title: Evaluation of fecal mutagenicity and colorectal cancer risk.
abstract: Colorectal cancer is one of the most common internal malignancies in Western society. The cause of this disease appears to be multifactorial and involves genetic as well as environmental aspects. The human colon is continuously exposed to a complex mixture of compounds, which is either of direct dietary origin or the result of digestive, microbial and excretory processes. In order to establish the mutagenic burden of the colorectal mucosa, analysis of specific compounds in feces is usually preferred. Alternatively, the mutagenic potency of fecal extracts has been determined, but the interpretation of these more integrative measurements is hampered by methodological shortcomings. In this review, we focus on exposure of the large bowel to five different classes of fecal mutagens that have previously been related to colorectal cancer risk. These include heterocyclic aromatic amines (HCA) and polycyclic aromatic hydrocarbons (PAH), two exogenous factors that are predominantly ingested as pyrolysis products present in food and (partially) excreted in the feces. Additionally, we discuss N-nitroso-compounds, fecapentaenes and bile acids, all fecal constituents (mainly) of endogenous origin. The mutagenic and carcinogenic potency of the above mentioned compounds as well as their presence in feces, proposed mode of action and potential role in the initiation and promotion of human colorectal cancer are discussed. The combined results from in vitro and in vivo research unequivocally demonstrate that these classes of compounds comprise potent mutagens that induce many different forms of genetic damage and that particularly bile acids and fecapentaenes may also affect the carcinogenic process by epigenetic mechanisms. Large inter-individual differences in levels of exposures have been reported, including those in a range where considerable genetic damage can be expected based on evidence from animal studies. Particularly, however, exposure profiles of PAH and N-nitroso compounds (NOC) have to be more accurately established to come to a risk evaluation. Moreover, lack of human studies and inconsistency between epidemiological data make it impossible to describe colorectal cancer risk as a result of specific exposures in quantitative terms, or even to indicate the relative importance of the mutagens discussed. Particularly, the polymorphisms of genes involved in the metabolism of heterocyclic amines are important determinants of carcinogenic risk. However, the present knowledge of gene-environment interactions with regard to colorectal cancer risk is rather limited. We expect that the introduction of DNA chip technology in colorectal cancer epidemiology will offer new opportunities to identify combinations of exposures and genetic polymorphisms that relate to increased cancer risk. This knowledge will enable us to improve epidemiological study design and statistical power in future research.
authors.affiliation: Department of Health Risk Analysis and Toxicology, University of Maastricht, PO Box 616, 6200 MD, Maastricht, Netherlands. t.dekok@grat.unimaas.nl
authors.forename: T M
authors.initials: TM
authors.lastname: de Kok
authors.forename: J M
authors.initials: JM
authors.lastname: van Maanen
mesh_terms: D000588:Amines / Q000009:adverse effects; D001647:Bile Acids and Salts / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000209:etiology*; D003296:Cooking; D005243:Feces / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000009:adverse effects; D006801:Humans; D016296:Mutagenesis; D009153:Mutagens / Q000009:adverse effects* / Q000032:analysis; D009603:Nitroso Compounds / Q000009:adverse effects; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects; D011090:Polyenes / Q000009:adverse effects; D012307:Risk Factors
chemical_list: D000588:Amines; D001647:Bile Acids and Salts; D006571:Heterocyclic Compounds; D009153:Mutagens; D009603:Nitroso Compounds; D011084:Polycyclic Aromatic Hydrocarbons; D011090:Polyenes; C037358:1-(1-glycero)tetradeca-1,3,5,7,9-pentaene; C037357:1-(1-glycero)dodeca-1,3,5,7,9-pentaene