Effects of High-Fructose Diet vs. Teklad Diet in the MNUInduced Rat Mammary Cancer Model: Altered Tumorigenesis, Metabolomics and Tumor RNA Expression

Abstract

Epidemiology, clinical and experimental animal studies suggest high fructose diets are detrimental to metabolic status and may contribute to tumor development. This due to increased obesity and metabolic syndrome, known risk factors for many types of cancer. We compared tumor development in N-methyl-N-nitrosourea (MNU)-treated rats fed either a high (60%)-fructose diet (HFD) or a standard diet (SD). Female Sprague-Dawley rats at 43 days of age (DOA) were fed a SD or HFD followed by administration of MNU at 50 DOA. Rats were palpated weekly and sacrificed at 190 DOA. MNU-treated rats on HFD exhibited decreased tumor latency and roughly a two-fold increase in tumor multiplicity. RNA-Seq on frozen tumors (SD vs. HFD rats) showed altered expression of approximately 10% of genes (P < 0.05). When examined by Ingenuity Pathway Analysis, multiple highly significant pathways were identified including A) mechanisms of cancer, B) Wnt pathway, C) immune response (e.g., "Th1 and Th2 activation" and "antigen presentation") and D) LXR/RXR nuclear receptor. These generalized pathways were indirectly confirmed by alterations of various interrelated disease pathways (epithelial cancers, T cell numbers and apoptosis). In a second study, serum was collected from rats on the HFD or SD pre-MNU and at the time of sacrifice. Metabolomics revealed that the HFD yielded: A) increased levels of fructose, B) increases of various monoglycerols, C) reduced levels of various diacylglycerols and oxygenated inflammatory lipids (9 and 13 HODE and 12,13 DHOME) and D) increased levels of secondary bile acids (hyodeoxycholate and 6-oxolithocholate), which may reflect microbiome changes. These metabolomic changes, which are distinct from those on a high-fat diet, may prove relevant when examining individuals who consume higher levels of fructose.