Fine structure of interphase liver cell nuclei in subacute ethionine intoxication

Abstract

The nuclei of liver cells were examined in rats maintained on a 16% casein, 5% corn oil diet, supplemented by 0.5% or 0.75% of dl-ethionine, and in rats maintained on an adequate diet supplemented with 0.5% ethionine in their water supply. The changes were not demonstrable in isocalorically fed controls. The nuclei became progressively larger. The largest diameters were recorded in cells in hyperplastic nodules. At the time of development of the nodules, the diameter of the nuclei in the extranodular parenchyma returned to normal values. There was an inverse relationship between the number of nucleoli per nucleus and the size of nucleoli. These changes could be assessed reliably only by light microscopy. Electron micrographs showed a marked and increasing irregularity of the nuclear envelope with the formation of false nuclear inclusions of cytoplasmic components. True filamentous spherical and vacuolar inclusions, apparently not in contact with the cytoplasm, became common with progression of time. Aggregates of interchromatin granules formed prominent clusters. Chromatin seemed less in amount than normally, though this might have been due to a relative dispersion within enlarged nuclei. Nuclear pore complexes were often seen in en face projection around most of the circumference of some nuclei. This was thought to be due to a displacement of their long axes from their normal concordance with the radii of nuclei. The nucleoli, which were at first disorganized, became progressively more spherical. Their nucleolonema became polarized into a rope-like arrangement, and the pars amorpha stood out distinctly. In hyperplastic nodules, many nucleoli reverted to the disorganized appearance which characterizes normal nucleoli, and those in the early stages of ethionine intoxication. In the absence of an adequate literature on the subject of fine structural changes of nuclei of liver cells, it was difficult to determine the specificity of any of the alterations. It was suggested that they might reflect changes in the chemistry of DNA and of RNA, which are known to occur as a result of ethylation of various rat liver cell metabolites by ethionine. Attention was drawn to the reversal of the nucleolar changes to almost normal in the hyperplastic nodules from which ethionine-induced hepatocellular neoplasms are thought to arise. This might point to the development of “tolerance” to the action of ethionine by the cells of the hyperplastic nodules.