Profound postinitiation enhancement by short-term severe methionine, choline, vitamin B12, and folate deficiency of hepatocarcinogenesis in F344 rats given a single low-dose diethylnitrosamine injection
Hoover, K.L.; Lynch, P.H.; Poirier, L.A.
Journal of the National Cancer Institute 73(6): 1327-1336
1984
ISSN/ISBN: 0027-8874 PMID: 6595443 Document Number: 225782
The potential promoting and/or complete carcinogenic activity of a methyl group-deficient (MD) diet lacking methionine, choline, vitamin B12, and folate on liver tumor induction in weanling male F344/NCr rats was examined. Each of 50 rats/group received 1 injection of 20 mg diethylnitrosamine [(DENA) CAS:55-18-5; N-nitrosodiethylamine]/kg body wt at 4 wk of age, and then each was maintained on a methyl group-adequate (MA) diet for 52 wk (groups 2 and 5) or on an MD diet for 15 wk followed by the MA diet for 37 wk (group 4). Controls received injections of saline and were maintained on the same 2 respective diet regimens (groups 1 and 3, respectively). Histologic results from sacrifices at 6, 10, 15, 22, 39 and 52 wk revealed early development of foci of eosinophilic .gamma.-glutamyltransferase (GGT)-positive hepatocytes by 6 wk in DENA-MD diet-treated rats, with subsequent development of a diffuse hyperplasia of hepatocytes, oval cell proliferation, cholangiofibrosis, nodular cirrhosis and neoplastic nodule (NN) formation and, at 52 wk, hepatocellular carcinomas (HCC) in 13 of 15 rats. Similar but significantly fewer lesions were observed at slightly later sacrifice times in the livers of saline-MD diet-treated rats, with development of NN in 5 of 12 rats and an HCC in 1 of 12 rats at 52 wk. DENA-treated rats on MA diets developed relatively few GGT-positive foci, and none developed any neoplastic lesions. Except for basophilic foci, areas and foci of cellular alteration containing glycogen-rich hepatocytes frequently exhibited diminished uptake of injected Fe and decreased glucose-6-phosphatase and ATPase contents focally or throughout. Thus, a relatively brief exposure of both untreated and DENA-treated weanling rats to a severely MD diet produces classical preneoplastic and neoplastic lesions in their livers.