Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    New concepts for risk and safety assessment of botanicals and botanical preparations including plant food supplements (PFS)
    Berg, S.J.P.L. van den - \ 2014
    Wageningen University. Promotor(en): Ivonne Rietjens, co-promotor(en): Ans Punt. - Wageningen : Wageningen University - ISBN 9789461739377 - 253
    voedselsupplementen - plantaardige producten - plantextracten - risicoschatting - genotoxiciteit - carcinogenese - ocimum basilicum - venkel - food supplements - plant products - plant extracts - risk assessment - genotoxicity - carcinogenesis - ocimum basilicum - fennel
    Transient inflammatory-like state and microbial dysbiosis are pivotal in establishment of mucosal homeostasis during colonisation of germ-free mice
    Aidy, S.F. El; Derrien, M.M.N. ; Aardema, R. ; Hooiveld, G.J. ; Richards, S.E. ; Dane, A. ; Dekker, J. ; Vreeken, R. ; Levenez, F. ; Doré, J. ; Zoetendal, E.G. ; Baarlen, P. van; Kleerebezem, M. - \ 2014
    Beneficial Microbes 5 (2014)1. - ISSN 1876-2883 - p. 67 - 77.
    bowel-disease - gut microbiota - nitric-oxide - intestinal inflammation - ulcerative-colitis - nkt cells - carcinogenesis - infection - responses - glutamine
    The gut microbiota is increasingly recognised as a key-player in defining the health status of the gastrointestinal tract. Recently, we demonstrated that colonisation of healthy germfree mice with a conventional microbiota (conventionalisation) elicits temporal and region specific host-microbe communication responses that lead to the establishment of a microbiota-accommodating homeostatic state within 30 days. Here, the microbiota composition profiles, mucosal transcriptomes and plasma-analytes in germ-free and conventionalised C57/BL 6 J mice were assessed to decipher the features of the distinctive and pivotal events occurring four days after initiation of the conventionalisation process. The dominance of the microbial genera Helicobacter, Sphingomonas and Mucispirillum in the gut microbiota coincided with the transient mounting of proinflammatory responses in the mucosa and the transiently elevated levels of specific (inflammatory) cytokines and amines in plasma. The overrepresented microbes have previously been associated with the potential to cause disease under certain conditions, illustrating that conventionalisation proceeds through a transient state that resembles situations associated with dysbiosis. However, no overt mucosal inflammation was observed, suggesting a pivotal role of the overrepresented bacterial groups in priming and maturation of the immune system during the process of conventionalisation. These findings imply that the transiently elevated relative overgrowth of particular microbial genera functions as pivotal adjuvants to elicit the corresponding proinflammatory cascades, which precede the full maturation of the different arms of the immune system following these events and is required to achieve a microbiota-accommodating homeostasis in healthy animals
    Dietary heme induces acute oxidative stress, but delayed cytotoxicity and compensatory hyperproliferation in mouse colon
    IJssenagger, N. ; Rijnierse, A. ; Wit, N.J.W. de; Boekschoten, M.V. ; Dekker, J. ; Schonewille, A. ; Müller, M.R. ; Meer, M. van der - \ 2013
    Carcinogenesis 34 (2013)7. - ISSN 0143-3334 - p. 1628 - 1635.
    colorectal-cancer risk - red meat - rat colon - distal colon - ppar-alpha - consumption - chlorophyll - fish - carcinogenesis - proliferation
    Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by generating cytotoxic and oxidative stress. Recently, we found that this surface injury is compensated by hyperproliferation and hyperplasia of crypt cells, which was induced by a changed surface to crypt signaling. It is unknown whether this changed signaling is caused by cytotoxic stress and/or oxidative stress, as these processes were never studied separately. The aim of this study was to determine the possible differential effects of dietary heme on these luminal stressors and their impact on the colonic mucosa after 2, 4, 7 and 14 days of heme feeding. Mice received a purified, humanized, control diet or the diet supplemented with 0.2 µmol heme/g. Oxidative and cytotoxic stress were measured in fecal water. Proliferation was determined by Ki67-immunohistochemistry and mucosal responses by whole-genome transcriptomics. After heme ingestion, there was an acute increase in reactive oxygen species (ROS) leading to increased levels of lipid peroxidation products. Mucosal gene expression showed an acute antioxidant response, but no change in cell turnover. After day 4, cytotoxicity of the colonic contents was increased and this coincided with differential signaling and hyperproliferation, indicating that cytotoxicity was the causal factor. Simultaneously, several oncogenes were activated, whereas the tumor suppressor p53 was inhibited. In conclusion, luminal cytotoxicity, but not ROS, caused differential surface to crypt signaling resulting in mucosal hyperproliferation and the differential expression of oncogenes and tumor suppressor genes.
    Fruit and vegetable consumption and risk of aggressive and non-aggressive urothelial cell carcinomas in the European prospective investigation into cancer and nutrition
    Ros, M. ; Bueno-de-Mesquita, H.B. ; Kampman, E. ; Büchner, F.L. ; Aben, K.K. ; Egevad, L. ; Overvad, K. ; Tjonneland, A. ; Roswall, N. ; Clavel-Chapelon, F. ; Boutron-Ruault, M.C. ; Moiros, S. ; Kaaks, R. ; Teucher, B. ; Weikert, S. ; Ruesten, A.V. ; Trichopoulou, A. ; Naska, A. ; Benetou, V. ; Saieva, C. ; Pala, V. ; Ricceri, F. ; Tumino, R. ; Mattiello, A. ; Peeters, P.H.M. ; Gils, C.H. van; Gram, I.T. ; Engeset, D. ; Chirlaque, M.D. ; Ardanazx, E. ; Rodriguez, L. - \ 2012
    European Journal of Cancer 48 (2012)17. - ISSN 0959-8049 - p. 3267 - 3277.
    bladder-cancer - vitamin-c - prospective cohort - carotenoids - smoking - diet - carcinogenesis - prevention - nutrient - folate
    Background - Many epidemiological studies have examined fruit and vegetable consumption in relation to the risk of urothelial cell carcinoma (UCC) of the bladder, but results are inconsistent. The association between fruit and vegetable consumption and UCC risk may vary by bladder tumour aggressiveness. Therefore, we examined the relation between fruit and vegetable consumption and the risk of aggressive and non-aggressive UCC in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods - After 8.9 years of follow-up, 947 UCC were diagnosed among 468,656 EPIC participants. Of these, 421 could be classified as aggressive UCC and 433 as non-aggressive UCC cases. At recruitment, fruit and vegetable consumption was assessed by validated dietary questionnaires. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for smoking status, duration and intensity of smoking, and energy intake. Results - Total consumption of fruits and vegetables was not associated with aggressive UCC nor with non-aggressive UCC. A 25 g/day increase in leafy vegetables and grapes consumption was associated with a reduced risk of non-aggressive UCC (hazard ratio (HR) 0.88; 95% confidence interval (CI) 0.78–1.00 and HR 0.87; 95% CI 0.77–0.98, respectively), while the intake of root vegetables was inversely associated with risk of aggressive UCC (HR 0.87; 95% CI 0.77–0.98). Conclusion - Our study did not confirm a protective effect of total fruit and/or vegetable consumption on aggressive or non-aggressive UCC. High consumption of certain types of vegetables and of fruits may reduce the risk of aggressive or non-aggressive UCC; however chance findings cannot be excluded.
    Dietary heme-mediated PPARa activation does not affect the heme-induced epithelial hyperproliferation and hyperplasia in mouse colon
    IJssenagger, N. ; Wit, N.J.W. de; Muller, M.R. ; Meer, R. van der - \ 2012
    PLoS ONE 7 (2012)8. - ISSN 1932-6203
    acid-binding protein - oxidative stress - red meat - gene-expression - rat colon - cancer - mice - carcinogenesis - cells - risk
    Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by luminal cytotoxicity and reactive oxygen species. This surface injury is overcompensated by hyperproliferation and hyperplasia of crypt cells. Transcriptome analysis of mucosa of heme-fed mice showed, besides stress- and proliferation-related genes, many upregulated lipid metabolism-related PPARa target genes. The aim of this study was to investigate the role of PPARa in heme-induced hyperproliferation and hyperplasia. Male PPARa KO and WT mice received a purified diet with or without heme. As PPARa is proposed to protect against oxidative stress and lipid peroxidation, we hypothesized that the absence of PPARa leads to more surface injury and crypt hyperproliferation in the colon upon heme-feeding. Heme induced luminal cytotoxicity and lipid peroxidation and colonic hyperproliferation and hyperplasia to the same extent in WT and KO mice. Transcriptome analysis of colonic mucosa confirmed similar heme-induced hyperproliferation in WT and KO mice. Stainings for alkaline phosphatase activity and expression levels of Vanin-1 and Nrf2-targets indicated a compromised antioxidant defense in heme-fed KO mice. Our results suggest that the protective role of PPARa in antioxidant defense involves the Nrf2-inhibitor Fosl1, which is upregulated by heme in PPARa KO mice. We conclude that PPARa plays a protective role in colon against oxidative stress, but PPARa does not mediate heme-induced hyperproliferation. This implies that oxidative stress of surface cells is not the main determinant of heme-induced hyperproliferation and hyperplasia
    The development of improved and new in vitro assays for detecting the genotoxic and non-genotoxic carcinogenic potential of chemicals in the discovery phase of drug development
    Westerink, W.M.A. - \ 2011
    Wageningen University. Promotor(en): Ivonne Rietjens; John Groten, co-promotor(en): W.G.E.J. Schoonen. - [S.l. : S.n. - ISBN 9789085858478 - 288
    genotoxiciteit - carcinogenese - nieuwe geneesmiddelen - geneesmiddelenontwikkeling - in vitro - in vitro kweek - genotoxicity - carcinogenesis - new drugs - drug development - in vitro - in vitro culture
    In drug development, toxicity is an important factor for attrition, resulting in a failure rate of 30%-40%. Hepatotoxicity, nephrotoxicity, cardiovascular safety, reproduction toxicity, developmental toxicity (teratogenicity), genotoxicity and carcinogenicity are the main causes for attrition in safety assessment.
    Screening on these aspects in the early discovery phase of drug development and using these data for compound optimization and deselection might result in drug development candidates with an improved success rate. The present thesis focused on early screening for genotoxicity and carcinogenicity.
    In recent years some progress has been made with assays to assess genotoxicity and non-genotoxic carcinogenicity at the end of the discovery phase. However, the time point at which these genotoxicity and carcinogenicity assays are performed is still relatively late, only a few assays for such a strategy are available, the throughput of these assays is in general still low and most of them have not yet been validated extensively. An additional drawback is that the currently used in vitro assays for the detection of genotoxicity give a high rate of false positive results, which makes application in the early discovery phase of drug development cumbersome.
    The goal of the present thesis was therefore to develop improved and new in vitro assays for detecting the genotoxic and non-genotoxic carcinogenic potential of chemicals, validate these assays with proper reference compounds, and to develop a strategy for application of these assays in the early discovery phase of drug development.
    High throughput assays based on bacteria, yeast and human/rodent cell lines were developed. In the case of human cell lines, the focus was on the HepG2 cell line as the properties of HepG2 cells are expected to give a good prediction for in vivo genotoxicity. The results in this thesis show that an early prediction can be made for bacterial mutagenicity (gene mutations), mammalian genotoxicity (chromosome damage), and non-genotoxic carcinogenic potential by aryl hydrocarbon receptor (AhR) activation. To develop a strategy for application of the HTS genotoxicity assays in the early discovery phase several combinations of assays were evaluated. The combination VitotoxTM + HepG2 p53 reporter assay was based on the presented results in this thesis the most useful for screening compounds for their genotoxic potential in the early drug discovery phase without the risk on high numbers of false positives. CYP1A induction assays in human HepG2 and rat H4IIE cells may be performed in parallel with these assays to be able to detect non-genotoxic carcinogenic potential by AhR activators. Further application of these assays may prove useful in future drug development strategies.

    Increasing fish consumption does not affect genotozicity markers in the colon in an intervention study
    Pot, G.K. ; Habermann, N. ; Majsak-Newman, G. ; Harvey, L.J. ; Geelen, A. ; Witteman, B.J.M. ; Meeberg, P.C. van de; Hart, A.R. ; Schaafsma, G. ; Hooiveld, G.J.E.J. ; Glei, M. ; Lund, E.K. ; Pool-Zobel, B.L. ; Kampman, E. - \ 2010
    Carcinogenesis 31 (2010)6. - ISSN 0143-3334 - p. 1087 - 1091.
    polyunsaturated fatty-acids - rectal cell-proliferation - fecal water genotoxicity - colorectal-cancer risk - induced dna-damage - comet assay - oxidative stress - eicosapentaenoic acid - dietary - carcinogenesis
    Observational studies suggest that fish consumption is associated with a decreased colorectal cancer (CRC) risk. A possible mechanism by which fish could reduce CRC risk is by decreasing colonic genotoxicity. However, concerns have also been raised over the levels of toxic compounds found in mainly oil-rich fish, which could increase genotoxicity. Therefore, the objective was to investigate the effects of fish on genotoxicity markers in the colon in a randomized controlled parallel intervention study. For a period of 6 months, subjects were randomly allocated to receive two extra weekly portions of (i) oil-rich fish (salmon), (ii) lean fish (cod) or (iii) just dietary advice (DA). The Comet Assay was used to measure the DNA damage-inducing potential of fecal water (n = 89) and DNA damage in colonocytes (n = 70) collected pre- and post-intervention as markers of genotoxicity. Genotoxicity of fecal water was not markedly changed after fish consumption: 1.0% increase in tail intensity (TI) [95% confidence interval (CI) -5.1; 7.0] in the salmon group and 0.4% increase in TI (95% CI -5.3; 6.1) in the cod group compared with the DA group. DNA damage in colonocytes was also not significantly changed after fish consumption, in either the salmon group (-0.5% TI, 95% CI -6.9; 6.0) or cod group (-3.3% TI, 95% CI -10.8; 4.3) compared with the DA group. Measurements of genotoxicity of fecal water and DNA damage in colonocytes did not correlate (r = 0.06, n = 34). In conclusion, increasing consumption of either oil-rich or lean fish did not affect genotoxicity markers in the colon.
    Increased consumption of fatty and lean fish reduces serum c-reactive protein concentrations but not inflammation markers in feces and in colonic biopsies
    Pot, G.K. ; Geelen, A. ; Majsak-Newman, G. ; Harvey, L.J. ; Nagengast, F.M. ; Witteman, B.J.M. ; Meeberg, P.C. van de; Hart, A.R. ; Schaafsma, G. ; Lund, E.K. ; Rijkers, G.T. ; Kampman, E. - \ 2010
    The Journal of Nutrition 140 (2010)2. - ISSN 0022-3166 - p. 371 - 376.
    colorectal-cancer risk - multiplex immunoassay - oxidative stress - bowel-disease - cytokines - acids - plasma - carcinogenesis - validation - sample
    Fish consumption is associated with a reduced colorectal cancer risk. A possible mechanism by which fish consumption could decrease colorectal cancer risk is by reducing inflammation. However, thus far, intervention studies investigating both systemic and local gut inflammation markers are lacking. Our objective in this study was to investigate the effects of fatty and lean fish consumption on inflammation markers in serum, feces, and gut. In an intervention study, participants were randomly allocated to receive dietary advice (DA) plus either 300 g of fatty fish (salmon) or 300 g of lean fish (cod) per week for 6 mo, or only DA. Serum C-reactive protein (CRP) concentrations were measured pre- and postintervention (n = 161). In a subgroup (n = 52), we explored the effects of the fish intervention on fecal calprotectin and a wide range of cytokines and chemokines in fecal water and in colonic biopsies. Serum CRP concentrations were lower in the salmon (-0.5 mg/L; 95% CI -0.9, -0.2) and cod (-0.4 mg/L; 95% CI -0.7, 0.0) groups compared with the DA group. None of the inflammation markers in fecal water and colonic biopsies differed between the DA group and the groups that consumed extra fish. In conclusion, increasing salmon or cod consumption for 6 mo resulted in lower concentrations of the systemic inflammation marker CRP. However, exploratory analysis of local markers of inflammation in the colon or feces did not reveal an effect of fish consumption.
    Fish consumption, does it beneficially affect markers of colorectal carcinogenesis?
    Pot, G.K. - \ 2009
    Wageningen University. Promotor(en): Ellen Kampman; G. Schaafsma, co-promotor(en): Anouk Geelen. - [S.l. : S.n. - ISBN 9789085854456 - 118
    visconsumptie - colorectaal kanker - carcinogenese - fish consumption - colorectal cancer - carcinogenesis
    Background: Fish consumption is possibly associated with a decreased risk of colorectal cancer, as has been shown in several observational studies. However, most of these studies did not discriminate between the effects of oil-rich and lean fish. To date, no randomized controlled trials (RCTs) have examined the possible beneficial effects of fish intake on colorectal cancer risk.
    Aim: The aim of this thesis was to investigate whether fish consumption beneficially affects markers of colorectal carcinogenesis.
    Methods and Results: In a case control study (363 cases, 498 controls), we studied the association of serum n 3 polyunsaturated fatty acid (PUFA) levels as a marker of oil rich fish intake with colorectal adenomas, a precursor lesion of colorectal cancer. We found that individuals with high serum long chain n 3 PUFA levels had a decreased risk of colorectal adenomas (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.46; 0.96), whereas individuals with high serum n 6 PUFA levels had an increased risk of colorectal adenomas (OR 1.68, 95% CI 1.17; 2.42).
    In an RCT, we studied the effects of 3.5g/d fish oil (~1.5g/d n 3 PUFA) for 12 weeks on 19 serum inflammation markers in 77 healthy subjects and found that serum levels of these cytokines and chemokines were not changed.
    Finally, we studied the effects of increasing fish consumption compared with no additional fish, on markers of colorectal carcinogenesis in an RCT. Subjects (n=242), at an increased risk of colorectal cancer and those with no macroscopic signs of disease, were randomly allocated to receive dietary advice (DA) plus either two additional weekly portions of oil rich fish (salmon, ~1.4g/d n 3 PUFA) or lean fish (cod, ~0.09 g/d n 3 PUFA), or only DA for six months. We observed no change in apoptotic and mitotic cell numbers after the 6 months intervention with either salmon or cod compared with DA. Furthermore, colorectal genotoxicity, levels of cytokines and chemokines in colonic biopsies and feces, and fecal calprotectin were also not markedly changed after fish consumption. Only serum C reactive protein (CRP) levels were statistically significantly decreased after consumption of salmon ( 0.5 mg/l, 95% CI 0.9; 0.2) and cod ( 0.4 mg/l, 95% CI 0.7; 0.0) compared with DA.
    Conclusion: The results of this thesis do not provide strong evidence for beneficial effects of fish consumption on markers of colorectal carcinogenesis.

    Physiologically based biokinetic (PBBK) models to characterize dose dependent effects, species differences, and interindividual human variation and detoxification of estragole
    Punt, A. - \ 2009
    Wageningen University. Promotor(en): Ivonne Rietjens; Peter van Bladeren, co-promotor(en): B. Schilter. - [S.l.] : s.n. - ISBN 9789085853718 - 251
    toxiciteit - soortverschillen - metabolische detoxificatie - etherische oliën - risicoschatting - carcinogenese - toxicity - species differences - metabolic detoxification - essential oils - risk assessment - carcinogenesis - cum laude
    cum laude graduation (with distinction)
    An n-3 PUFA-rich microalgal oil diet protects to a similar extent as a fish oil-rich diet against AOM-induced colonic aberrant crypt foci in male F344 rats
    Beelen, V.A. van; Spenkelink, A. ; Mooibroek, H. ; Sijtsma, L. ; Bosch, H.J. ; Rietjens, I.M.C.M. ; Alink, G.M. - \ 2009
    Food and Chemical Toxicology 47 (2009)2. - ISSN 0278-6915 - p. 316 - 320.
    polyunsaturated fatty-acids - tumor-incidence - chemopreventive agents - docosahexaenoic acid - oxidation-products - regulated genes - corn-oil - cancer - carcinogenesis - azoxymethane
    The chemopreventive effects of high fat microalgal oil diet on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were studied in male Fischer 344 rats following 8 weeks of dietary treatment. These effects were compared to the effects of high fat fish oil and high fat corn oil diets to determine whether microalgal oil is a good alternative for fish oil regarding protection against colorectal cancer. Despite the difference in fatty acid composition and total amount of n-3 polyunsaturated fatty acids (PUFAs) between microalgal oil and fish oil, both these oils gave the same 50% reduction of AOM-induced ACF when compared to corn oil. To determine whether oxidative stress could play a role in the chemoprevention of colorectal cancer by n-3 PUFAs, feces and caecal content were examined using the TBA assay. The results showed that lipid peroxidation does occur in the gastrointestinal tract. As several lipid peroxidation products of n-3 PUFAs can induce phase II detoxifying enzymes by an EpRE-mediated pathway, the in vivo results suggest that this route may contribute to n-3 PUFA-mediated chemoprevention. All in all, n-3 PUFA-rich oil from microalgae is as good as fish oil regarding chemoprevention in the colon of the rat.
    Diet, lifestyle, heritable factors and colorectal carcinogenesis: associations with histopathological and molecular endpoints
    Wark, P.A. - \ 2007
    Wageningen University. Promotor(en): Pieter van 't Veer; Frans Kok, co-promotor(en): M.P. Weijenberg. - [S.l.] : S.n. - ISBN 9789085045755 - 191
    colorectaal kanker - carcinogenese - dieet - levensstijl - overerving - histopathologie - fruit - groenten - colorectal cancer - carcinogenesis - diet - lifestyle - inheritance - histopathology - fruit - vegetables

    Background: Diet, lifestyle and heritable factors have been related to colorectal cancer risk; to date, their relevance to the overall scope of colorectal carcinogenesis, has not been clearly established.

    Aim and Methods: To evaluate whether distinguishing colorectal tissue by its histopathological and molecular characteristics sheds further light on the etiology of colorectal cancer. Five research questions addressed associations between diet, lifestyle and heritable factors, and specific tissue characteristics.

    Results: First, we observed that consumption of fruits, in particular citrus fruits, was associated with increased rectal glutathione S-transferase activity in a cross-sectional study of 94 Dutch individuals. Consumption of cruciferous vegetables was also associated with increased activity, but only among individuals who carried the GSTM1 genotype.

    Second, we observed that intake of vitamin B2 was inversely associated with adenomas with a K-ras mutation (n=81) but not with adenomas without a K-ras mutation (n=453) in a case-control study conducted in the Netherlands. A positive association with monounsaturated fat was confined to K-ras mutation-negative adenomas. We found indications for differential associations with some additional factors, but the epidemiological evidence on risk factors and K-ras mutations remains inconsistent.

    Third, in a cohort study of 26,769 American men, we observed that most risk factors were similarly associated with advanced (=1cm or with any villous characteristics or carcinoma in situ) and non-advanced colorectal adenomas after 17 years of follow-up. However, smoking had a stronger positive association with advanced adenomas than with non-advanced adenomas, and ahigh glycemic index was inversely associated with advanced but not with non-advanced adenomas.

    Fourth, associations with family history of colorectal cancer were stronger for men with multiple distal adenomas than for men with a single distal adenoma at first diagnosis, in the aforementioned cohort study among US men. Associations between family history, and advanced and non-advanced adenomas, were of similar strength, but a tendency towards a somewhat stronger association with non-advanced adenomas was found.

    Fifth, fruit consumption was inversely associated with hMLH1 protein-deficient colon cancer (n=54) but not with hMLH1 protein-proficient colon cancer (n=387) in a cohort study of 120,852 people who were followed-up over 7.3 years, while ignoring information from the initial 2.3 years of follow-up. Clear associations with consumption of vegetables, or nutrients related to fruits and vegetables, could not be detected.

    Conclusions: We showed that distinguishing colorectal tumors by their histopathological and molecular characteristics may indeed shed further light on the role of diet, lifestyle and heritable factors in colorectal carcinogenesis. Such an approach may alleviate some of the weaknesses of traditional epidemiology, but also adds another layer of complexity. It is a challenge for the future to develop a framework into which specific associations can be integrated, using risk markers signaling the molecular and biochemical pathways from normal to cancerous tissue.

    Association of smoking, alcohol drinking and dietary factors with esophageal cancer in high- and low-risk areas of Jiangsu Province, China
    Wu Ming, ; Zhao, Jin-Kou ; Hu, Xiao-Shu ; Wang, Pei-Hua ; Qin, Yu ; Lu, Yin-Chang ; Yang, Jie ; Liu, Ai-Min ; Wu De-Lin, ; Zhang, Zuo-Feng ; Kok, F.J. ; Veer, P. van 't - \ 2006
    World Journal of Gastroenterology 12 (2006)11. - ISSN 1007-9327 - p. 1686 - 1693.
    body-mass index - tobacco smoking - stomach cancers - gastric cardia - mate drinking - united-states - consumption - men - adenocarcinomas - carcinogenesis
    To study the main environmental and lifestyle factors that account for the regional differences in esophageal cancer (EC) risk in low- and high-risk areas of Jiangsu Province, China. Since 2003, a population-based casecontrol study has been conducted simultaneously in lowrisk (Ganyu County) and high-risk (Dafeng County) areas of Jiangsu Province, China. Using identical protocols and pre-tested standardized questionnaire, following written informed consent, eligible subjects were inquired about their detail information on potential determinants of EC, including demographic information, socio-economic status, living conditions, disease history, family cancer history, smoking, alcohol drinking, dietary habits, frequency, amount of food intake, etc. Conditional logistic regression with maximum likelihood estimation was used to obtain Odds ratio (OR) and 95 % confi dence interval (95% CI), after adjustment for potential confounders In the preliminary analysis of the ongoing study, we recruited 291 pairs of cases and controls in Dafeng and 240 pairs of cases and controls in Ganyu, respectively. In both low-risk and high-risk areas, EC was inversely associated with socio-economic status, such as level of education, past economic status and body mass index. However, this disease was more frequent among those who had a family history of cancer or encountered misfortune in the past 10 years. EC was also more frequent among smokers, alcohol drinkers and fast eaters. Furthermore, there was a geographic variation of the associations between smoking, alcohol drinking and EC risk despite the similar prevalence of these risk factors in both low-risk and high-risk areas. The dose-response relationship of smoking and smoking related variables, such as age of the fi rst smoking, duration and amount were apparent only in high-risk areas. On the contrary, a dose-response relationship on the effect of alcohol drinking on EC was observed only in low-risk areas
    Green vegetables and colon cancer: the mechanism of a protective effect by chlorophyll
    Vogel, J. de - \ 2006
    Wageningen University. Promotor(en): M.B. Katan; Roelof van der Meer. - [S.l. ] : S.n. - ISBN 9789085043478 - 151
    colorectaal kanker - bladgroenten - chlorofyl - vlees - carcinogenese - ratten - dierproeven - colorectal cancer - leafy vegetables - chlorophyll - meat - carcinogenesis - rats - animal experiments
    One of the important environmental determinants of the risk of colon cancer is the composition of the diet. Regular consumption of high amounts of red meat increases colon cancer risk. In contrast, consumption of green vegetables decreases the risk of colon cancer. This thesis provides a molecular mechanism of how these two dietary components might modulate colon cancer risk.
    Folate metabolism in the human colon: cellular responses identified through in vitro studies
    Pellis, E.P.M. - \ 2006
    Wageningen University. Promotor(en): Frans Kok, co-promotor(en): Jaap Keijer; Ellen Kampman. - s.l. : S.n. - ISBN 9789085044277 - 160
    foliumzuur - metabolisme - karteldarm - colorectaal kanker - vitaminetoevoegingen - carcinogenese - in vitro - folic acid - metabolism - colon - colorectal cancer - vitamin supplements - carcinogenesis - in vitro
    Low folate intake influences the risk of not only neural tube defects and vascular diseases, but also colorectal tumours. Folate forms have different roles in the one-carbon metabolism. This includes DNA synthesis and methylation reactions. Folate is present as 5'-methyltetrahydrofolate (MTHF) in the diet and plasma, while in supplements the synthetic form is present, known as folic acid (pteryol glutamic acid, PGA). In animal studies, PGA seemed to have dual modulatory effects on colorectal carcinogenesis depending on the timing and dose of intervention. In this thesis the effect of different folate forms and dosages in the colon were studied in vitro using a nutrigenomics approach. The DNA microarray technique was applied to study the expression pattern of thousands of genes, and assess known and identify new processes affected by folate. Gene expression analysis revealed that high PGA concentrationsincreased energy metabolism and lowered iron metabolism related genes in the human colorectal cell line, HT29. Further investigation showed that intracellular iron concentration was decreased in three human colorectal cell lines. This effect on iron metabolism was studied in an existing human randomized, placebo-controlled trial. After six months of folate supplementation the serum ferritin, but not the colonic iron, was decreased. We also studied the difference between PGA and MTHF exposure in HT29 cells, using a physiological concentration range of both folates. A dose dependent effect was found for both folates. The normal serum values of PGA increased genes involved in the folate metabolism, compared to identical MTHF concentration. Supplemental concentrations of MTHF affected protein synthesis, endoplasmatic reticulum/Golgi and cancer related genes, compared to identical PGA concentrations. More specifically, high MTHF increased differentiation, adhesion and cell viability; all known cancer related processes. This may suggest a more beneficial effect of MTHF as compared to PGA. However we need to further investigate the effect of PGA and MTHF on iron metabolism, cancer related processes or energy metabolism in humans. Hopefully this will lead to more insight in the effect of folate supplementation with regard to colorectal carcinogenesis.
    Differential induction of electrophile-responsive element-regulated genes by n-3 and n-6 polyunsaturated fatty acids
    Beelen, V.A. van; Aarts, M.G.M. ; Reus, A. ; Mooibroek, H. ; Sijtsma, L. ; Bosch, H.J. ; Rietjens, I.M.C.M. ; Alink, G.M. - \ 2006
    FEBS Letters 580 (2006)19. - ISSN 0014-5793 - p. 4587 - 4590.
    antioxidant response - fish-oil - dietary - carcinogenesis - mechanisms - protection - oxidation - reductase - pathway - cancer
    In this study the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid and docosahexaenoic acid appear to be effective inducers of electrophile-responsive element (EpRE) regulated genes, whereas the n-6 PUFA arachidonic acid is not. These n-3 PUFAs need to be oxidized to induce EpRE-regulated gene expression, as the antioxidant vitamin E can partially inhibit the PUFA induced dose-dependent effect. Results were obtained using a reporter gene assay, real-time RT-PCR and enzyme activity assays. The induction of EpRE-regulated phase II genes by n-3 PUFAs may be a major pathway by which n-3 PUFAs, in contrast to n-6 PUFAs, are chemopreventive and anticarcinogenic.
    The role of B-vitamins - gene interactions in colorectal carcinogenesis: A molecular epidemiological approach
    Donk, M. van den - \ 2005
    Wageningen University. Promotor(en): Frans Kok, co-promotor(en): Ellen Kampman; Jaap Keijer. - [S.l.] : S.n. - ISBN 9789085043287
    colorectaal kanker - carcinogenese - foliumzuur - vitamine b complex - genetische variatie - colorectal cancer - carcinogenesis - folic acid - vitamin b complex - genetic variation
    Folate deficiency can affect DNA methylation and DNA synthesis. Both factors may be operative in colorectal carcinogenesis. Many enzymes, like methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MTR), and serine hydroxymethyltransferase (SHMT), are needed for conversions in folate metabolism. Flavin adenine dinucleotide, a metabolite of vitamin B2, is a cofactor for MTHFR; vitamin B6 is a cofactor for SHMT; and vitamin B12 is a cofactor for MTR. Polymorphisms exist in most of the genes encoding the enzymes that play a role in folate metabolism. Therefore, genetic variation might influence DNA methylation and synthesis processes and thus colorectal carcinogenesis. This thesis describes studies that have been conducted to clarify the role of folate, related B-vitamins, and genetic variation in colorectal carcinogenesis.

    In a meta-analysis of human observational studies on the association between folate intake and risk of colorectal adenomas, includingdata from 4 cohort studies and 10 case-control studies, pooled relative risks (95% confidence interval (CI)) for highestvs.lowest exposure category of 0.85 (0.71;1.01) for dietary folate intake and 0.75 (0.61;0.93) for total folate intake were found.

    In a Dutch case-control study, including data of colorectal adenoma cases (n=768) and endoscopy controls with no history colorectal polyps (n=709), a slightly positive association between folate and colorectal adenoma risk (odds ratio (OR) highest vs. lowest tertile 1.32, 95% CI 1.01;1.73), and an inverse association between vitamin B2 intake and colorectal adenoma risk (OR highestvs.lowest tertile 0.51, 95% CI 0.36;0.73) was found, especially among those withMTHFR 677 TTgenotype. A null association was found for vitamin B6 and vitamin B12. Furthermore, the combined intake of B-vitamins might be important: the positive association between folate intake and colorectal adenomas seemed to be more pronounced among those with low vitamin B2 intakes. The polymorphisms in the folate metabolism studied (MTHFR, TSandSHMT1) did not seem to influence colorectal adenoma risk when dietary factors were not taken into account. Furthermore, relatively high folate intake (>212μg/day) was mildly inversely associated with promoter methylation of six selected tumor suppressor and DNA repair genes in adenoma tissue as compared with low folate intake (<183μg/day), with statisticallynon-significant ORs ranging from 0.54 to 0.86. This effect was mainly restricted to those carrying theMTHFR 677 TTgenotype.

    In a randomized, controlled intervention study including 86 subjects with a history of colorectal adenomas, a high dosage of synthetic folic acid (5 mg/day) and vitamin B12 (1.25 mg/day) for six months seemed to increase uracil incorporation (Δintervention-Δplacebo0.45, 95% CI -0.19;1.09) and promoter methylation of six selected tumor suppressor and DNA repair genes(OR upmethylation 1.67, 95% CI 0.95;2.95), both biomarkers measured inDNA from rectal mucosa biopsies. Again, the effect seemed more pronounced in those with theMTHFR 677 TTgenotype.

    The results of these relatively small studies suggest that a potential adverse effect of folic acid should be considered, especially when administered after colorectal neoplastic lesions have been established. However, these results need to be confirmed by larger studies among other populations with similar relatively low intakes of vitamin B2, in which theMTHFR C677Tgenotype or other polymorphisms in folate metabolism should be taken into account.

    Natural chlorophyll but not chlorophyllin prevents heme-induced cytotoxic and hyperproliferative effects in rat colon
    Vogel, J. de; Jonker-Termont, D.S.M.L. ; Katan, M.B. ; Meer, R. van der - \ 2005
    The Journal of Nutrition 135 (2005)8. - ISSN 0022-3166 - p. 1995 - 2000.
    aberrant crypt foci - colorectal-cancer - cell-proliferation - complex-formation - meat consumption - dna-adducts - red meat - absorption - risk - carcinogenesis
    Diets high in red meat and low in green vegetables are associated with an increased risk of colon cancer. In rats, dietary heme, mimicking red meat, increases colonic cytotoxicity and proliferation of the colonocytes, whereas addition of chlorophyll from green vegetables inhibits these heme-induced effects. Chlorophyllin is a water-soluble hydrolysis product of chlorophyll that inhibits the toxicity of many planar aromatic compounds. The present study investigated whether chlorophyllins could inhibit the heme-induced luminal cytotoxicity and colonic hyperproliferation as natural chlorophyll does. Rats were fed a purified control diet, the control diet supplemented with heme, or a heme diet with 1.2 mmol/kg diet of chlorophyllin, copper chlorophyllin, or natural chlorophyll for 14 d (n = 8/group). The cytotoxicity of fecal water was determined with an erythrocyte bioassay and colonic epithelial cell proliferation was quantified in vivo by [methyl-3H]thymidine incorporation into newly synthesized DNA. Exfoliation of colonocytes was measured as the amount of rat DNA in feces using quantitative PCR analysis. Heme caused a >50-fold increase in the cytotoxicity of the fecal water, a nearly 100% increase in proliferation, and almost total inhibition of exfoliation of the colonocytes. Furthermore, the addition of heme increased TBARS in fecal water. Chlorophyll, but not the chlorophyllins, completely prevented these heme-induced effects. In conclusion, inhibition of the heme-induced colonic cytotoxicity and epithelial cell turnover is specific for natural chlorophyll and cannot be mimicked by water-soluble chlorophyllins.
    Possible mechanisms behind the differential effects of soy protein and casein feedings on colon cancer biomarkers in the rat
    Vis, E.H. ; Geerse, G.J. ; Klaassens, E.S. ; Boekel, M.A.J.S. van; Alink, G.M. - \ 2005
    Nutrition and Cancer 51 (2005)1. - ISSN 0163-5581 - p. 37 - 44.
    dietary soybean protein - bile-acids - cell-proliferation - saponin content - carcinogenesis - methionine - calcium - 1,2-dimethylhydrazine - methylation - consumption
    In the present studies, several hypotheses were tested to explain previously reported differential effects of soy and casein on colon cancer biomarkers like cell proliferation, fecal fat, fecal bile acid, alkaline phosphatase, and magnesium excretion in rats. In Study 1, the effect of methionine, a limiting amino acid in soy protein and an amino acid that is thought to have a marked effect on colonic cell proliferation, was tested. It was concluded that methionine up to 1% in the diet had no effect on cell proliferation, using the 3H-thymidine assay. The same study revealed that fecal alkaline phosphatase excretion is a good marker for colonic epithelial damage and fecal magnesium excretion is not. In Study 2, the hypothesis was tested that soy fractions enriched with isoflavones and saponins may increase fat excretion and so influence colonic cell proliferation in rats. It was indeed shown that soy protein isolate and an ethanolic extract from soy protein isolate slightly increased fecal fat excretion (up to 1.7-fold). However, fecal water bile acid and free fatty acid concentrations were decreased after feeding soy protein-based diets compared with casein, and no difference in fecal alkaline phosphatase excretion was observed. In Study 3, the lytic potential of soy saponins and the interaction between saponins and some lytic bile acids were tested in vitro. Data suggest a protective effect from soy saponins by reducing lytic activity of cholic acid. The overall conclusion is that soy protein compared with casein influences several colon cancer risk parameters, indicating a more protective rather than a stimulating effect on colon cancer risk.
    Effect of diets fortified with tomatoes or onions with variable quercetin-glycoside content on azoxymethane-induced aberrant crypt foci in the colon of rats
    Femia, A.P. ; Caderni, G. ; Ianni, M. ; Salvadori, M. ; Schijlen, E.G.W.M. ; Collins, G. ; Bovy, A.G. ; Dolara, P. - \ 2003
    European Journal of Nutrition 42 (2003)6. - ISSN 1436-6207 - p. 346 - 352.
    chemopreventive agents - f344 rats - cancer - carcinogenesis - consumption - acid - chalcone - rectum - fruit - rutin
    Background: Onion and tomato are vegetables widely consumed by humans and epidemiological studies show an inverse association between vegetable consumption and colon cancer risk; however, the effect on colon cancer of diets containing high levels of vegetables like onion and tomato are not clear. Aims of the study: To investigate whether tomatoes and onions,with low or high quercetin-glycoside content, could reduce azoxymethane (AOM)-induced Aberrant Crypt Foci (ACF), preneoplastic lesions in the colon of rats. Methods: Male Fisher 344 rats were fed the following diets: a) high fat (HF) diet (control diet); b) HF diet containing 20 % (w/w) tomatoes with a low quercetin-glycoside content (final concentration in the diet: 5 mg/kg of quercetin aglycone equivalents); c) HF diet containing 20% (w/w) high quercetin-glycoside tomatoes (100 mg/kg final concentration of quercetin aglycone equivalents); d) HF diet containing 20 % (w/w) low quercetin-glycoside onions (14 mg/kg of quercetin aglycone equivalents in the diet); e) HF diet containing 20 % (w/w) high quercetin-glycoside onions (360 mg/kg quercetin aglycone equivalents in the diet). After 2 wks of feeding, all rats were treated twice, 1 wk apart, with AOM (12 mg/kg, s. c.). The dietary treatments continued until sacrifice, 7 wks after the first injection with AOM. Results: ACF induction did not vary in animals fed low or high quercetin-glycoside tomatoes relative to controls. On the contrary, rats fed 20% (w/w) onion-based diets, with low or high quercetin-glycoside content, showed an increase in number, multiplicity and large ACF compared to the control group (number of ACF/colon 145 ± 15 (SE), 255 ± 11 and 218 ± 16 in controls, low and high-quercetin-glycoside groups, respectively; p <0.01). Proliferative activity of the colon did not vary between animals fed control and high quercetin-glycoside tomato diet. The height of the crypts in normal mucosa of rats fed high quercetinglycoside onions was significantly increased compared to control rats (cells/emicrypt 38.4 ± 1.2 (SE) and 41.3 ± 0.6 in controls and high quercetin-glycoside onions group, p <0.05). Conclusions: None of the diets supplemented with onion or tomato with variable quercetin-glycoside content demonstrated a potential chemopreventive effect on ACF-induction by AOM in rats
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