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Vitamin D deficiency in the ApcPirc/+ rat does not exacerbate colonic tumorigenesis, while low dietary calcium might be protective.

ABSTRACT: Human studies have shown that individuals with colon cancer tend to have lower serum 25-hydroxy-vitamin D3 [25(OH)D3] levels compared with healthy controls, but whether this link is causative, a result of the disease or an indicator of another factor altogether has yet to be demonstrated. In humans, vitamin D, calcium and UV exposure are inextricably linked; therefore, understanding the individual and combined roles of each of these will require animal models specifically designed to address these questions. To begin to untangle this network, our group has employed the ApcPirc/+ rat, which contains a truncating mutation in the Apc gene, leading to the development of colonic tumors. Our group previously utilized this model to demonstrate that vitamin D supplementation above normal does not reduce colonic tumor burden and, in fact, increased tumor multiplicity in a dose-dependent manner. In the current study, we tested whether vitamin D deficiency plays a causative role in tumor development using two strains which differ in their susceptibility to intestinal tumorigenesis. In the colon, vitamin D deficiency did not increase the development of tumors in either strain, and was actually protective in one strain. Unexpectedly, low dietary calcium combined with vitamin D deficiency significantly suppressed tumor development in the small intestine and colon of both strains. The vast majority of tumors in the human intestine occur in the colon, and we find no evidence to support a direct role of vitamin D deficiency in increasing colonic tumorigenesis, and low calcium might protect against tumor development.This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Irving AA

PROVIDER: S-EPMC5897728 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Vitamin D deficiency in the ApcPirc/+ rat does not exacerbate colonic tumorigenesis, while low dietary calcium might be protective.

Irving Amy A AA Duchow Elizabeth G EG Plum Lori A LA DeLuca Hector F HF

Disease models & mechanisms 20180307 3

Human studies have shown that individuals with colon cancer tend to have lower serum 25-hydroxy-vitamin D3 [25(OH)D3] levels compared with healthy controls, but whether this link is causative, a result of the disease or an indicator of another factor altogether has yet to be demonstrated. In humans, vitamin D, calcium and UV exposure are inextricably linked; therefore, understanding the individual and combined roles of each of these will require animal models specifically d ...[more]

PMID: 29590632

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Project description:BACKGROUND: We previously reported that lifetime consumption of soy proteins or whey proteins reduced the incidence of azoxymethane (AOM)-induced colon tumors in rats. To obtain insights into these effects, global gene expression profiles of colons from rats with lifetime ingestion of casein (CAS, control diet), soy protein isolate (SPI), and whey protein hydrolysate (WPH) diets were determined. RESULTS: Male Sprague Dawley rats, fed one of the three purified diets, were studied at 40 weeks after AOM injection and when tumors had developed in some animals of each group. Total RNA, purified from non-tumor tissue within the proximal half of each colon, was used to prepare biotinylated probes, which were hybridized to Affymetrix RG_U34A rat microarrays containing probes sets for 8799 rat genes. Microarray data were analyzed using DMT (Affymetrix), SAM (Stanford) and pair-wise comparisons. Differentially expressed genes (SPI and/or WPH vs. CAS) were found. We identified 31 induced and 49 repressed genes in the proximal colons of the SPI-fed group and 44 induced and 119 repressed genes in the proximal colons of the WPH-fed group, relative to CAS. Hierarchical clustering identified the co-induction or co-repression of multiple genes by SPI and WPH. The differential expression of I-FABP (2.92-, 3.97-fold down-regulated in SPI and WPH fed rats; P = 0.023, P = 0.01, respectively), cyclin D1 (1.61-, 2.42-fold down-regulated in SPI and WPH fed rats; P = 0.033, P = 0.001, respectively), and the c-neu proto-oncogene (2.46-, 4.10-fold down-regulated in SPI and WPH fed rats; P < 0.001, P < 0.001, respectively) mRNAs were confirmed by real-time quantitative RT-PCR. SPI and WPH affected colonic neuro-endocrine gene expression: peptide YY (PYY) and glucagon mRNAs were down-regulated in WPH fed rats, whereas somatostatin mRNA and corresponding circulating protein levels, were enhanced by SPI and WPH. CONCLUSIONS: The identification of transcripts co- or differentially-regulated by SPI and WPH diets suggests common as well as unique anti-tumorigenesis mechanisms of action which may involve growth factor, neuroendocrine and immune system genes. SPI and WPH induction of somatostatin, a known anti-proliferative agent for colon cancer cells, would inhibit tumorigenesis.

Project description:BackgroundDietary silicon has been positively linked with vascular health and protection against atherosclerotic plaque formation, but the mechanism of action is unclear.ObjectivesWe investigated the effect of dietary silicon on 1) serum and aorta silicon concentrations, 2) the development of aortic lesions and serum lipid concentrations, and 3) the structural and biomechanic properties of the aorta.MethodsTwo studies, of the same design, were conducted to address the above objectives. Female mice, lacking the apolipoprotein E (apoE) gene, and therefore susceptible to atherosclerosis, were separated into 3 groups of 10-15 mice, each exposed to a high-fat diet (21% wt milk fat and 1.5% wt cholesterol) but with differing concentrations of dietary silicon, namely: silicon-deprived (-Si; <3-μg silicon/g feed), silicon-replete in feed (+Si-feed; 100-μg silicon/g feed), and silicon-replete in drinking water (+Si-water; 115-μg silicon/mL) for 15-19 wk. Silicon supplementation was in the form of sodium metasilicate (feed) or monomethylsilanetriol (drinking water).ResultsThe serum silicon concentration in the -Si group was significantly lower than in the +Si-feed (by up to 78%; P < 0.003) and the +Si-water (by up to 84%; P < 0.006) groups. The aorta silicon concentration was also lower in the -Si group than in the +Si-feed group (by 65%; P = 0.025), but not compared with the +Si-water group. There were no differences in serum and aorta silicon concentrations between the silicon-replete groups. Body weights, tissue wet weights at necropsy, and structural, biomechanic, and morphologic properties of the aorta were not affected by dietary silicon; nor were the development of fatty lesions and serum lipid concentrations.ConclusionsThese findings suggest that dietary silicon has no effect on atherosclerosis development and vascular health in the apoE mouse model of diet-induced atherosclerosis, contrary to the reported findings in the cholesterol-fed rabbit model.

Project description:Consumption of a Western-type diet has been linked to gut-microbiota-mediated colon inflammation that constitutes a risk factor for colorectal cancer. A high salt diet (HSD) exacerbates IL-17A-induced inflammation in inflammatory bowel disease and other autoimmune diseases. Enterotoxigenic Bacteroides fragilis (ETBF) is a gut commensal bacterium and reported to be a potent initiator of colitis via secretion of the Bacteroides fragilis toxin (BFT). BFT induces ectodomain cleavage of E-cadherin in colonic epithelial cells, consequently leading to cell rounding, epithelial barrier disruption, and the secretion of IL-8, which promotes tumorigenesis in mice via IL-17A-mediated inflammation. A HSD is characteristic of the Western-type diet and can exhibit inflammatory effects. However, a HSD induces effects in ETBF-induced colitis and tumorigenesis remain unknown. In this study, we investigated HSD effects in ETBF-colonized mice with azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis as well as ETBF colitis mice. Unexpectedly, ETBF-infected mice fed a HSD exhibited decreased weight loss and splenomegaly and reduction of colon inflammation. The HSD significantly decreased the expression of IL-17A and inducible nitric oxide synthase (iNOS) in the colonic tissues of ETBF-infected mice. In addition, serum levels of IL-17A and nitric oxide (NO) were also diminished. However, HT29/C1 colonic epithelial cells treated with sodium chloride showed no changes in BFT-induced cellular rounding and IL-8 expression. Furthermore, HSD did not affect ETBF colonization in mice. In conclusion, HSD decreased ETBF-induced tumorigenesis through suppression of IL-17A and iNOS expression in the colon. HSD also inhibited colonic polyp numbers in the ETBF-infected AOM/DSS mice. Taken together, these findings suggest that a HSD consumption inhibited ETBF-promoted colon carcinogenesis in mice, indicating that a HSD could have beneficial effects under certain conditions.

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Vitamin D deficiency in the ApcPirc/+ rat does not exacerbate colonic tumorigenesis, while low dietary calcium might be protective.

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Vitamin D deficiency in the <i>Apc<sup>Pirc/+</sup></i> rat does not exacerbate colonic tumorigenesis, while low dietary calcium might be protective.

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