Dietary fish oil reduces O6-methylguanine DNA adduct levels in rat colon in part by increasing apoptosis during tumor initiation

There is epidemiological, clinical, and experimental evidence that dietary fish oil, containing n-3 polyunsaturated fatty acids, protects against colo n tumor development. However, its effects on colonocytes in vivo remain poo rly understood. Therefore, we investigated the ability of fish oil to modul ate colonic methylation-induced DNA damage, repair, and deletion. Sprague D awley rats were provided with complete diets containing either corn oil or fish oil (15% by weight). Animals were injected with azoxymethane, and the distal colon was removed 3, 6, 9, or 12 h later. Targeted apoptosis and DNA damage were assessed by cell position within the crypt using the terminal deoxynucleotidyl transferase-mediated nick end labeling assay and quantitat ive immunohistochemical analysis of O-6-methylguanine adducts, respectively , Localization and expression of the alkyl group acceptor, O-6-methylguanin e-DNA-methyltransferase, was also determined. Lower levels of adducts were detected at 6, 9, and 12 h in fish oil- versus corn oh-fed animals (P < 0.0 5), In addition, fish oil supplementation had the greatest effect on apopto sis in the top one-third of the crypt, increasing the apoptotic index compa red with corn oil-fed rats (P < 0.05), In the top one-third of the crypt, f ish oil feeding caused an incremental stimulation of apoptosis as adduct le vel increased. In contrast, a negative correlation between apoptosis and ad duct incidence occurred with corn oil feeding (P < 0.05), Diet had no main effect (all tertiles combined) on O-6-methylguanine-DNA-methyltransferase e xpression over the time frame of the experiment The enhancement of targeted apoptosis combined with the reduced formation of O-6-methylguanine adducts may account, in part, for the observed protective effect of n-3 polyunsatu rated fatty acids against experimentally induced colon cancer.