H. Enzmann et al., EFFECTS OF LOW-DOSES OF N-NITROSOMORPHOLINE ON THE DEVELOPMENT OF EARLY STAGES OF HEPATOCARCINOGENESIS, Carcinogenesis, 16(7), 1995, pp. 1513-1518
Male Sprague-Dawley rats received the hepatocarcinogen N-nitrosomorpho
line (NNM) in the drinking water at low dose levels ranging from 6 mg/
l to 60 mg/l for 6 and 12 weeks, respectively. Foci of altered hepatoc
ytes (FAH) were demonstrated histochemically using changes in the acti
vities of glucose-6-phosphate dehydrogenase and glycogen phosphorylase
, and in the glycogen content as markers. Proliferating cells were det
ected by the immunohistochemical reaction for proliferating cell nucle
ar antigen (PCNA), The number and size of foci of altered hepatocytes
increased in a time and dose-related manner, The dose-effect curves we
re non-linear with a slight positive slope at the low doses and a mark
edly increased slope at higher doses, The number of PCNA positive hepa
tocytes showed a dose-dependent increase, In addition to the granular
distribution of PCNA in the nuclei, hepatocyte nuclei with homogeneous
ly distributed PCNA occurred in animals exposed to 60 mg/l NNM, It is
proposed that these cells are related to the occurrence of hepatocytes
with higher ploidy induced by NNM and may be regarded as cells in the
G2 phase of the cell cycle, The non-linear shape of the dose-response
-curve of the FAH suggests that some mechanisms contribute to carcinog
enesis over the whole dose range, whereas other mechanisms enhance car
cinogenesis only at higher doses. The relevance of the non-linear dose
-effect curve for the risk assessment of carcinogens is discussed.