EFFECTS OF DOCOSAHEXAENOIC ACID (DHA) ON INTESTINAL POLYP DEVELOPMENT IN APC(DELTA-716) KNOCKOUT MICE

Epidemiological studies and animal experiments show an association of dietary intake of fish oils and low incidence of several types of cancers. The active ingredients of fish oils appear to be polyunsaturated fatty acids of omega-3 type such as eicosapentaenoic acid and docosahexaenoic acid (DHA), We have investigated chemopreventive effects of DHA on mouse intestinal polyposis using adenomatous polyposis coh (Apc) gene knockout mice. Damage to the human APC gene is responsible for not only familial adenomatous polyposis but also many sporadic cancers of the entire digestive tract, Using homologous recombination in embryonic stem cells, we recently constructed gene knockout mice containing a truncation mutation in the Ape gene at codon 716 (Apc(Delta 716)), The heterozygous mice developed numerous intestinal polyps, and all microadenomas dissected from the earliest polyps had already lost the wild-type allele, indicating the loss of heterozygosity [Oshima et al. (1995), Proc. Natl Acad. Sci. USA, 92, 4482- 4486], We fed Apc(Delta 716) heterozygotes with AIN-76A purified diet containing 3% DHA for 7 weeks, and scored the number and size of intestinal polyps, Average DHA intakes per day were 4.1 and 4.3 g/kg body wt for males and females, respectively, DHA-fed females had only 31% of polyps compared with the control females that developed about 220 polyps, whereas DHA-fed males showed no significant decrease in the polyp number, As for the polyp size, the proportion of larger polyps decreased more significantly in females than in males, This is the first demonstration that DHA inhibits intestinal polyposis induced by an Ape mutation at both its formation and growth.