Heterocyclic aromatic amines (HAA) are initiating agents of colon carcinogenesis in animals and are suspected in the aetiology of human colon cancer. In the context of prevention, it seems interesting to test possible protective compounds, such as fermented milk, against HAA food carcinogens. Male F344 rats were used in a model of HAA-induced colon carcinogenesis. The HAA, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (ratio 1:1:1) were administered in food for a 7 week induction period, with a cumulative dose of 250 mg of the HAA, per kg body weight. Four different diets were given to four rat groups: supplemented with 20% water, 30% non-fermented milk, 30% Bifidobacterium animalis DN-173 010 fermented milk and 30% Streptococcus thermophilus DN-001 158 fermented milk. Fecal mutagenicity was quantified during the induction period. At the end of the treatment, DNA lesion levels were determined in the liver and colon using the number of 8-oxo-7,8-dihydro-2'desoxyguanosine (8-oxodGuo) oxidized bases, "3D Test" and comet assay. The metabolic activity of hepatic and colon cytochrome P450 (CYP450) 1A1 and 1A2 was also evaluated. Aberrant colon crypts were scored, 8 weeks after the last HAA treatment. The results showed that dairy products decreased the incidence of aberrant crypts in rats: 66% inhibition with the milk-supplemented diet, 96% inhibition with the B.animalis fermented milk-supplemented diet and 93% inhibition with the S.thermophilus fermented milk-supplemented diet. Intermediate biomarkers showed that there was a decrease in HAA metabolism, fecal mutagenicity and colon DNA lesions. These results demonstrate the early protective effect of milk in the carcinogenesis process. This effect being more pronounced in the case of milk fermented by lactic acid bacteria.

This study reports the modulating effect of some dairy products on initiation of putative preneoplasic lesions in rat colon (aberrant crypts) by 1,2-dimethylhydrazine dihydrochloride. Uninoculated skim milk, skim milk fermented with Bifidobacterium sp Bio (Danone strain 173010), and a suspension of the same lactic acid bacteria were incorporated in the animals' diet. The tested diets significantly reduced the incidence of aberrant crypts compared with the control diet by 51%, 49%, and 61%, respectively. The effects of the diets on cecal pH, hepatic UDP-glucuronyltransferase activity, and cecal microflora enzyme beta-glucuronidase were also studied. There was no significant difference in cecal pH between rats fed experimental diets and control rat. The diet supplemented with the Bifidobacterium strain suspension significantly decreased only the cecal beta-glucuronidase activity. Both enzyme activities were reduced in rats fed fermented skim milk- or uninoculated skim milk-supplemented diets compared with control animals.

Epidemiologic studies suggest that intake of high energy from fat, inducing overweight, increases the risk of cancer development and promotes colon carcinogenesis. It is therefore important to understand which parameters are affected early on by a high-fat diet in order to devise and improve protective nutritional strategies. We investigated the effect of high energy/fat intake on colon mucosa of male Wistar rats induced by a single 1,2-dimethylhydrazine (DMH) injection. Aberrant crypt foci (ACF) were numbered and modifications in cyclooxygenase-2 (COX-2) and b-catenin levels assessed. Peroxisome proliferator-and retinoic acid-activated receptors (PPAR and RAR, RXR) are key transcription factors regulating gene expression in response to nutrient-activated signals. A short-term study was designed to evaluate whether alterations in mRNA expression of nuclear receptors can be detected at the beginning of the weight gain phase induced by an appetizing hyperlipidic diet (HLD). HLD consumption induced early downregulation of PPARc (-33.1%) and RARb (-53.1%) mRNA expression concomitant with an increase in levels of COX-2 (145.5%) and b-catenin (184.56%) and in the number of ACF (191.56 6 88.60 vs. 21.14 6 11.64, p < 0.05). These findings suggest that HLD increases ACF occurrence, possibly through alterations in the mRNA expression profile of nuclear receptors. Moreover, the use HLD rich in retinyl esters or supplemented with all-trans retinoic acid led to a reduction in the number of ACF. Vitamin A also prevented HLD-induced alterations and the increase in levels of COX-2 and b-catenin. The present observations show a protective role for vitamin A against disturbances associated with HLD exposure in induced colon carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: colon carcinogenesis; nuclear receptor; high energy/fat intake; vitamin A The incidence of obesity and colon cancer is increasing in all industrialized countries. Colon carcinogenesis is a multifactorial disease, and diet is strongly involved in its etiology. A prospective cohort study has reported that increased body weight was associated with increased death rates form cancer.1 Thus, the high prevalence of obesity, explained by a lifestyle characterized by high energy/fat intake, led to increased risk of colon cancer development. These conclusions are reinforced by data suggesting that the number of preneoplastic colonic lesions 2-4 induced by a high-fat diet is reduced by restriction of energy intake 5 or by fiber-and vitamin-rich diets. 6,7 These data illustrate the potential of nutritional methods for reducing the deleterious consequences of high fat/energy intake on the risk of colon cancer.It is likely that diet affects cancer occurrence at the level of the cell signaling pathways rather than at the level of mutations. Nuclear receptors have a central role in the regulation of gene expression in response to diet. Thus, growing evidence points to the involvement of nuclear receptors in colon tumorigenesis. Indeed, they function as ligand-activated transcr...

In order to study the effects of dietary lipids and vitamin A on the development of adipose tissues, young rats were submitted for 8 d to a control or to two cafeteria diets with normal (Caf) or higher (Caf þ ) vitamin A levels. Retinoid (retinoic acid receptor (RAR) a, RARg, retinoid X receptor (RXR) a) and fatty acid (PPARg) receptor mRNA was measured in the subcutaneous white adipose tissue (Swat) and in isolated mature adipocytes by RT-PCR. The stroma vascular fraction was cultured in vitro to test the capacities of the adipocyte precursors to proliferate and differentiate. The Caf diet enriched in vitamin A resulted in an increased adiposity, due to increased adipocyte hypertrophy. This was concomitant with a lower expression of RARa and RARg mRNA (234·6 and 238·6 %) and a higher expression of PPARg (þ 59 %) in the Swat and, to a less extent, in isolated adipocytes. Positive correlations were obtained between PPARg mRNA and Swat weights and between PPARg and RXRa mRNA. By contrast, RARg mRNA and Swat masses were negatively correlated. The adipocyte precursors from Caf þ Swat proliferated more, in vitro, at the beginning of the culture. This difference progressively disappeared and was totally absent after 8 d of culture, but with a higher percentage of differentiated preadipocytes (þ 80·3 %) in the Caf þ group. In conclusion, lipids and vitamin A act synergistically on the normal growth of the adipose tissue in young rats, concomitant with an imbalance in the pattern of the nuclear receptors. These changes influence the early normal development of the endogenous adipocyte precursors.Diet-induced obesity: Peroxisome proliferator-activated receptor: Retinoic acid receptor: Retinoid X receptor: Adipogenesis Today, it is clearly acknowledged that environmental factors and especially dietary factors may largely contribute to the development of obesity (1)

Background: Epidemiological studies on risk factors for colorectal cancer (CRC) have mainly focused on diet, and being overweight is now recognized to contribute significantly to CRC risk. Overweight and obesity are defined as an excess of adipose tissue mass and are associated with disorders in lipid metabolism. Peroxisome proliferator-activated receptors (PPARs) and retinoidactivated receptors (RARs and RXRs) are important modulators of lipid metabolism and cellular homeostasis. Alterations in expression and activity of these ligand-activated transcription factors might be involved in obesity-associated diseases, which include CRC. Cyclooxygenase-2 (COX-2) also plays a critical role in lipid metabolism and alterations in COX-2 expression have already been associated with unfavourable clinical outcomes in epithelial tumors. The objective of this study is to examine the hypothesis questioning the relationship between alterations in the expression of nuclear receptors and COX-2 and the weight status among male subjects with CRC.