title: Prevention of preneoplastic lesions by dietary vitamin D in a mouse model of colorectal carcinogenesis.
abstract: Colorectal cancer (CRC) is one of the leading causes of cancer morbidity and mortality in Western countries. One of the risk factors for colorectal tumorigenesis is vitamin D insufficiency. The aim of this study was to establish whether increasing dietary vitamin D intake can prevent or delay development of chemically induced preneoplastic lesions in the colon of mice. We fed six weeks old female C57BL/6J mice (n=28) with increasing vitamin D3 concentrations (100, 400, 1000, 2500, 5000IU/kg diet). To induce dysplasia, a preneoplastic lesion, we injected mice with the carcinogen azoxymethane (10mg/kg) intraperitoneally, followed by three cycles of 2% dextran sodium sulfate salt, a tumor promoter, in the drinking water. To test our hypothesis that high vitamin D intake prevents formation of preneoplastic lesions, we have investigated the effect of increasing dietary vitamin D on development of premalignant colorectal lesions, serum 25-hydroxyvitamin D3 (25-D3) levels, and expression of renal vitamin D system genes. Dietary vitamin D concentration correlated inversely with dysplasia score (Spearman's correlation coefficient, ρ: -0.579, p=0.002) and positively with serum 25-D3 levels (ρ: 0.752, p=0.001). Increasing dietary vitamin D concentration beyond 1000IU/kg led to no further increase in circulating 25-D3 levels, while the dysplasia score leveled out at ≥2500IU/kg vitamin D. High dietary vitamin D intake led to increased renal mRNA expression of the vitamin D catabolizing enzyme cyp24a1 (ρ: 0.518, p=0.005) and decreased expression of the vitamin D activating enzyme cyp27b1 (ρ: -0.452, p=0.016), protecting the body from toxic serum levels of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25-D3). Our data showed that increasing dietary vitamin D intake is able to prevent chemically induced preneoplastic lesions. The maximum impact was achieved when the mice consumed more than 2500IU vitamin D/kg diet. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
authors.affiliation: Department of Pathophysiology and Allergy Research, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. doris.hummel@meduniwien.ac.at
authors.forename: Doris Maria
authors.initials: DM
authors.lastname: Hummel
authors.forename: Ursula
authors.initials: U
authors.lastname: Thiem
authors.forename: Julia
authors.initials: J
authors.lastname: Höbaus
authors.forename: Ildiko
authors.initials: I
authors.lastname: Mesteri
authors.forename: Lukas
authors.initials: L
authors.lastname: Gober
authors.forename: Caroline
authors.initials: C
authors.lastname: Stremnitzer
authors.forename: João
authors.initials: J
authors.lastname: Graça
authors.forename: Barbara
authors.initials: B
authors.lastname: Obermayer-Pietsch
authors.forename: Enikö
authors.initials: E
authors.lastname: Kallay
mesh_terms: D000818:Animals; D002762:Cholecalciferol / Q000008:administration & dosage* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D019587:Dietary Supplements / Q000009:adverse effects; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*
chemical_list: D002762:Cholecalciferol