Colonic cell proliferation and aberrant crypt foci formation are inhibitedby dairy glycosphingolipids in 1,2-dimethylhydrazine-treated CF1 mice

Dietary sphingomyelin (SM) inhibits early stages of colon cancer (appearanc e of aberrant crypt foci, ACF) and decreases the proportion of adenocarcino mas vs. adenomas in 1,2-dimethylhydrazine (DMH)-treated CF1 mice. To elucid ate the structural specificity of this inhibition, the effects of the other major sphingolipids in milk (glycosphingolipids) were determined. Glucosyl ceramide (GluCer), lactosylceramide (LacCer) and ganglioside G(D3) were fed individually to DMH-treated (six doses of 30 mg/kg body weight) female CFI mice at 0.025 or 0.1 g/100 g of the diet for 4 wk. All reduced the number of ACF by > 40% (P < 0.001), which is comparable to the reduction by SM in earlier studies. Immunohistochemical analysis of the colons revealed that s phingolipid feeding also reduced proliferation, with the most profound effe ct (up to 80%; P < 0.001) in the upper half of the crypts. Since the bioact ive backbones of the glycosphingolipids (i.e., ceramide and other metabolit es) are the likely mediators of these effects, the susceptibility of these complex sphingolipids to digestion in the colon was examined by incubating 500 mu g of each sphingolipid with colonic segments from mice and analysis of substrate disappearance and product formation by tandem mass spectrometr y, All of the sphingolipids (including SM) disappeared over time with a sub stantial portion appearing as ceramide. Partially hydrolyzed intermediates (such as GluCer from LacCer or G(D3)) were not detected, which suggests tha t the cleavage involves colonic (or microflora) endoglycosidases. In summar y, consumption of dairy SM and glycosphingolipids suppresses colonic cell p roliferation and ACF formation in DMH-treated mice; hence, many categories of sphingolipids affect these key events in colon carcinogenesis.