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Carcinogenesis Advance Access originally published online on January 16, 2004
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Carcinogenesis, Vol. 25, No. 5, 847-855, May 2004
Carcinogenesis vol.25 no.5 © Oxford University Press 2004; all rights reserved.

ARTICLE

Modulation of N-methyl-N-nitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical

Eilish T. Donnelly1, Helen Bardwell2, Geraldine Anne Thomas2,6, E. Dillwyn Williams2, Margaret Hoper1, Paul Crowe1, Wilson G. McCluggage3, Michael Stevenson4, David H. Phillips5, Alan Hewer5, Martin R. Osborne5 and Frederick C. Campbell1,7

1 Department of Surgery, Cancer Centre, Queen's University Belfast, Belfast BT12 6BJ, UK, 2 Strangeways Research Laboratories, Worts Causeway, Cambridge CB1 8RN, UK, 3 Department of Pathology and 4 Department of Epidemiology, Cancer Centre, Queen's University Belfast, Belfast BT12 6BJ, UK and 5 Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Cotswold Road, Sutton SM2 5NG, UK
6 Present address: South West Wales Cancer Institute, Singleton Hospital, Sketty, Swansea SA2 8QA, UK

7 To whom correspondence should be addressed. Tel: +44 028 90322276; Fax: +44 028 90321811; Email: f.c.campbell{at}qub.ac.uk

Red meat consumption is associated with endogenous metabolic generation of mutagenic N-nitroso compounds (NOC) and may be implicated in causation of colorectal cancer. Assessment of a biologically relevant dose of NOCs is hampered by imperfect understanding of NOC interactions with other dietary components. This study tests the hypothesis that NOC effects upon mutational biomarkers in mouse colon may be modulated by a non-genotoxic diet-related compound. N-methyl-N-nitrosourea (MNU) and undegraded {lambda} carrageenan ({lambda}CgN) were selected as test chemicals, representing a NOC and a non-genotoxic agent, respectively. Study end-points included (i) DNA adduct formation and (ii) metallothionein (MT) crypt restricted immunopositivity indices (MTCRII) which are considered representative of crypt stem cell mutations. Frequency and size of MT immunopositive foci as well as total number of MT immunopositive crypts were assessed. Biologically effective doses of MNU and {lambda}CgN were determined in model validation studies and the agents were then tested alone and in combination. Continuous {lambda}CgN treatment for 10 weeks induced significantly greater colonic mucosal injury than a drinking water control. In combined treatment regimens, {lambda}CgN treatment did not significantly affect MNU-induced DNA adduct formation. However, combinations of {lambda}CgN with MNU significantly increased MTCRII in excess of those induced by MNU alone. Recurrent or continuous {lambda}CgN regimens had greater interactive effects with MNU upon MTCRII than short-term {lambda}CgN treatment. This study has shown that exposure to a non-genotoxic diet-related compound ({lambda}CgN) modulates the effective NOC dosimetry for induction of MT crypt restricted immunopositivity.


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