title: Modulation of N-methyl-N-nitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical.
abstract: 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 (lambdaCgN) 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 lambdaCgN were determined in model validation studies and the agents were then tested alone and in combination. Continuous lambdaCgN treatment for 10 weeks induced significantly greater colonic mucosal injury than a drinking water control. In combined treatment regimens, lambdaCgN treatment did not significantly affect MNU-induced DNA adduct formation. However, combinations of lambdaCgN with MNU significantly increased MTCRII in excess of those induced by MNU alone. Recurrent or continuous lambdaCgN regimens had greater interactive effects with MNU upon MTCRII than short-term lambdaCgN treatment. This study has shown that exposure to a non-genotoxic diet-related compound (lambdaCgN) modulates the effective NOC dosimetry for induction of MT crypt restricted immunopositivity.
authors.affiliation: Department of Surgery, Cancer Centre, Queen's University Belfast, Belfast BT12 6BJ, Northern Ireland, UK.
authors.forename: Eilish T
authors.initials: ET
authors.lastname: Donnelly
authors.forename: Helen
authors.initials: H
authors.lastname: Bardwell
authors.forename: Geraldine Anne
authors.initials: GA
authors.lastname: Thomas
authors.forename: E Dillwyn
authors.initials: ED
authors.lastname: Williams
authors.forename: Margaret
authors.initials: M
authors.lastname: Hoper
authors.forename: Paul
authors.initials: P
authors.lastname: Crowe
authors.forename: Wilson G
authors.initials: WG
authors.lastname: McCluggage
authors.forename: Michael
authors.initials: M
authors.lastname: Stevenson
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Alan
authors.initials: A
authors.lastname: Hewer
authors.forename: Martin R
authors.initials: MR
authors.lastname: Osborne
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Campbell
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts; D004032:Diet; D004338:Drug Combinations; D005243:Feces / Q000737:chemistry; D005260:Female; D008668:Metallothionein / Q000276:immunology / Q000378:metabolism*; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D018736:DNA Adducts; D004338:Drug Combinations; D008770:Methylnitrosourea; D002351:Carrageenan; D004247:DNA; D008668:Metallothionein