Researcher project: Interplay between environmental contaminants, genes and diet in obesity and intestinal cancer

Increased obesity and cancer are seen the last three decades. Obesity is a risk factor for intestinal cancer, but the mechanisms are not clear. Simultaneously, we are exposed to more environmental contaminants. We studied the association between obesity, caused by mutation or high fat diet, and intestinal tumorigenesis. This was done i.a. in a new model made by crossing a well-established intestinal cancer model (Min mouse) with a mouse that develops obesity due to lack of leptin hormone, which regulates food intake and energy expenditure (ob mouse). The project objectives were; to study if 1) obesity in adult mice can increase spontaneous (inherited) intestinal tumors, and tumors induced by the food mutagen PhIP, formed during cooking of meat and fish, and 2) obesogenic conditions in early life can affect body weight and susceptibility to contaminants in adults. This was done by studying intestinal tumors and body weight in offspring of female Min mice given high fat diet during various life periods. In 3) we examined if mice exposed in fetal life to chemicals in i.a. food packaging, PFOA or PFOS, had increased obesity and susceptibility to contaminants as adults. In 1), we found that mice with mutations in both leptin alleles, lacking leptin completely, developed severe obesity, which was further increased by high fat diet. The obese mice without leptin had increased small intestinal tumor number, further increased by high fat diet. Blood sugar regulation was disturbed and plasma insulin increased in these obese mice, which was even worse on high fat diet. There was a clear association between obesity caused by a genetic defect or diet, disturbed blood sugar regulation and intestinal tumors. The obese mice also had increased plasma levels of TNFalpha, an inflammation marker. Mice with only one defect leptin allele, producing some leptin, had somewhat increased body weight, but normal blood sugar and small intestinal tumor number. In 2), we found that mice given high fat diet via their dams in early life, as fetus and during nursing period, had increased body weight and small intestinal tumor number. Blood sugar was not affected by this early exposure as seen after adult exposure. In 3), we found that exposure to PFOA or PFOS during fetal life did not increase body weight, blood glucose or number of small intestinal tumors in the mice as adults.

The prevalence of both obesity and colorectal cancer has increased substantially in the last decades. Simultaneously have humans been exposed to increasing amounts of environmental contaminants. Three fundamental questions related to the interplay between environmental contaminants, genes and health outcomes, obesity and intestinal cancer, will be studied in this project. The question whether genetical or diet-induced obesity can affect food mutagen-induced or spontaneous, via mutation in the tumor suppre ssor gene adenomatous polyposis coli (Apc), intestinal tumorigenesis in adult mice, will be studied in a new double mutant Apc x ob mouse model. The obesity will be induced genetically via mutation in the ob (obese) gene coding for the hormone/cytokine le ptin, or through administration of an obesogenic diet. The next question is whether obesogenic conditions in utero and in early life can affect the risk of developing obesity as well as increase the susceptibility for environmental contaminants causing in testinal cancer in the offspring. The third question which will be studied is whether in utero exposure for environmental contaminants, i.e. endocrine disruptors such as perfluorooctanoic acid and bisphenol A, can increase the risk of developing obesity a s well as increase the susceptibility for other environmental contaminants in the offspring. Mechanisms for how obesity affects intestinal tumorigenesis and how environmental contaminants may contribute to obesity will be studied along two main hypotheses , via insulin resistance/hyperinsulinemia and/or inflammation. The information obtained in this project will increase the understanding of the mutual causal relationship between obesity and susceptibility for environmental contaminants, causing intestinal cancer. The results obtained will also be very useful in human risk assessment of substances such as perfluorooctanoic acid, for which data on toxic effects and dose-response relationships are still lacking.