,resistant starch,green tea,DNA adducts,colorectal cancer
Subject: Medicine thesis
Thesis type: Doctor of Philosophy
School: School of Medicine
Supervisor: Richard Le Leu