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This research project was a multidisciplinary collaboration combining development of biomarkers of DNA damage, biomarker use in human studies and research workshops.
Study Duration : April 1998 to February 2003
Contractor : MRC Institute for Environment and Health, MRC Toxicology Unit, MRC Dunn Human Nutrition Unit, Open University.
The intake of certain chemicals in the diet may have a causative role in DNA damage, which might lead to specific forms of cancer. The initial FORA project refined and applied methods for measuring human exposure to genotoxic agents that occur as a result of dietary intakes of various food types. Particular focus in the study was placed upon two commonly occurring compounds derived from food metabolism and found naturally in the human gut, which previous studies have implicated as having a role in carcinogenesis.
The initial FORA project involved 3 MRC units and Institutes with each bringing a particular area of expertise: the Toxicology Unit at Leicester for the development of novel methods to measure human exposure to genotoxic agents; the Risk Assessment group at the Institute for Environment and Health for the evaluation of risks to low-level environmental exposure; the Dunn Human Nutrition Unit for the conduct of studies of volunteers on standardised diets with particular reference to cancer.
The specific aims of the project centred on 4 themes:
The FORA project was extended in order to use methods developed in the initial project to gather more detailed information about fat and meat intake in particular and their effects on DNA damage. The second phase was exclusively experimental and was a collaboration between the Open University and the MRC Dunn Human Nutrition Unit.
The Fellowship was a multicentre and multidisciplinary collaboration. Initially it was collaboration between two Medical Research Council (MRC) Units and the MRC Institute for Environment and Health. The final stage was a collaboration between the MRC Dunn Human Nutrition Unit and the Open University.
The study developed rapid methods for estimating two types of diet-related DNA damage. These were based on very sensitive immunoslotblot assays requiring very small quantities of DNA.
This study also highlighted the need for further investigation into the long-term stability of DNA adducts.
An immunoslotblot assay was used successfully in a human volunteer study. Volunteers were given a standardised diet containing a relatively high level of fat to examine the extent to which dietary factors contribute to the burden of specific DNA damage. Malondialdehyde-deoxyguanosine levels in blood remained constant while volunteers consumed the standardised diet, but individuals following a similar diet that contained various combinations of vegetables and tea showed a reduction in malondialdehyde-deoxyguanosine levels indicating a protective effect.
Malondialdehyde-deoxyguanosine levels were measured in DNA extracted from colorectal biopsies taken from free-living volunteers, for whom good data on health and dietary habits was available. Results showed that both men and women with adenomatous polyps (a proportion of which may turn into colorectal cancer) tended to have high levels of malondialdehyde-deoxyguanosine in the surrounding tissue, providing further evidence for the role of malondialdehyde-deoxyguanosine in predicting the possible risk of cancer in the human gastrointestinal tract. Conclusions of the volunteer studies were consistent with the hypothesis that endogenous lipid peroxidation leads to the production of DNA damaging agents, such as malondialdehyde-deoxyguanosine, which may increase the risk of cancer.
The project was extended to investigate the effects of changes in dietary fat on serum malondialdehyde-deoxyguanosine levels. No detectable differences were observed in the concentration of malondialdehyde-deoxyguanosine in blood between volunteers consuming polyunsaturated and saturated fats. It was also shown that high doses of vitamin E, thought to reduce levels of lipid peroxidation, did not have any effect on reducing levels of malondialdehyde-deoxyguanosine DNA damage. It was concluded that measurement of blood levels of malondialdehyde-DNA adducts are insensitive to variations in dietary fatty acids.
Outputs from the main phase of the project included four workshop reports that focussed on various areas of food risk assessment. These have been published and are available (as FOR A 1-4) from the Institute of Environment and Health's website (External) http://www.le.ac.uk/ieh/publications/food.html . Topics covered by the workshops have been influential in directing future areas of research by the FSA.
The project extension also examined the link between red meat consumption and levels of O6-carboxymethylguanine (O 6 -CMdG) in blood DNA. Results confirmed the association of red meat consumption to increase levels of endogenous nitrosation in the colon, reflected by a rise in O 6 -carboxymethylguanine concentration in blood DNA. Direct evidence of nitrosation taking place in the human gastrointestinal tract was provided by the immunohistochemical staining of O 6 -carboxymethylguanine in exfoliated colonocytes. The evidence to suggest that mutations in the p53 tumour suppressor gene may be induced by O 6 -carboxymethylguanine, gives rise to a possible link between colonic nitrosation from red meat and tumour formation in humans.
Final report is available from the FSA Library and Information centre.
To obtain a copy, please contact the Enquiry Desk,
Dr Elsie Widdowson Library and Information Services, Food Standards Agency, tel: 020 7276 8181/8182 or email:
library&info@foodstandards.gsi.gov.uk
A number of papers have been generated from this contract and the extension, some are still awaiting publication:
Cupid BC, Zeng Z, Singh R, Shuker DE.
Detection of O
6
-carboxymethyl-2'-deoxyguanosine in DNA following reaction of nitric oxide with glycine and in human blood DNA using a quantitative immunoslot blot assay.
Chemical Research in Toxicoogy. 2004 Mar;
17
(3):294-300.
Bandaletova T, Bailey N, Bingham SA, Loktionov A.
Isolation of exfoliated colonocytes from human stool as a new technique for colonic cytology.
Acta Pathologica, Microbiologica et Immunologica Scandinavica (AOMIS). 2002 Mar;
110
(3):239-46.
Leuratti C, Watson MA, Deag EJ, Welch A, Singh R, Gottschalg E, Marnett LJ, Atkin W, Day NE, Shuker DE, Bingham SA.
Detection of malondialdehyde DNA adducts in human colorectal mucosa: relationship with diet and the presence of adenomas.
Cancer Epidemiology Biomarkers and Prevention. 2002 Mar;
11
(3):267-73.
Shuker DE, Atkin W, Bingham SA, Leuratti C, Singh R.
Malondialdehyde-DNA adducts in relation to diet and disease risk - a brief overview of recent results.
International Agency for Research on Cancer (IARC) - Scientific Publication. 2002;
156
:475-80. Review. No abstract available.
Shuker DE.
The enemy at the gates? DNA adducts as biomarkers of exposure to exogenous and endogenous genotoxic agents.
Toxicology Letters. 2002 Aug 5;
134
(1-3):51-6. Review.
Singh R, Leuratti C, Josyula S, Sipowicz MA, Diwan BA, Kasprzak KS, Schut HA, Marnett LJ, Anderson LM, Shuker DE.
Lobe-specific increases in malondialdehyde DNA adduct formation in the livers of mice following infection with Helicobacter hepaticus.
Carcinogenesis. 2001 Aug;
22
(8):1281-7.
Sharma RA, Ireson CR, Verschoyle RD, Hill KA, Williams ML, Leuratti C, Manson MM, Marnett LJ, Steward WP, Gescher A.
Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels.
Clinical Cancer Research. 2001 May;
7
(5):1452-8.
Sharma RA, Gescher A, Plastaras JP, Leuratti C, Singh R, Gallacher-Horley B, Offord E, Marnett LJ, Steward WP, Plummer SM.
Cyclooxygenase-2, malondialdehyde and pyrimidopurinone adducts of deoxyguanosine in human colon cells.
Carcinogenesis. 2001 Sep;
22
(9):1557-60.
Everett SM, Singh R, Leuratti C, White KL, Neville P, Greenwood D, Marnett LJ, Schorah CJ, Forman D, Shuker D, Axon AT.
Levels of malondialdehyde-deoxyguanosine in the gastric mucosa: relationship with lipid peroxidation, ascorbic acid, and Helicobacter pylori.
Cancer Epidemiology Biomarkers and Prevention. 2001 Apr;
10
(4):369-76.
Contact
: For any enquiries concerning this research project, please contact the relevant Programme contact or email
science@foodstandards.gsi.gov.uk
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