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 colon tumor development. However, its effects on colonocytes in vivo remain poorly understood. Therefore, we investigated the ability of fish oil to modulate colonic methylation-induced DNA damage, repair, and deletion. Sprague Dawley 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 quantitative immunohistochemical analysis of O6-methylguanine adducts, respectively. Localization and expression of the alkyl group acceptor, O6-methylguanine-DNA-methyltransferase, was also determined. Lower levels of adducts were detected at 6, 9, and 12 h in fish oil- versus corn oil-fed animals (P < 0.05). In addition, fish oil supplementation had the greatest effect on apoptosis in the top one-third of the crypt, increasing the apoptotic index compared with corn oil-fed rats (P < 0.05). In the top one-third of the crypt, fish oil feeding caused an incremental stimulation of apoptosis as adduct level increased. In contrast, a negative correlation between apoptosis and adduct incidence occurred with corn oil feeding (P < 0.05). Diet had no main effect (all tertiles combined) on O6-methylguanine-DNA-methyltransferase expression over the time frame of the experiment. The enhancement of targeted apoptosis combined with the reduced formation of O6-methylguanine adducts may account, in part, for the observed protective effect of n-3 polyunsaturated fatty acids against experimentally induced colon cancer.
Hong
M Y
MY
Molecular and Cell Biology Section, Faculty of Nutrition, Texas A&M University, College Station 77843-2471, USA.
Lupton
J R
JR
Morris
J S
JS
Wang
N
N
Carroll
R J
RJ
Davidson
L A
LA
Elder
R H
RH
Chapkin
R S
RS
D000704:Analysis of Variance; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D018736:DNA Adducts / Q000096:biosynthesis / Q000737:chemistry / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D005395:Fish Oils / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D016013:Likelihood Functions; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D012359:tRNA Methyltransferases / Q000096:biosynthesis
D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D005395:Fish Oils; D006147:Guanine; C008449:O-(6)-methylguanine; D012359:tRNA Methyltransferases; C023196:tRNA (guanine(10)-N(2))-dimethyltransferase