Hepatotoxic and carcinogenic effects of dimethylnitrosamine in low dosage. light and electron microscopic study

Dimethylnitrosamine (DMN) in low dosage was administered continuously in drinking water to female rats. These animals and controls were killed at intervals through the 386th day of the experiment, and the liver parenchyma of each rat was studied by light and electron microscopy. Of the 9 liver tumors that developed, the 6 largest were hepatomas, which were similarly studied. The cytoplasmic changes induced in the liver parenchyma by the DMN treatment were comparable to those caused by other hepatotoxins and included disorganization of rough endoplasmic reticulum, proliferation of smooth endoplasmic reticulum, glycogen depletion, lipid accumulation, formation of autophagic vacuoles, and distortion of mitochondria. These alterations increased in frequency and intensity through the 289th day and then regressed. The only persistent cytoplasmic abnormalities at late stages of the experiment were moderately reduced glycogen stores and relatively hypertrophied smooth endoplasmic reticulum. The DMN treatment also induced hepatic nuclear and nucleolar changes, including focal condensations of the fibrillar component of the nucleolonema. First appearing after 170 days of treatment, the nucleolar alteration increased in frequency at subsequent intervals and continued throughout the experiment as a common, though not universal, feature of the parenchyma. The hepatoma cells displayed poor cytoplasmic differentiation, but their nuclei generally contained multiple, large nucleoli with focal condensations of the fibrillar component of the nucleolonema. It was concluded that the persistent nucleolar changes in the livers were more likely related to DMN hepatocarcinogenesis than the evanescent toxic alterations in the parenchymal cytoplasm.